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Sample records for agonist chlordimeform cdm

  1. BODY TEMPERATURE-DEPENDENT AND INDEPENDENT ACTIONS OF CHLORDIMEFORM ON VISUAL EVOKED POTENTIALS AND AXONAL TRANSPORT IN OPTIC SYSTEM OF RAT

    EPA Science Inventory

    Pattern reversal evoked potentials (PREPs), flash evoked potentials (FEPs), optic nerve axonal transport, and body temperature were measured in hooded rats treated with either saline or the formamidine insecticide/acaricide, chlordimeform (CDM). Rats receiving CDM had low body te...

  2. EFFECTS OF CHLORDIMEFORM ON CARDIOVASCULAR FUNCTIONAL PARAMETERS. PART 1. LETHALITY AND ARRHYTHMOGENICITY IN THE GERIATRIC RAT

    EPA Science Inventory

    Chlordimeform (CDM), a formamidine pesticide, had a profound effect on the cardiovascular function of geriatric rats. Two-year-old pentobarbital-anesthetized Sprague-Dawley rats (n=8) received sequential intravenous CDM injections of 5, 10, 30, and 60 mg/kg. A control group of ra...

  3. COMPARISON OF CHLORDIMEFORM AND CARBARYL USING A FUNCTIONAL OBSERVATIONAL BATTERY (JOURNAL VERSION)

    EPA Science Inventory

    The effects of the formamidine pesticide chlordimeform (CDM), and the carbamate carbaryl (CAR) were compared using a functional observational battery (FOB). The FOB, a series of observations and measurements that can be rapidly administered to toxicant-treated rats, includes home...

  4. CHLORDIMEFORM PRODUCES PROFOUND, SELECTIVE, AND TRANSIENT CHANGES IN VISUAL EVOKED POTENTIALS OF HOODED RATS

    EPA Science Inventory

    Rat visual function was tested after acute exposure to chlordimeform (CDM), a formamidine insecticide/acaricide. Adult male Long-Evans rats were surgically implanted with epidural recording electrodes overlying visual cortex and tested 1 week later. Pattern reversal-evoked potent...

  5. EFFECTS OF CHLORDIMEFORM ON CARDIOVASCULAR FUNCTIONAL PARAMETERS. PART 2. ACUTE AND DELAYED EFFECTS FOLLOWING INTRAVENOUS ADMINISTRATION IN THE POSTWEANLING RAT

    EPA Science Inventory

    The differential effects of intravenous (IV) intraperitoneal (IP) administration of chlordimeform (CDM) were investigated in 22-30 day old pentobarbital-anesthetized Sprague-Dawley rats. The first group of animals (N=25) were given sequential IV injections of 5, 10, 30, 60, and 1...

  6. Lethal and behavioral effects of chlordimeform in bobwhite.

    PubMed

    Fleming, W J; Heinz, G H; Schuler, C A

    1985-07-01

    The 7-day LC50 of chlordimeform to bobwhite (Colinus virginianus) chicks was 2835 ppm (95% CI = 2169-3705 ppm). Bobwhite chicks fed 1000 ppm (approximately LC4) chlordimeform for 7 days ate less, weighed less, travelled farther from a fright stimulus in an avoidance test, and had significantly more groups make greater than or equal to 10 light beam interruptions in an open-field test at 8 days of age than bobwhite fed 0, 1, 10, or 100 ppm chlordimeform (P less than or equal to 0.05). Groups fed 100 ppm (P less than or equal to 0.05) and 1000 ppm (P = 0.11) for 7 days crossed more often from the shallow to deep side of a visual cliff at 8 days of age than birds fed lesser concentrations of chlordimeform. Bobwhites were retested at 15 days of age, after being fed untreated diets for 7 days following the chlordimeform diets. The 1000 ppm group still travelled greater distances in the avoidance test (P less than or equal to 0.05). But open-field and visual cliff performances were similar to controls and other treatment groups. Chlordimeform concentrations causing behavioral aberrations in bobwhite were appreciably higher than environmental concentrations following field applications of chlordimeform. PMID:4024127

  7. Biochemical and physiological effects of chlordimeform.

    PubMed Central

    Matsumura, F; Beeman, R W

    1976-01-01

    Chlordimeform is a relatively new acaricide/insecticide, whose mode of action we have investigated. It appears to interfere with amine-mediated control of nervous and endocrine systems in a variety of ways. Specifically, chlordimeform causes a build-up of the amines 5-hydroxytryptamine and to a lesser extent norepinephrine in the rat brain in vivo, antagonizes the in vivo action of reserpine in the rat (reserpine depletes amine stores in the CNS), inhibits monoamine oxidase from rat liver in vitro, and causes hypotension in rabbits. In the American cockroach it directly stimulates the heart in situ, acts synergistically with tryptamine in vivo, inhibits amine-N-acetyltransferase from cockroach head in vitro, causes accumulation of indolamines in cockroaches in vivo, and blocks the stimulation of adenylate cyclase by octopamine in the cockroach CNS in situ. It also inhibits tryptamine metabolism in whole mites in vitro. Images FIGURE 3. FIGURE 4. A FIGURE 4. B FIGURE 4. C FIGURE 4. D PMID:976227

  8. CHLORDIMEFORM EFFECTS ON SCHEDULE-CONTROLLED BEHAVIOR IN RATS

    EPA Science Inventory

    Chlordimeform (CDMF) is a member of a relatively new class of insecticide/acaricide, the formamidines, which has rather unique effects. Unlike the widely used organophosphate and carbamate insecticides, CDMF does not appear to inhibit cholinesterases, and intoxication is not acco...

  9. The role of octopamine receptor agonists in the synergistic toxicity of certain insect growth regulators (IGRs) in controlling Dengue vector Aedes aegypti (Diptera: Culicidae) mosquito.

    PubMed

    Ahmed, Mohamed Ahmed Ibrahim; Vogel, Christoph Franz Adam

    2016-03-01

    The synergistic action of octopamine receptor agonists (OR agonists) on many insecticide classes (e.g., organophosphorus, pyrethroids, and neonicotinoids) on Aedes aegypti L. has been reported recently. An investigation of OR agonist's effect on insect growth regulators (IGRs) was undertaken to provide a better understanding of the mechanism of action. Based on the IGR bioassay, pyriproxyfen was the most potent IGR insecticide tested (EC50=0.0019ng/ml). However, the lethal toxicity results indicate that diafenthiuron was the most potent insecticide (LC50=56ng/cm(2)) on A. aegypti adults after 24h of exposure. The same trend was true after 48 and 72h of exposure. Further, the synergistic effects of OR agonists plus amitraz (AMZ) or chlordimeform (CDM) was significant on adults. Among the tested synergists, AMZ increased the potency of the selected IGRs on adults the greatest. As results, OR agonists were largely synergistic with the selected IGRs. OR agonists enhanced the lethal toxicity of IGRs, which is a valuable new tool in the field of A. aegypti control. However, further field experiments need to be done to understand the unique potential role of OR agonists and their synergistic action on IGRs. PMID:26672383

  10. CDM analysis

    NASA Technical Reports Server (NTRS)

    Larson, Robert E.; Mcentire, Paul L.; Oreilly, John G.

    1993-01-01

    The C Data Manager (CDM) is an advanced tool for creating an object-oriented database and for processing queries related to objects stored in that database. The CDM source code was purchased and will be modified over the course of the Arachnid project. In this report, the modified CDM is referred to as MCDM. Using MCDM, a detailed series of experiments was designed and conducted on a Sun Sparcstation. The primary results and analysis of the CDM experiment are provided in this report. The experiments involved creating the Long-form Faint Source Catalog (LFSC) database and then analyzing it with respect to following: (1) the relationships between the volume of data and the time required to create a database; (2) the storage requirements of the database files; and (3) the properties of query algorithms. The effort focused on defining, implementing, and analyzing seven experimental scenarios: (1) find all sources by right ascension--RA; (2) find all sources by declination--DEC; (3) find all sources in the right ascension interval--RA1, RA2; (4) find all sources in the declination interval--DEC1, DEC2; (5) find all sources in the rectangle defined by--RA1, RA2, DEC1, DEC2; (6) find all sources that meet certain compound conditions; and (7) analyze a variety of query algorithms. Throughout this document, the numerical results obtained from these scenarios are reported; conclusions are presented at the end of the document.

  11. Losing Chlordimeform Use in Cotton Production. Its Effects on the Economy and Pest Resistance. Agricultural Economic Report Number 587.

    ERIC Educational Resources Information Center

    Osteen, Craig; Suguiyama, Luis

    This report examines the economic implications of losing chlordimeform use on cotton and considers chlordimeform's role in managing the resistance of bollworms and tobacco budworms to synthetic pyrethroids. It estimates changes in prices, production, acreage, consumer expenditures, aggregate producer returns, regional crop effects, and returns to…

  12. Synergistic action of octopamine receptor agonists on the activity of selected novel insecticides for control of dengue vector Aedes aegypti (Diptera: Culicidae) mosquito.

    PubMed

    Ahmed, Mohamed Ahmed Ibrahim; Vogel, Christoph Franz Adam

    2015-05-01

    Studying insecticide resistance in mosquitoes has attracted the attention of many scientists to elucidate the pathways of resistance development and to design novel strategies in order to prevent or minimize the spread and evolution of resistance. Here, we tested the synergistic action of piperonyl butoxide (PBO) and two octopamine receptor (OR) agonists, amitraz (AMZ) and chlordimeform (CDM) on selected novel insecticides to increase their lethal action on the fourth instar larvae of Aedes aegypti L. However, chlorfenapyr was the most toxic insecticide (LC50 = 193, 102, and 48 ng/ml, after 24, 48, and 72 h exposure, respectively) tested. Further, PBO synergized all insecticides and the most toxic combinatorial insecticide was nitenpyram even after 48 and 72 h exposure. In addition, OR agonists significantly synergized most of the selected insecticides especially after 48 and 72 h exposure. The results imply that the synergistic effects of amitraz are a promising approach in increasing the potency of certain insecticides in controlling the dengue vector Ae. aegypti mosquito. PMID:25987220

  13. ALPHA(2)-ADRENERGIC MODE OF ACTION OF CHLORDIMEFORM ON RAT VISUAL FUNCTION

    EPA Science Inventory

    The hypothesis that chlordimeform increased the amplitude of components N;P1 and P1N3 in rat pattern-reversal visual evoked potentials through actions on alpha2 adrenergic receptors was tested. Yohimbine alone had no effect on pattern-reversal evoked potential amplitude. Clonidin...

  14. INFLUENCE OF THE FORMAMIDINE PESTICIDE CHLORDIMEFORM ON OVULATION IN THE FEMALE HAMSTER

    EPA Science Inventory

    The pesticide chlordimeform (CDF) has been found to interfere with the hormonal control of ovulation in the rat by a likely disruption in the adrenergic regulation of the midcycle surge of luteinizing hormone (LH). hile the brain mechanisms underlying generation of the surge in t...

  15. The efficacy of chlordimeform for the control of the northern fowl mite, Ornithonyssus sylvarium (Canestrini and Fanzago) (Acarina, Dermanyssidae).

    PubMed

    Christensen, C M; Knapp, F W; Tuttle, J W

    1977-01-01

    Chlordimeform applied as a 0.06% low pressure spray controlled the northern fowl mite (NFM) for at least 90 days. Tetrachlorvinphos applied as a 0.5% low pressure spray was equally effective. Chi square analysis of NFM population estimates indicated that NFM populations on the untreated control birds stayed essentially the same throughout the test, whereas, the NFM populations on both acaricide-treated groups were significantly lowered by the seventh day of the test (P less than .01). Chlordimeform seemed to work more slowly than tetrachlorvinphos in controlling NFM. PMID:605027

  16. INFLUENCE OF CHLORDIMEFORM ON ALPHA-ADRENERGIC RECEPTOR-ASSOCIATED MECHANISMS OF HORMONAL REGULATIONS: PITUITARY AND ADRENOCORTICAL SECRETION

    EPA Science Inventory

    The acaricide chlordimeform (CDF) has been reported to have effects on the central nervous system that appear to involve an interaction with adrenergic receptor mediated mechanisms of neurotransmission. The present study examined the influence of CDF on pituitary-adrenocortical h...

  17. Stem revenue losses with effective CDM management.

    PubMed

    Alwell, Michael

    2003-09-01

    Effective CDM management not only minimizes revenue losses due to denied claims, but also helps eliminate administrative costs associated with correcting coding errors. Accountability for CDM management should be assigned to a single individual, who ideally reports to the CFO or high-level finance director. If your organization is prone to making billing errors due to CDM deficiencies, you should consider purchasing CDM software to help you manage your CDM. PMID:14503149

  18. Dynamic CDM strategies in an EHR environment.

    PubMed

    Bieker, Michael; Bailey, Spencer

    2012-02-01

    A dynamic charge description master (CDM) integrates information from clinical ancillary systems into the charge-capture process, so an organization can reduce its reliance on the patient accounting system as the sole source of billing information. By leveraging the information from electronic ancillary systems, providers can eliminate the need for paper charge-capture forms and see increased accuracy and efficiency in the maintenance of billing information. Before embarking on a dynamic CDM strategy, organizations should first determine their goals for implementing an EHR system, include revenue cycle leaders on the EHR implementation team, and carefully weigh the pros and cons of CDM design decisions. PMID:22372294

  19. The galaxy velocity field and CDM models

    NASA Technical Reports Server (NTRS)

    Tormen, Giuseppe; Moscardini, Lauro; Lucchin, Francesco; Matarrese, Sabino

    1993-01-01

    It is generally accepted that some kind of non-baryonic dark matter accounts for most of the mass density of the universe. Considering such a component has become, in the last decade, a key ingredient in current theories of structure formation. In particular, the Cold Dark Matter (CDM) scenario has proven to be quite successful in explaining most of the observed properties of galaxies and of their large-scale distribution. The standard CDM model is characterized by a primordial Zel'dovich spectrum, of random-phase adiabatic perturbations in a universe with density parameter omega sub 0 = 1 and vanishing cosmological constant. This poster paper presents an analysis of observational data on peculiar motion of optical galaxies in comparison to the predictions of CDM models where the assumptions of the standard scenario: omega sub 0 = 1, n = 1, and bias parameter b = 1 are relaxed. In particular, CDM models with 0 less than n less than 1 and 0.4 less than omega sub 0 less than 1 are considered.

  20. Degeneracy between CCDM and Λ CDM cosmologies

    NASA Astrophysics Data System (ADS)

    Santos, Marcelo Vargas dos; Waga, Ioav; Ramos, Rudnei O.

    2014-12-01

    The creation of cold dark matter cosmology model is studied beyond the linear perturbation level. The skewness is explicitly computed, and the results are compared to those from the Λ CDM model. It is explicitly shown that both models have the same signature for the skewness and cannot be distinguished by using this observable.

  1. MASS FUNCTION PREDICTIONS BEYOND {Lambda}CDM

    SciTech Connect

    Bhattacharya, Suman; Lukic, Zarija; Habib, Salman; Heitmann, Katrin; White, Martin; Wagner, Christian

    2011-05-10

    The statistics of dark matter halos is an essential component of precision cosmology. The mass distribution of halos, as specified by the halo mass function, is a key input for several cosmological probes. The sizes of N-body simulations are now such that, for the most part, results need no longer be statistics-limited, but are still subject to various systematic uncertainties. Discrepancies in the results of simulation campaigns for the halo mass function remain in excess of statistical uncertainties and of roughly the same size as the error limits set by near-future observations; we investigate and discuss some of the reasons for these differences. Quantifying error sources and compensating for them as appropriate, we carry out a high-statistics study of dark matter halos from 67 N-body simulations to investigate the mass function and its evolution for a reference {Lambda}CDM cosmology and for a set of wCDM cosmologies. For the reference {Lambda}CDM cosmology (close to WMAP5), we quantify the breaking of universality in the form of the mass function as a function of redshift, finding an evolution of as much as 10% away from the universal form between redshifts z = 0 and z = 2. For cosmologies very close to this reference we provide a fitting formula to our results for the (evolving) {Lambda}CDM mass function over a mass range of 6 x 10{sup 11}-3 x 10{sup 15} M{sub sun} to an estimated accuracy of about 2%. The set of wCDM cosmologies is taken from the Coyote Universe simulation suite. The mass functions from this suite (which includes a {Lambda}CDM cosmology and others with w {approx_equal} -1) are described by the fitting formula for the reference {Lambda}CDM case at an accuracy level of 10%, but with clear systematic deviations. We argue that, as a consequence, fitting formulae based on a universal form for the mass function may have limited utility in high-precision cosmological applications.

  2. Mass Function Predictions Beyond ΛCDM

    NASA Astrophysics Data System (ADS)

    Bhattacharya, Suman; Heitmann, Katrin; White, Martin; Lukić, Zarija; Wagner, Christian; Habib, Salman

    2011-05-01

    The statistics of dark matter halos is an essential component of precision cosmology. The mass distribution of halos, as specified by the halo mass function, is a key input for several cosmological probes. The sizes of N-body simulations are now such that, for the most part, results need no longer be statistics-limited, but are still subject to various systematic uncertainties. Discrepancies in the results of simulation campaigns for the halo mass function remain in excess of statistical uncertainties and of roughly the same size as the error limits set by near-future observations; we investigate and discuss some of the reasons for these differences. Quantifying error sources and compensating for them as appropriate, we carry out a high-statistics study of dark matter halos from 67 N-body simulations to investigate the mass function and its evolution for a reference ΛCDM cosmology and for a set of wCDM cosmologies. For the reference ΛCDM cosmology (close to WMAP5), we quantify the breaking of universality in the form of the mass function as a function of redshift, finding an evolution of as much as 10% away from the universal form between redshifts z = 0 and z = 2. For cosmologies very close to this reference we provide a fitting formula to our results for the (evolving) ΛCDM mass function over a mass range of 6 × 1011-3 × 1015 M sun to an estimated accuracy of about 2%. The set of wCDM cosmologies is taken from the Coyote Universe simulation suite. The mass functions from this suite (which includes a ΛCDM cosmology and others with w ~= -1) are described by the fitting formula for the reference ΛCDM case at an accuracy level of 10%, but with clear systematic deviations. We argue that, as a consequence, fitting formulae based on a universal form for the mass function may have limited utility in high-precision cosmological applications.

  3. Weak lensing cosmology beyond ΛCDM

    SciTech Connect

    Das, Sudeep; Linder, Eric V.; Nakajima, Reiko; Putter, Roland de E-mail: rdeputter@icc.ub.edu E-mail: reiko@astro.uni-bonn.de

    2012-11-01

    Weak gravitational lensing is one of the key probes of the cosmological model, dark energy, and dark matter, providing insight into both the cosmic expansion history and large scale structure growth history. Taking into account a broad spectrum of physics affecting growth — dynamical dark energy, extended gravity, neutrino masses, and spatial curvature — we analyze the cosmological constraints. Similarly we consider the effects of a range of systematic uncertainties, in shear measurement, photometric redshifts, intrinsic alignments, and the nonlinear power spectrum, on cosmological parameter extraction. We also investigate, and provide fitting formulas for, the influence of survey parameters such as redshift depth, galaxy number densities, and sky area on the cosmological constraints in the beyond-ΛCDM parameter space. Finally, we examine the robustness of results for different fiducial cosmologies.

  4. Axion BEC: A model beyond CDM

    NASA Astrophysics Data System (ADS)

    Yang, Qiaoli

    I started work on the field of dark matter and cosmology with Dr. Sikivie three years ago with a goal to distinguish observationally axions or axion-like particles (ALPs) from other dark matter candidates such as weakly interacting massive particles (WIMPs) and sterile neutrinos. The subject is exciting because if one can determine the identity of the dark matter, it will be a mile-stone of physics beyond the standard model. On the high energy frontier, the standard model with three generation fermions is firmly established. However, it is not complete because the theory does not contain a plausible dark matter candidate, with properties required from observation, and the theory has fine-tuning problems such as the strong CP problem. On the cosmology and astrophysics frontiers, new observations of the dynamics of galaxy clusters, the rotation curves of galaxies, the abundances of light elements, gravitational lensing, and the anisotropies of the CMBR reach unprecedented accuracy. They imply cold dark matter (CDM) is 23% of the total energy density of the universe. Although many "beyond the standard model" theories may provide proper candidates to serve as CDM particles, the axion is especially compelling because it not only serves as the CDM particle, but also solves the strong CP problem. The axion was initially motivated by the strong CP problem, namely the puzzle why there is no CP violation in the strong interactions. Peccei and Quinn solved the problem by introducing a new UPQ(1) symmetry, and later Weinberg and Wilczek pointed out that the spontaneous breaking of UPQ(1) symmetry leads to a new pseudoscalar particle, the axion[1][2][3]. Axion models were proposed in which the symmetry breaking scale may be much larger than the electroweak scale, in which case the axion is very light and couples extremely weakly to ordinary matter. Furthermore, it was realized [4] that the cold axions, produced by the misalignment mechanism during the QCD phase transition, have

  5. CDM accelerating cosmology as an alternative to ΛCDM model

    SciTech Connect

    Lima, J.A.S.; Jesus, J.F.; Oliveira, F.A. E-mail: jfernando@astro.iag.usp.br

    2010-11-01

    A new accelerating cosmology driven only by baryons plus cold dark matter (CDM) is proposed in the framework of general relativity. In this scenario the present accelerating stage of the Universe is powered by the negative pressure describing the gravitationally-induced particle production of cold dark matter particles. This kind of scenario has only one free parameter and the differential equation governing the evolution of the scale factor is exactly the same of the ΛCDM model. For a spatially flat Universe, as predicted by inflation (Ω{sub dm}+Ω{sub baryon} = 1), it is found that the effectively observed matter density parameter is Ω{sub meff} = 1−α, where α is the constant parameter specifying the CDM particle creation rate. The supernovae test based on the Union data (2008) requires α ∼ 0.71 so that Ω{sub meff} ∼ 0.29 as independently derived from weak gravitational lensing, the large scale structure and other complementary observations.

  6. Courseware Development Model (CDM): The Effects of CDM on Primary School Pre-Service Teachers' Achievements and Attitudes

    ERIC Educational Resources Information Center

    Efendioglu, Akin

    2012-01-01

    The main purpose of this study is to design a "Courseware Development Model" (CDM) and investigate its effects on pre-service teachers' academic achievements in the field of geography and attitudes toward computer-based education (ATCBE). The CDM consisted of three components: content (C), learning theory, namely, meaningful learning (ML), and…

  7. Differentiating CDM and baryon isocurvature models with 21 cm fluctuations

    SciTech Connect

    Kawasaki, Masahiro; Sekiguchi, Toyokazu; Takahashi, Tomo E-mail: sekiguti@icrr.u-tokyo.ac.jp

    2011-10-01

    We discuss how one can discriminate models with cold dark matter (CDM) and baryon isocurvature fluctuations. Although current observations such as cosmic microwave background (CMB) can severely constrain the fraction of such isocurvature modes in the total density fluctuations, CMB cannot differentiate CDM and baryon ones by the shapes of their power spectra. However, the evolution of CDM and baryon density fluctuations are different for each model, thus it would be possible to discriminate those isocurvature modes by extracting information on the fluctuations of CDM/baryon itself. We discuss that observations of 21 cm fluctuations can in principle differentiate these modes and demonstrate to what extent we can distinguish them with future 21 cm surveys. We show that, when the isocurvature mode has a large blue-tilted initial spectrum, 21 cm surveys can clearly probe the difference.

  8. CDM/baryon isocurvature perturbations in a sneutrino curvaton model

    SciTech Connect

    Harigaya, Keisuke; Kawasaki, Masahiro; Hayakawa, Taku; Yokoyama, Shuichiro E-mail: taku1215@icrr.u-tokyo.ac.jp E-mail: shuichiro@rikkyo.ac.jp

    2014-10-01

    Matter isocurvature perturbations are strictly constrained from cosmic microwave background observations. We study a sneutrino curvaton model where both cold dark matter (CDM)/baryon isocurvature perturbations are generated. In our model, total matter isocurvature perturbations are reduced since the CDM/baryon isocurvature perturbations compensate for each other. We show that this model can not only avoid the stringent observational constraints but also suppress temperature anisotropies on large scales, which leads to improved agreement with observations.

  9. Is ΛCDM an effective CCDM cosmology?

    NASA Astrophysics Data System (ADS)

    Lima, J. A. S.; Santos, R. C.; Cunha, J. V.

    2016-03-01

    We show that a cosmology driven by gravitationally induced particle production of all non-relativistic species existing in the present Universe mimics exactly the observed flat accelerating ΛCDM cosmology with just one dynamical free parameter. This kind of scenario includes the creation cold dark matter (CCDM) model [1] as a particular case and also provides a natural reduction of the dark sector since the vacuum component is not needed to accelerate the Universe. The new cosmic scenario is equivalent to ΛCDM both at the background and perturbative levels and the associated creation process is also in agreement with the universality of the gravitational interaction and equivalence principle. Implicitly, it also suggests that the present day astronomical observations cannot be considered the ultimate proof of cosmic vacuum effects in the evolved Universe because ΛCDM may be only an effective cosmology.

  10. Can a void mimic the Λ in ΛCDM?

    NASA Astrophysics Data System (ADS)

    Sundell, Peter; Mörtsell, Edvard; Vilja, Iiro

    2015-08-01

    We investigate Lemaítre-Tolman-Bondi (LTB) models, whose early time evolution and bang time are homogeneous and the distance-redshift relation and local Hubble parameter are inherited from the ΛCDM model. We show that the obtained LTB models and the ΛCDM model predict different relative local expansion rates and that the Hubble functions of the models diverge increasingly with redshift. The LTB models show tension between low redshift baryon acoustic oscillation and supernova observations and including Lyman-α forest or cosmic microwave background observations only accentuates the better fit of the ΛCDM model compared to the LTB model. The result indicates that additional degrees of freedom are needed to explain the observations, for example by renouncing spherical symmetry, homogeneous bang time, negligible effects of pressure, or the early time homogeneity assumption.

  11. Suitable scheme study of Chinese Building Energy Efficiency CDM Projects

    NASA Astrophysics Data System (ADS)

    Huang, Beijia; Yang, Haizhen; Wang, Shaoping; Wang, Feng

    2010-11-01

    China has great potential to develop Building Energy Efficiency Clean Development Mechanism (BEE CDM) projects, although have many challenges. Our results show that large-scale public buildings and urban residential buildings have relatively high BEE CDM potential, when comparing their characteristics to the CDM project requirements. The building enclosure, illumination energy conservation, air condition energy saving, solar thermal, and solar photovoltaic technology have relatively high application potential while considering the energy saving potential and marginal emission reduction cost. Case study of large-scale buildings shows that technology integration of building enclosure, illumination energy conservation, air condition energy saving, solar thermal can reduce required building number to 130 in order to meet the 1×105 tCO2 e/a reduction criteria. Some suggestions are also given in this paper.

  12. Constraints on deviations from ΛCDM within Horndeski gravity

    NASA Astrophysics Data System (ADS)

    Bellini, Emilio; Cuesta, Antonio J.; Jimenez, Raul; Verde, Licia

    2016-02-01

    Recent anomalies found in cosmological datasets such as the low multipoles of the Cosmic Microwave Background or the low redshift amplitude and growth of clustering measured by e.g., abundance of galaxy clusters and redshift space distortions in galaxy surveys, have motivated explorations of models beyond standard ΛCDM. Of particular interest are models where general relativity (GR) is modified on large cosmological scales. Here we consider deviations from ΛCDM+GR within the context of Horndeski gravity, which is the most general theory of gravity with second derivatives in the equations of motion. We adopt a parametrization in which the four additional Horndeski functions of time αi(t) are proportional to the cosmological density of dark energy ΩDE(t). Constraints on this extended parameter space using a suite of state-of-the art cosmological observations are presented for the first time. Although the theory is able to accommodate the low multipoles of the Cosmic Microwave Background and the low amplitude of fluctuations from redshift space distortions, we find no significant tension with ΛCDM+GR when performing a global fit to recent cosmological data and thus there is no evidence against ΛCDM+GR from an analysis of the value of the Bayesian evidence ratio of the modified gravity models with respect to ΛCDM, despite introducing extra parameters. The posterior distribution of these extra parameters that we derive return strong constraints on any possible deviations from ΛCDM+GR in the context of Horndeski gravity. We illustrate how our results can be applied to a more general frameworks of modified gravity models.

  13. Supporting Open Access to European Academic Courses: The ASK-CDM-ECTS Tool

    ERIC Educational Resources Information Center

    Sampson, Demetrios G.; Zervas, Panagiotis

    2013-01-01

    Purpose: This paper aims to present and evaluate a web-based tool, namely ASK-CDM-ECTS, which facilitates authoring and publishing on the web descriptions of (open) academic courses in machine-readable format using an application profile of the Course Description Metadata (CDM) specification, namely CDM-ECTS. Design/methodology/approach: The paper…

  14. The Learning Process and Technological Change in Wind Power: Evidence from China's CDM Wind Projects

    ERIC Educational Resources Information Center

    Tang, Tian; Popp, David

    2016-01-01

    The Clean Development Mechanism (CDM) is a project-based carbon trade mechanism that subsidizes the users of climate-friendly technologies and encourages technology transfer. The CDM has provided financial support for a large share of Chinese wind projects since 2002. Using pooled cross-sectional data of 486 registered CDM wind projects in China…

  15. 78 FR 32250 - CDM Smith and Dynamac Corp; Transfer of Data

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-29

    ... AGENCY CDM Smith and Dynamac Corp; Transfer of Data AGENCY: Environmental Protection Agency (EPA). ACTION... Confidential Business Information (CBI) by the submitter, will be transferred to CDM Smith and its subcontractor, Dynamac Corp, in accordance with 40 CFR 2.307(h)(3) and 2.308(i)(2). CDM Smith and...

  16. Sustainable waste management in Africa through CDM projects.

    PubMed

    Couth, R; Trois, C

    2012-11-01

    Only few Clean Development Mechanism (CDM) projects (traditionally focussed on landfill gas combustion) have been registered in Africa if compared to similar developing countries. The waste hierarchy adopted by many African countries clearly shows that waste recycling and composting projects are generally the most sustainable. This paper undertakes a sustainability assessment for practical waste treatment and disposal scenarios for Africa and makes recommendations for consideration. The appraisal in this paper demonstrates that mechanical biological treatment of waste becomes more financially attractive if established through the CDM process. Waste will continue to be dumped in Africa with increasing greenhouse gas emissions produced, unless industrialised countries (Annex 1) fund carbon emission reduction schemes through a replacement to the Kyoto Protocol. Such a replacement should calculate all of the direct and indirect carbon emission savings and seek to promote public-private partnerships through a concerted support of the informal sector. PMID:22498573

  17. Beyond Λ CDM: Problems, solutions, and the road ahead

    NASA Astrophysics Data System (ADS)

    Bull, Philip; Akrami, Yashar; Adamek, Julian; Baker, Tessa; Bellini, Emilio; Beltrán Jiménez, Jose; Bentivegna, Eloisa; Camera, Stefano; Clesse, Sébastien; Davis, Jonathan H.; Di Dio, Enea; Enander, Jonas; Heavens, Alan; Heisenberg, Lavinia; Hu, Bin; Llinares, Claudio; Maartens, Roy; Mörtsell, Edvard; Nadathur, Seshadri; Noller, Johannes; Pasechnik, Roman; Pawlowski, Marcel S.; Pereira, Thiago S.; Quartin, Miguel; Ricciardone, Angelo; Riemer-Sørensen, Signe; Rinaldi, Massimiliano; Sakstein, Jeremy; Saltas, Ippocratis D.; Salzano, Vincenzo; Sawicki, Ignacy; Solomon, Adam R.; Spolyar, Douglas; Starkman, Glenn D.; Steer, Danièle; Tereno, Ismael; Verde, Licia; Villaescusa-Navarro, Francisco; von Strauss, Mikael; Winther, Hans A.

    2016-06-01

    Despite its continued observational successes, there is a persistent (and growing) interest in extending cosmology beyond the standard model, Λ CDM. This is motivated by a range of apparently serious theoretical issues, involving such questions as the cosmological constant problem, the particle nature of dark matter, the validity of general relativity on large scales, the existence of anomalies in the CMB and on small scales, and the predictivity and testability of the inflationary paradigm. In this paper, we summarize the current status of Λ CDM as a physical theory, and review investigations into possible alternatives along a number of different lines, with a particular focus on highlighting the most promising directions. While the fundamental problems are proving reluctant to yield, the study of alternative cosmologies has led to considerable progress, with much more to come if hopes about forthcoming high-precision observations and new theoretical ideas are fulfilled.

  18. Comparison of Cluster Lensing Profiles with Lambda CDM Predictions

    SciTech Connect

    Broadhurst, Tom; Umetsu, Keiichi; Medezinski, Elinor; Oguri, Masamune; Rephaeli, Yoel; /Tel Aviv U. /San Diego, CASS

    2008-05-21

    We derive lens distortion and magnification profiles of four well known clusters observed with Subaru. Each cluster is very well fitted by the general form predicted for Cold Dark Matter (CDM) dominated halos, with good consistency found between the independent distortion and magnification measurements. The inferred level of mass concentration is surprisingly high, 8 < c{sub vir} < 15 ( = 10.39 {+-} 0.91), compared to the relatively shallow profiles predicted by the {Lambda}CDM model, c{sub vir} = 5.06 {+-} 1.10 (for = 1.25 x 10{sup 15} M{sub {circle_dot}}/h). This represents a 4{sigma} discrepancy, and includes the relatively modest effects of projection bias and profile evolution derived from N-body simulations, which oppose each other with little residual effect. In the context of CDM based cosmologies, this discrepancy implies some modification of the widely assumed spectrum of initial density perturbations, so clusters collapse earlier (z {ge} 1) than predicted (z < 0.5) when the Universe was correspondingly denser.

  19. Dark subhalo accretion onto dwarf galaxies in CDM

    NASA Astrophysics Data System (ADS)

    Laporte, Chervin Fabien Pierre; Penarrubia, Jorge

    2015-08-01

    Baryonic feedback at high redshifts has been proposed to explain the inference of dark matter (DM) cores in low-surface brightness and dwarf spheroidal galaxies. However, in the currently favoured cosmological model, structure grows hierarchically and CDM predicts a myriad of small substructures orbiting dwarf galaxies, some luminous (which habe been observationally identified in recent years), some dark. If such dark subhalos get close enough to the centre of cored dwarfs, they could potentially lead to cusp regrowth.In this talk, I will present the evolution of the DM profiles of dwarf galaxies driven by the accretion of DM substructures through controlled N-body experiments. The initial conditions assume that supernova feedback erases the primordial DM cusps at high redshift of halos with final masses $10^{9}-10^{10} \\rm{M_{\\odot}}$ by z=0. The orbits and masses of the infalling substructures are borrowed from the {\\it Aquarius} cosmological simulations. I will show that some halos that undergo 1:3 down to 1:30 mergers are susceptible to reform a DM cusp by $z\\approx 0$ and how this depends on the internal structure of the infalling substructures. I will show that within CDM a non-negligible level of scatter in the mass profiles of dwarfs is to be expected given their stochastic mass accretion histories and their diverse (observed) star formation histories and that this effect could possibly explain the existence of dense dwarfs like Draco, Ursa Minor or Tucana. I will argue how this process is unique to CDM and may be falsifiable. If time allows, I will show preliminary results from suites of cosmological N-body simulations designed to address the statistics of this effect.

  20. GAS CLUMPING IN THE OUTSKIRTS OF {Lambda}CDM CLUSTERS

    SciTech Connect

    Nagai, Daisuke; Lau, Erwin T.

    2011-04-10

    Recent Suzaku X-ray observations revealed that the observed entropy profile of the intracluster medium (ICM) deviates significantly from the prediction of hydrodynamical simulations of galaxy clusters. In this work, we show that gas clumping introduces significant biases in X-ray measurements of the ICM profiles in the outskirts of galaxy clusters. Using hydrodynamical simulations of galaxy cluster formation in a concordance {Lambda}CDM model, we demonstrate that gas clumping leads to an overestimate of the observed gas density and causes flattening of the entropy profile. Our results suggest that gas clumping must be taken into account when interpreting X-ray measurements of cluster outskirts.

  1. Which spectral distortions does ΛCDM actually predict?

    NASA Astrophysics Data System (ADS)

    Chluba, Jens

    2016-04-01

    Ever refined cosmological measurements have established the ΛCDM concordance model, with the key cosmological parameters being determined to percent-level precision today. This allows us to make explicit predictions for the spectral distortions of the cosmic microwave background (CMB) created by various processes occurring in the early Universe. Here, we summarize all guaranteed CMB distortions and assess their total uncertainty within ΛCDM. We also compare simple methods for approximating them, highlighting some of the subtle aspects when it comes to interpreting future distortion measurements. Under simplified assumptions, we briefly study how well a PIXIE-like experiment may measure the main distortion parameters (i.e., μ and y). Next generation CMB spectrometers are expected to detect the distortion caused by reionization and structure formation at extremely high significance. They will also be able to constrain the small-scale power spectrum through the associated μ-distortion, improving limits on running of the spectral index. Distortions from the recombination era, adiabatic cooling of matter relative to the CMB and dark matter annihilation require a higher sensitivity than PIXIE in its current design. The crucial next step is an improved modeling of foregrounds and instrumental aspects, as we briefly discuss here.

  2. Which spectral distortions does ΛCDM actually predict?

    NASA Astrophysics Data System (ADS)

    Chluba, Jens

    2016-07-01

    Ever refined cosmological measurements have established the ΛCDM concordance model, with the key cosmological parameters being determined to per cent-level precision today. This allows us to make explicit predictions for the spectral distortions of the cosmic microwave background (CMB) created by various processes occurring in the early Universe. Here, we summarize all guaranteed CMB distortions and assess their total uncertainty within ΛCDM. We also compare simple methods for approximating them, highlighting some of the subtle aspects when it comes to interpreting future distortion measurements. Under simplified assumptions, we briefly study how well a PIXIE-like experiment may measure the main distortion parameters (i.e. μ and y). Next-generation CMB spectrometers are expected to detect the distortion caused by reionization and structure formation at extremely high significance. They will also be able to constrain the small-scale power spectrum through the associated μ-distortion, improving limits on running of the spectral index. Distortions from the recombination era, adiabatic cooling of matter relative to the CMB and dark matter annihilation require a higher sensitivity than PIXIE in its current design. The crucial next step is an improved modelling of foregrounds and instrumental aspects, as we briefly discuss here.

  3. Sustainable waste management in Africa through CDM projects

    SciTech Connect

    Couth, R.; Trois, C.

    2012-11-15

    Highlights: Black-Right-Pointing-Pointer This is a compendium on GHG reductions via improved waste strategies in Africa. Black-Right-Pointing-Pointer This note provides a strategic framework for Local Authorities in Africa. Black-Right-Pointing-Pointer Assists LAs to select Zero Waste scenarios and achieve sustained GHG reduction. - Abstract: Only few Clean Development Mechanism (CDM) projects (traditionally focussed on landfill gas combustion) have been registered in Africa if compared to similar developing countries. The waste hierarchy adopted by many African countries clearly shows that waste recycling and composting projects are generally the most sustainable. This paper undertakes a sustainability assessment for practical waste treatment and disposal scenarios for Africa and makes recommendations for consideration. The appraisal in this paper demonstrates that mechanical biological treatment of waste becomes more financially attractive if established through the CDM process. Waste will continue to be dumped in Africa with increasing greenhouse gas emissions produced, unless industrialised countries (Annex 1) fund carbon emission reduction schemes through a replacement to the Kyoto Protocol. Such a replacement should calculate all of the direct and indirect carbon emission savings and seek to promote public-private partnerships through a concerted support of the informal sector.

  4. BULLET CLUSTER: A CHALLENGE TO {Lambda}CDM COSMOLOGY

    SciTech Connect

    Lee, Jounghun; Komatsu, Eiichiro

    2010-07-20

    To quantify how rare the bullet-cluster-like high-velocity merging systems are in the standard {Lambda} cold dark matter (CDM) cosmology, we use a large-volume (27 h {sup -3} Gpc{sup 3}) cosmological N-body MICE simulation to calculate the distribution of infall velocities of subclusters around massive main clusters. The infall velocity distribution is given at (1-3)R{sub 200} of the main cluster (where R{sub 200} is similar to the virial radius), and thus it gives the distribution of realistic initial velocities of subclusters just before collision. These velocities can be compared with the initial velocities used by the non-cosmological hydrodynamical simulations of 1E0657-56 in the literature. The latest parameter search carried out by Mastropietro and Burkert has shown that an initial velocity of 3000 km s{sup -1} at about 2R{sub 200} is required to explain the observed shock velocity, X-ray brightness ratio of the main and subcluster, X-ray morphology of the main cluster, and displacement of the X-ray peaks from the mass peaks. We show that such a high infall velocity at 2R{sub 200} is incompatible with the prediction of a {Lambda}CDM model: the probability of finding 3000 km s{sup -1} in (2-3)R{sub 200} is between 3.3 x 10{sup -11} and 3.6 x 10{sup -9}. A lower velocity, 2000 km s{sup -1} at 2R{sub 200}, is also rare, and moreover, Mastropietro and Burkert have shown that such a low initial velocity does not reproduce the X-ray brightness ratio of the main and subcluster or morphology of the main cluster. Therefore, we conclude that the existence of 1E0657-56 is incompatible with the prediction of a {Lambda}CDM model, unless a lower infall velocity solution for 1E0657-56 with {approx}<1800 km s{sup -1} at 2R{sub 200} is found.

  5. Magnetized completion of the {lambda}CDM paradigm

    SciTech Connect

    Giovannini, Massimo; Kunze, Kerstin E.

    2008-03-15

    The standard {lambda}CDM paradigm is complemented with a magnetized contribution whose effects on the anisotropies of the cosmic microwave background are assessed by means of a dedicated numerical approach. The accuracy on the temperature and polarization correlations stems from the inclusion of the large-scale magnetic fields both at the level of the initial conditions and at the level of the Einstein-Boltzmann hierarchy which is consistently embedded in a generalized magnetohydrodynamical framework. Examples of the calculations of the temperature and polarization angular power spectra are illustrated and discussed. The reported results and the described numerical tools set the groundwork for a consistent inclusion of a magnetized contribution in current strategies of cosmological parameter estimation.

  6. Relativistic perturbations in ΛCDM: Eulerian & Lagrangian approaches

    NASA Astrophysics Data System (ADS)

    Villa, Eleonora; Rampf, Cornelius

    2016-01-01

    We study the relativistic dynamics of a pressure-less and irrotational fluid of dark matter (CDM) with a cosmological constant (Λ), up to second order in cosmological perturbation theory. In our analysis we also account for vector and tensor perturbations and include primordial non-Gaussianity. We consider three gauges: the synchronous-comoving gauge, the Poisson gauge and the total matter gauge, where the first is the unique relativistic Lagrangian frame of reference, and the latters are convenient gauge choices for Eulerian frames. Our starting point is the metric and fluid variables in the Poisson gauge up to second order. We then perform the gauge transformations to the synchronous-comoving gauge and subsequently to the total matter gauge. Our expressions for the metrics, densities, velocities, and the gauge generators are novel and coincide with known results in the limit of a vanishing cosmological constant.

  7. Dynamical history of the Local Group in ΛCDM

    NASA Astrophysics Data System (ADS)

    Banik, Indranil; Zhao, Hongsheng

    2016-06-01

    The positions and velocities of galaxies in the Local Group (LG) measure the gravitational field within it. This is mostly due to the Milky Way (MW) and Andromeda (M31). We constrain their masses using distance and radial velocity (RV) measurements of 32 LG galaxies. To do this, we follow the trajectories of many simulated particles starting on a pure Hubble flow at redshift 9. For each observed galaxy, we obtain a trajectory which today is at the same position. Its final velocity is the model prediction for the velocity of that galaxy. Unlike previous simulations based on spherical symmetry, ours are axisymmetric and include gravity from Centaurus A. We find the total LG mass is {4.33^{+0.37}_{-0.32}× {10}^{12} M_{⊙}}, with 0.14 ± 0.07 of this being in the MW. We approximately account for IC 342, M81, the Great Attractor and the Large Magellanic Cloud. No plausible set of initial conditions yields a good match to the RVs of our sample of LG galaxies. Observed RVs systematically exceed those predicted by the best-fitting Lambda Cold Dark Matter (ΛCDM) model, with a typical disagreement of {45.1^{+7.0}_{-5.7}} km s-1 and a maximum of 110 ± 13 km s-1 for DDO 99. Interactions between LG dwarf galaxies cannot easily explain this. One possibility is a past close flyby of the MW and M31. This arises in some modified gravity theories but not in ΛCDM. Gravitational slingshot encounters of material in the LG with either of these massive fast-moving galaxies could plausibly explain why some non-satellite LG galaxies are moving away from us even faster than a pure Hubble flow.

  8. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

  9. The correlated factors of the uneven performances of the CDM host countries

    NASA Astrophysics Data System (ADS)

    Zhu, Jinshan

    2012-03-01

    The Kyoto Protocol’s Clean Development Mechanism (CDM) has experienced a rapid growth. Up to 2010, 2763 projects have been registered, standing for about 433 million ton CO2 equivalent (CO2-eq.) of annual carbon credits. However, the performances of CDM host countries are remarkably unbalanced. Previous literature suggested that economic and investment conditions, energy intensity, energy structure, the share of annual carbon credits from high global warming potential (GWP) green house gas (GHG), capacity and institutional buildings of domestic CDM governance can play important roles in promoting CDM. This quantitative analysis shows that domestic economic and investment conditions are the most decisive factors determining the performance of the CDM host countries. Additionally, the influence of carbon intensity of energy consumption is relatively modest, and energy intensity of GDP as well as the share of annual carbon credits from high GWP GHG is less significant. Moreover, several leading CDM countries are not as successful as they seem to be, when the influences of their vast territories, distinguished economic and investment conditions are excluded. Therefore, to simply transplant the CDM governances of these countries can hardly guarantee that other countries will boost their carbon credit outputs.

  10. Preliminary assessment of potential CDM early start projects in Brazil

    SciTech Connect

    Meyers, S.; Sathaye, J.; Lehman, B.; Schumacher, K.; van Vliet, O.; Moreira, J.R.

    2000-11-01

    The Brazil/US Aspen Global Forum on Climate Change Policies and Programs has facilitated a dialogue between key Brazil and US public and private sector leaders on the subject of the Clean Development Mechanism (CDM). With support from the US government, a cooperative effort between Lawrence Berkeley National Laboratory and the University of Sao Paulo conducted an assessment of a number of projects put forth by Brazilian sponsors. Initially, we gathered information and conducted a screening assessment for ten projects in the energy sector and six projects in the forestry sector. Some of the projects appeared to offer greater potential to be attractive for CDM, or had better information available. We then conducted a more detailed assessment of 12 of these projects, and two other projects that were submitted after the initial screening. An important goal was to assess the potential impact of Certified Emission Reductions (CERs) on the financial performance of projects. With the exception of the two forestry-based fuel displacement projects, the impact of CERs on the internal rate of return (IRR) is fairly small. This is true for both the projects that displace grid electricity and those that displace local (diesel-based) electricity production. The relative effect of CERs is greater for projects whose IRR without CERs is low. CERs have a substantial effect on the IRR of the two short-rotation forestry energy substitution projects. One reason is that the biofuel displaces coke and oil, both of which are carbon-intensive. Another factor is that the product of these projects (charcoal and woodfuel, respectively) is relatively low value, so the revenue from carbon credits has a strong relative impact. CERs also have a substantial effect on the NPV of the carbon sequestration projects. Financial and other barriers pose a challenge for implementation of most of the projects. In most cases, the sponsor lacks sufficient capital, and loans are available only at high interest

  11. GRAVITATIONAL LENSING CORRECTIONS IN FLAT {Lambda}CDM COSMOLOGY

    SciTech Connect

    Kantowski, Ronald; Chen Bin; Dai Xinyu E-mail: Bin.Chen-1@ou.ed

    2010-08-01

    We compute the deflection angle to order (m/r {sub 0}){sup 2} and m/r{sub 0} x {Lambda}r {sup 2}{sub 0} for a light ray traveling in a flat {Lambda}CDM cosmology that encounters a completely condensed mass region. We use a Swiss cheese model for the inhomogeneities and find that the most significant correction to the Einstein angle occurs not because of the nonlinear terms but instead occurs because the condensed mass is embedded in a background cosmology. The Swiss cheese model predicts a decrease in the deflection angle of {approx}2% for weakly lensed galaxies behind the rich cluster A1689 and that the reduction can be as large as {approx}5% for similar rich clusters at z {approx} 1. Weak-lensing deflection angles caused by galaxies can likewise be reduced by as much as {approx}4%. We show that the lowest order correction in which {Lambda} appears is proportional to m/r{sub 0} x {radical}({Lambda}r{sub 0}{sup 2}) and could cause as much as a {approx}0.02% increase in the deflection angle for light that passes through a rich cluster. The lowest order nonlinear correction in the mass is proportional to m/r{sub 0}x{radical}(m/r{sub 0}) and can increase the deflection angle by {approx}0.005% for weak lensing by galaxies.

  12. The HII Galaxy Hubble Diagram Strongly Favors Rh = ct over ΛCDM

    NASA Astrophysics Data System (ADS)

    Wei, Jun-Jie; Wu, Xue-Feng; Melia, Fulvio

    2016-08-01

    We continue to build support for the proposal to use HII galaxies (HIIGx) and giant extragalactic HII regions (GEHR) as standard candles to construct the Hubble diagram at redshifts beyond the current reach of Type Ia supernovae. Using a sample of 25 high-redshift HIIGx, 107 local HIIGx, and 24 GEHR, we confirm that the correlation between the emission-line luminosity and ionized-gas velocity dispersion is a viable luminosity indicator, and use it to test and compare the standard model ΛCDM and the Rh = ct Universe by optimizing the parameters in each cosmology using a maximization of the likelihood function. For the flat ΛCDM model, the best fit is obtained with Ω _m= 0.40_{-0.09}^{+0.09}. However, statistical tools, such as the Akaike (AIC), Kullback (KIC) and Bayes (BIC) Information Criteria favor Rh = ct over the standard model with a likelihood of ≈94.8% - 98.8% versus only ≈1.2% - 5.2%. For wCDM (the version of ΛCDM with a dark-energy equation of state wde ≡ pde/ρde rather than wde = wΛ = -1), a statistically acceptable fit is realized with Ω _m=0.22_{-0.14}^{+0.16} and w_de= -0.51_{-0.25}^{+0.15} which, however, are not fully consistent with their concordance values. In this case, wCDM has two more free parameters than Rh = ct, and is penalized more heavily by these criteria. We find that Rh = ct is strongly favored over wCDM with a likelihood of ≈92.9% - 99.6% versus only 0.4% - 7.1%. The current HIIGx sample is already large enough for the BIC to rule out ΛCDM/wCDM in favor of Rh = ct at a confidence level approaching 3σ.

  13. Policy, institutional and market barriers to the implementation of clean development mechanisms (CDM) in China

    SciTech Connect

    Zeng, L.; Yan, J.Y.

    2005-07-15

    This paper reviews current Chinese policies and administrative and institutional settings for CDM cooperation, and discusses existing policy, institutional and other barriers in the energy market by drawing on observations and experience from previous initiatives such as Cleaner Production and energy efficiency. Some options to remove these barriers are addressed. In order to make CDM projects feasible, China's government needs to promote awareness, streamline administrative systems, and be more active in budding a competitive edge in the world carbon market.

  14. The First Generation of Stars in Lambda-CDM Cosmology

    SciTech Connect

    Gao, Liang; Abel, T.; Frenk, C.S.; Jenkins, A.; Springel, V.; Yoshida, N.; /Nagoya U.

    2006-10-10

    We have performed a large set of high-resolution cosmological simulations using smoothed particle hydrodynamics (SPH) to study the formation of the first luminous objects in the {Lambda}CDM cosmology. We follow the collapse of primordial gas clouds in eight early structures and document the scatter in the properties of the first star-forming clouds. Our first objects span formation redshifts from z {approx} 10 to z {approx} 50 and cover an order of magnitude in halo mass. We find that the physical properties of the central star-forming clouds are very similar in all of the simulated objects despite significant differences in formation redshift and environment. This suggests that the formation path of the first stars is largely independent of the collapse redshift; the physical properties of the clouds have little correlation with spin, mass, or assembly history of the host halo. The collapse of proto-stellar objects at higher redshifts progresses much more rapidly due to the higher densities, which accelerates the formation of molecular hydrogen, enhances initial cooling and shortens the dynamical timescales. The mass of the star-forming clouds cover a broad range, from a few hundred to a few thousand solar masses, and exhibit various morphologies: some have disk-like structures which are nearly rotational supported; others form flattened spheroids; still others form bars. All of them develop a single protostellar ''seed'' which does not fragment into multiple objects up to the moment that the central gas becomes optically thick to H{sub 2} cooling lines. At this time, the instantaneous mass accretion rate onto the centre varies significantly from object to object, with disk-like structures having the smallest mass accretion rates. The formation epoch and properties of the star-forming clouds are sensitive to the values of cosmological parameters.

  15. THE ABUNDANCE OF BULLET GROUPS IN ΛCDM

    SciTech Connect

    Fernández-Trincado, J. G.; Forero-Romero, J. E.; Foex, G.; Motta, V.; Verdugo, T. E-mail: je.forero@uniandes.edu.co

    2014-06-01

    We estimate the expected distribution of displacements between the two dominant dark matter (DM) peaks (DM-DM displacements) and between the DM and gaseous baryon peak (DM-gas displacements) in DM halos with masses larger than 10{sup 13} h {sup –1} M {sub ☉}. As a benchmark, we use the observation of SL2S J08544–0121, which is the lowest mass system (1.0 × 10{sup 14} h {sup –1} M {sub ☉}) observed so far, featuring a bi-modal DM distribution with a dislocated gas component. We find that (50 ± 10)% of the DM halos with circular velocities in the range 300-700 km s{sup –1} (groups) show DM-DM displacements equal to or larger than 186 ± 30 h {sup –1} kpc as observed in SL2S J08544–0121. For DM halos with circular velocities larger than 700 km s{sup –1} (clusters) this fraction rises to (70 ± 10)%. Using the same simulation, we estimate the DM-gas displacements and find that 0.1%-1.0% of the groups should present separations equal to or larger than 87 ± 14 h {sup –1} kpc, corresponding to our observational benchmark; for clusters, this fraction rises to (7 ± 3)%, consistent with previous studies of DM to baryon separations. Considering both constraints on the DM-DM and DM-gas displacements, we find that the number density of groups similar to SL2S J08544–0121 is ∼6.0 × 10{sup –7} Mpc{sup –3}, three times larger than the estimated value for clusters. These results open up the possibility for a new statistical test of ΛCDM by looking for DM-gas displacements in low mass clusters and groups.

  16. Effects of AGN feedback on ΛCDM galaxies

    NASA Astrophysics Data System (ADS)

    Lagos, Claudia Del P.; Cora, Sofía A.; Padilla, Nelson D.

    2008-08-01

    We study the effects of active galactic nuclei (AGN) feedback on the formation and evolution of galaxies by using a combination of a cosmological N-body simulation of the concordance Lambda cold dark matter (ΛCDM) paradigm and a semi-analytic model of galaxy formation. This model is an improved version of the one described by Cora (2006), which now considers the growth of black holes (BHs) as driven by (i) gas accretion during merger-driven starbursts and mergers with other BHs, (ii) accretion during starbursts triggered by disc instabilities and (iii) accretion of gas cooled from quasi-hydrostatic hot gas haloes. It is assumed that feedback from AGN operates in the last case. The model has been calibrated in order to reproduce observational correlations between BH mass and mass, velocity dispersion and absolute magnitudes of the galaxy bulge. AGN feedback has a strong impact on reducing or even suppressing gas cooling, an effect that becomes important at lower redshifts. This phenomenon helps to reproduce the observed galaxy luminosity function (LF) in the optical and near-infrared bands at z = 0, and the cosmic star formation rate and stellar mass functions over a wide redshift range (0 <~ z <~ 5). It also allows us to have a population of massive galaxies already in place at z >~ 1, which are mostly early-type and have older and redder stellar populations than lower mass galaxies, reproducing the observed bimodality in the galaxy colour distribution, and the morphological fractions. The evolution of the optical QSO LF is also reproduced, provided that the presence of a significant fraction of obscured QSOs is assumed. We explore the effects of AGN feedback during starbursts finding that, in order to obtain a good agreement with observations, these need to be strong enough to expel the reheated gas away from the galaxy halo. We also test new, recent prescriptions for dynamical friction time-scales, and find that they produce an earlier formation of elliptical

  17. INVESTIGATIONS OF AMITRAZ NEUROTOXICITY IN RATS. 1. EFFECTS ON OPERANT PERFORMANCE (JOURNAL VERSION)

    EPA Science Inventory

    Amitraz (AMZ), a formamidine pesticide, displayed a unique spectrum of neurobehavioral effects which differed from that of the prototypic formamidine, chlordimeform (CDM). In male Long-Evans rats, general signs of intoxication included hypothermia, hyperreactivity, vasodilation, ...

  18. σCDM coupled to radiation: Dark energy and Universe acceleration

    NASA Astrophysics Data System (ADS)

    Abbyazov, Renat R.; Chervon, Sergey V.; Müller, Volker

    2015-07-01

    Recently, the Chiral Cosmological Model (CCM) coupled to cold dark matter (CDM) has been investigated as σCDM model to study the observed accelerated expansion of the Universe. Dark sector fields (as Dark Energy content) coupled to cosmic dust were considered as the source of Einstein gravity in Friedmann-Robertson-Walker (FRW) cosmology. Such model had a beginning at the matter-dominated era. The purposes of our present investigation are two-fold: To extend “life” of the σCDM for earlier times to radiation-dominated era and to take into account variation of the exponential potential V = V0exp -λ φ MP + V0exp -λ χ MP via variation of the interaction parameter λ. We use Markov Chain Monte Carlo (MCMC) procedure to investigate possible values of initial conditions constrained by the measured amount of the dark matter, dark energy and radiation component today. Our analysis includes dark energy contribution to critical density, the ratio of the kinetic and potential energies, deceleration parameter, effective equation of state (EoS) and evolution of DE EoS with variation of coupling constant λ. A comparison with the ΛCDM model was performed. A new feature of the model is the existence of some values of potential coupling constant, leading to a σCDM solution without transition into accelerated expansion epoch.

  19. Where the world stands still: turnaround as a strong test of ΛCDM cosmology

    SciTech Connect

    Pavlidou, V.; Tomaras, T.N. E-mail: tomaras@physics.uoc.gr

    2014-09-01

    Our intuitive understanding of cosmic structure formation works best in scales small enough so that isolated, bound, relaxed gravitating systems are no longer adjusting their radius; and large enough so that space and matter follow the average expansion of the Universe. Yet one of the most robust predictions of ΛCDM cosmology concerns the scale that separates these limits: the turnaround radius, which is the non-expanding shell furthest away from the center of a bound structure. We show that the maximum possible value of the turnaround radius within the framework of the ΛCDM model is, for a given mass M, equal to (3GM/Λ c{sup 2}){sup 1/3}, with G Newton's constant and c the speed of light, independently of cosmic epoch, exact nature of dark matter, or baryonic effects. We discuss the possible use of this prediction as an observational test for ΛCDM cosmology. Current data appear to favor ΛCDM over alternatives with local inhomogeneities and no Λ. However there exist several local-universe structures that have, within errors, reached their limiting size. With improved determinations of their turnaround radii and the enclosed mass, these objects may challenge the limit and ΛCDM cosmology.

  20. Evaluating the CDM-Robustness of the input buffer with very fast transmission line pulse

    NASA Astrophysics Data System (ADS)

    Kao, Tzu-Cheng; Lee, Jian-Hsing; Hung, Chung-Yu; Lien, Chen-Hsin; Su, Hung-Der

    2015-02-01

    In this paper, a scheme for how to utilize VFTLP (very fast transmission line pulse) data to design an input buffer circuit for CDM (charged-device model) ESD protection is reported. The impedance of the ESD device under VFTLP stress is nearly 120 Ω at the beginning of turn-on transient, and decreases with time toward 10 Ω prior to the voltage falling below 0 V. In this work, the fact that the dynamic-characteristic impedance of the ESD device under VFTLP testing is independent of the stress current is found. Since both VFTLP zapping and the CDM are nanosecond events, the dynamic-characteristic impedance of the ESD device can be used to evaluate the CDM threshold voltage of the input buffer based on the equivalent and simplified RLC circuit.

  1. The integrated Sachs-Wolfe imprint of cosmic superstructures: a problem for ΛCDM

    SciTech Connect

    Nadathur, Seshadri; Sarkar, Subir; Hotchkiss, Shaun E-mail: shaun.hotchkiss@helsinki.fi

    2012-06-01

    A crucial diagnostic of the ΛCDM cosmological model is the integrated Sachs-Wolfe (ISW) effect of large-scale structure on the cosmic microwave background (CMB). The ISW imprint of superstructures of size ∼ 100 h{sup −1}Mpc at redshift z ∼ 0.5 has been detected with > 4σ significance, however it has been noted that the signal is much larger than expected. We revisit the calculation using linear theory predictions in ΛCDM cosmology for the number density of superstructures and their radial density profile, and take possible selection effects into account. While our expected signal is larger than previous estimates, it is still inconsistent by > 3σ with the observation. If the observed signal is indeed due to the ISW effect then huge, extremely underdense voids are far more common in the observed universe than predicted by ΛCDM.

  2. The stacked ISW signal of rare superstructures in ΛCDM

    SciTech Connect

    Flender, Samuel; Hotchkiss, Shaun; Nadathur, Seshadri E-mail: shaun.hotchkiss@helsinki.fi

    2013-02-01

    A detection of the stacked integrated Sachs-Wolfe (ISW) signal in the CMB of rare superstructures identified in the SDSS Luminous Red Galaxy catalogue has been reported at very high statistical significance. The magnitude of the observed signal has previously been argued to be more than 3σ larger than the theoretical ΛCDM expectation. However, this calculation was made in the linear approximation, and relied on assumptions that may potentially have caused the ΛCDM expectation to be underestimated. Here we update the theoretical model calculation and compare it with an analysis of ISW maps obtained from N-body simulations of a ΛCDM universe. The differences between model predictions and the map analyses are found to be small and cannot explain the discrepancy with observation, which remains at > 3σ significance. We discuss the cosmological significance of this anomaly and speculate on the potential of alternative models to explain it.

  3. Galaxy clustering, CMB and supernova data constraints on ϕCDM model with massive neutrinos

    NASA Astrophysics Data System (ADS)

    Chen, Yun; Xu, Lixin

    2016-01-01

    We investigate a scalar field dark energy model (i.e., ϕCDM model) with massive neutrinos, where the scalar field possesses an inverse power-law potential, i.e., V (ϕ) ∝ϕ-α (α > 0). We find that the sum of neutrino masses Σmν has significant impacts on the CMB temperature power spectrum and on the matter power spectrum. In addition, the parameter α also has slight impacts on the spectra. A joint sample, including CMB data from Planck 2013 and WMAP9, galaxy clustering data from WiggleZ and BOSS DR11, and JLA compilation of Type Ia supernova observations, is adopted to confine the parameters. Within the context of the ϕCDM model under consideration, the joint sample determines the cosmological parameters to high precision: the angular size of the sound horizon at recombination, the Thomson scattering optical depth due to reionization, the physical densities of baryons and cold dark matter, and the scalar spectral index are estimated to be θ* = (1.0415-0.0011+0.0012) ×10-2, τ =0.0914-0.0242+0.0266, Ωbh2 = 0.0222 ± 0.0005, Ωch2 = 0.1177 ± 0.0036, and ns =0.9644-0.0119+0.0118, respectively, at 95% confidence level (CL). It turns out that α < 4.995 at 95% CL for the ϕCDM model. And yet, the ΛCDM scenario corresponding to α = 0 is not ruled out at 95% CL. Moreover, we get Σmν < 0.262 eV at 95% CL for the ϕCDM model, while the corresponding one for the ΛCDM model is Σmν < 0.293 eV. The allowed scale of Σmν in the ϕCDM model is a bit smaller than that in the ΛCDM model. It is consistent with the qualitative analysis, which reveals that the increases of α and Σmν both can result in the suppression of the matter power spectrum. As a consequence, when α is larger, in order to avoid suppressing the matter power spectrum too much, the value of Σmν should be smaller.

  4. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs. PMID:19275609

  5. Formation of Primordial Stars in a Lambda-CDM Universe

    SciTech Connect

    Yoshida, Naoki; Omukai, Kazuyuki; Hernquist, Lars; Abel, Tom; /KIPAC, Menlo Park

    2006-06-09

    Primordial stars are formed from a chemically pristine gas consisting of hydrogen and helium. They are believed to have been born at some early epoch in the history of the Universe and to have enriched the interstellar medium with synthesized heavy elements before the emergence of ordinary stellar populations. We study the formation of the first generation of stars in the standard cold dark matter model. We follow the gravitational collapse and thermal evolution of primordial gas clouds within early cosmic structures using very high-resolution, cosmological hydrodynamic simulations. Our simulation achieves a dynamic range of {approx} 10{sup 10} in length scale. With accurate treatment of atomic and molecular physics, it allows us to study the chemo-thermal evolution of primordial gas clouds to densities up to {rho} {approx} 2 x 10{sup -8}g cm{sup -3} (n{sub H} {approx} 10{sup 16}cm{sup -3}) without assuming any a priori equation of state; a six orders of magnitudes improvement over previous three-dimensional calculations. We implement an extensive chemistry network for hydrogen, helium and deuterium. All the relevant atomic and molecular cooling and heating processes, including cooling by collision-induced continuum emission, are implemented. For calculating optically thick H{sub 2} cooling at high densities, we use the Sobolev method (Sobolev 1960) and evaluate the molecular line opacities for a few hundred lines. We validate the accuracy of the method by performing a spherical collapse test and comparing the results with those of accurate one-dimensional calculations that treat the line radiative transfer problem in a fully self-consistent manner. We then perform a cosmological simulation adopting the standard {Lambda}CDM model. Dense gas clumps are formed at the centers of low mass ({approx} 10{sup 5-6}M{sub {circle_dot}}) dark matter halos at redshifts z {approx} 20, and they collapse gravitationally when the cloud mass exceeds a few hundred solar masses. To

  6. DIFFERENTIAL EFFECTS OF FORMAMIDINE PESTICIDES ON FIXED-INTERVAL BEHAVIOR IN RATS

    EPA Science Inventory

    Chlordimeform (CDM), amitraz (AMZ), and formetanate (FMT) are members of the formamidine class of pesticides. To date, effects on operant behavior have been determined only for CDM. The experiment compared the effects of CDM, AMZ, and FMT on schedule-controlled responding. Nine m...

  7. Complexation of synthetic CDM-AM copolymer with natamycin and carbendazim to improve solubility and fungicidal activity.

    PubMed

    Li, Yong-Fu; Jin, Jing; Guo, Qin; Ha, Yi-Ming; Li, Qing-Peng

    2015-07-10

    The β-cyclodextrin-acrylamide (CDM-AM) copolymer was prepared from acrylamide and β-CD maleate (CDM) using K2S2O8 as initiator. The effects of the CDM-AM copolymer on the solubility and fungicidal activity of natamycin (NM) and carbendazim (MBC) were investigated. The stability constant of NM·CDM-AM and MBC·CDM-AM complexes at 303 K were of 10,725.45 M(-1) and 3000.89 M(-1), respectively. The complexes were characterized using phase solubility diagrams, NMR spectra and FT-IR spectra. The analysis of the biological activities of these two complexes indicated that they possessed enhancing fungicidal activities compared to NM and MBC alone. PMID:25857986

  8. Testing ΛCDM with the growth function δ(a): Current constraints

    NASA Astrophysics Data System (ADS)

    Nesseris, S.; Perivolaropoulos, L.

    2008-01-01

    We have compiled a data set consisting of 22 data points at a redshift range (0.15, 3.8) which can be used to constrain the linear perturbation growth rate f=(dln⁡δ)/(dln⁡a). Five of these data points constrain directly the growth rate f through either redshift distortions or change of the power spectrum with redshift. The rest of the data points constrain f indirectly through the rms mass fluctuation σ8(z) inferred from Ly-α at various redshifts. Our analysis tests the consistency of the ΛCDM model and leads to a constraint of the Wang-Steinhardt growth index γ [defined from f=Ωm(a)γ] as γ=0.67-0.17+0.20. This result is clearly consistent at 1σ with the value γ=(6)/(11)=0.545 predicted by ΛCDM. We also apply our analysis on a new null test of ΛCDM which is similar to the one recently proposed by Chiba and Nakamura (arXiv:0708.3877) but does not involve derivatives of the expansion rate H(z). This also leads to the fact that ΛCDM provides an excellent fit to the current linear growth data.

  9. Consistency of the nonflat Λ CDM model with the new result from BOSS

    NASA Astrophysics Data System (ADS)

    Kumar, Suresh

    2015-11-01

    Using 137,562 quasars in the redshift range 2.1 ≤z ≤3.5 from the data release 11 (DR11) of the baryon oscillation spectroscopic survey (BOSS) of Sloan Digital Sky Survey (SDSS)-III, the BOSS-SDSS collaboration estimated the expansion rate H (z =2.34 )=222 ±7 km /s /Mpc of the Universe, and reported that this value is in tension with the predictions of flat Λ CDM model at around a 2.5 σ level. In this paper, we briefly describe some attempts made in the literature to relieve the tension, and show that the tension can naturally be alleviated in a nonflat Λ CDM model with positive curvature. We also perform the observational consistency check by considering the constraints on the nonflat Λ CDM model from Planck, WP and BAO data. We find that the nonflat Λ CDM model constrained with Planck+WP data fits better to the line of sight measurement H (z =2.34 )=222 ±7 km /s /Mpc , but only at the expense of still having a poor fit to the BAO transverse measurements.

  10. Density profiles of CDM microhalos and their implications for annihilation boost factors

    SciTech Connect

    Anderhalden, Donnino; Diemand, Juerg E-mail: diemand@physik.uzh.ch

    2013-04-01

    In a standard cold dark matter (CDM) cosmology, microhalos at the CDM cutoff scale are the first and smallest objects expected to form in the universe. Here we present results of high resolution simulations of three representative roughly Earth-mass microhalos in order to determine their inner density profile. We find that CDM microhalos in simulations without a cutoff in the power spectrum roughly follow the NFW density profile, just like the much larger CDM halos on galaxy and galaxy cluster scales. But having a cutoff in the initial power spectrum at a typical neutralino free streaming scale of 10{sup −7}M{sub s}un makes their inner density profiles considerably steeper, i.e. ρ∝r{sup −(1.3−1.4)}, in good agreement with the results from Ishiyama et al. (2010). An extrapolation of the halo and subhalo mass functions down to the cutoff scale indicates that microhalos are extremely abundant throughout the present day dark matter distribution and might contribute significantly to indirect dark matter detection signals. Assuming a transition from a NFW to a steeper inner profile (ρ∝r{sup −1.4}) two orders of magnitude above the cutoff scale, the total boost factor for a Milky Way sized dark matter halo increases from about 3.5 to 4. We further find that CDM microhalo concentrations are consistent with the Bullock et al. (2001) model and clearly rule out simplistic power law models for the mass dependence of concentrations and subhalo annihilation, which would erroneously lead to very large boost factors (a few hundred for galaxy halos and over 1000 for clusters)

  11. A correction in the CDM methodological tool for estimating methane emissions from solid waste disposal sites.

    PubMed

    Santos, M M O; van Elk, A G P; Romanel, C

    2015-12-01

    Solid waste disposal sites (SWDS) - especially landfills - are a significant source of methane, a greenhouse gas. Although having the potential to be captured and used as a fuel, most of the methane formed in SWDS is emitted to the atmosphere, mainly in developing countries. Methane emissions have to be estimated in national inventories. To help this task the Intergovernmental Panel on Climate Change (IPCC) has published three sets of guidelines. In addition, the Kyoto Protocol established the Clean Development Mechanism (CDM) to assist the developed countries to offset their own greenhouse gas emissions by assisting other countries to achieve sustainable development while reducing emissions. Based on methodologies provided by the IPCC regarding SWDS, the CDM Executive Board has issued a tool to be used by project developers for estimating baseline methane emissions in their project activities - on burning biogas from landfills or on preventing biomass to be landfilled and so avoiding methane emissions. Some inconsistencies in the first two IPCC guidelines have already been pointed out in an Annex of IPCC latest edition, although with hidden details. The CDM tool uses a model for methane estimation that takes on board parameters, factors and assumptions provided in the latest IPCC guidelines, while using in its core equation the one of the second IPCC edition with its shortcoming as well as allowing a misunderstanding of the time variable. Consequences of wrong ex-ante estimation of baseline emissions regarding CDM project activities can be of economical or environmental type. Example of the first type is the overestimation of 18% in an actual project on biogas from landfill in Brazil that harms its developers; of the second type, the overestimation of 35% in a project preventing municipal solid waste from being landfilled in China, which harms the environment, not for the project per se but for the undue generated carbon credits. In a simulated landfill - the same

  12. Using the Millennium II simulation to test CDM predictions for the structure of massive galaxies

    NASA Astrophysics Data System (ADS)

    Cooper, Andrew P.; Kauffmann, Guinevere; Wang, Jing; White, Simon D. M.

    2013-07-01

    We have combined the semi-analytic galaxy formation model of Guo et al. (2011) with a novel particle-tagging technique to predict galaxy surface brightness profiles in a representative sample of ~1900 massive dark matter haloes (1012-1014 M⊙) from the Millennium II ΛCDM N body simulation. We focus on the outer regions of galaxies and stars accreted in mergers. Our simulations cover scales from the stellar haloes of Milky Way-like galaxies to the `cD envelopes' of groups and clusters, and resolve low surface brightness substructure such as the tidal streams of dwarf galaxies. We find that the spatial distribution of stars in low surface brightness regions is tightly correlated with DM halo mass and that collisionless merging during the hierarchical assembly of galaxies largely determines the structure of spheroidal stellar components. Our ΛCDM model agrees well with the available data.

  13. Hierarchy of N-point functions in the {Lambda}CDM and ReBEL cosmologies

    SciTech Connect

    Hellwing, Wojciech A.; Juszkiewicz, Roman; Weygaert, Rien van de

    2010-11-15

    In this work we investigate higher-order statistics for the {Lambda}CDM and ReBEL scalar-interacting dark matter models by analyzing 180h{sup -1} Mpc dark matter N-body simulation ensembles. The N-point correlation functions and the related hierarchical amplitudes, such as skewness and kurtosis, are computed using the counts-in-cells method. Our studies demonstrate that the hierarchical amplitudes S{sub n} of the scalar-interacting dark matter model significantly deviate from the values in the {Lambda}CDM cosmology on scales comparable and smaller than the screening length r{sub s} of a given scalar-interacting model. The corresponding additional forces that enhance the total attractive force exerted on dark matter particles at galaxy scales lower the values of the hierarchical amplitudes S{sub n}. We conclude that hypothetical additional exotic interactions in the dark matter sector should leave detectable markers in the higher-order correlation statistics of the density field. We focused in detail on the redshift evolution of the dark matter field's skewness and kurtosis. From this investigation we find that the deviations from the canonical {Lambda}CDM model introduced by the presence of the 'fifth' force attain a maximum value at redshifts 0.5

  14. A consistent approach to falsifying ΛCDM with rare galaxy clusters

    SciTech Connect

    Harrison, Ian; Hotchkiss, Shaun E-mail: shaun.hotchkiss@helsinki.fi

    2013-07-01

    We consider methods with which to answer the question ''is any observed galaxy cluster too unusual for ΛCDM?'' After emphasising that many previous attempts to answer this question will overestimate the confidence level at which ΛCDM can be ruled out, we outline a consistent approach to these rare clusters, which allows the question to be answered. We define three statistical measures, each of which are sensitive to changes in cluster populations arising from different modifications to the cosmological model. We also use these properties to define the ''equivalent mass at redshift zero'' for a cluster — the mass of an equally unusual cluster today. This quantity is independent of the observational survey in which the cluster was found, which makes it an ideal proxy for ranking the relative unusualness of clusters detected by different surveys. These methods are then used on a comprehensive sample of observed galaxy clusters and we confirm that all are less than 2σ deviations from the ΛCDM expectation. Whereas we have only applied our method to galaxy clusters, it is applicable to any isolated, collapsed, halo. As motivation for future surveys, we also calculate where in the mass redshift plane the rarest halo is most likely to be found, giving information as to which objects might be the most fruitful in the search for new physics.

  15. The Use of CDM Analysis Techniques in High Temperature Creep Failure of Welded Structures

    NASA Astrophysics Data System (ADS)

    Hayhurst, David R.; Wong, Man Tak; Vakili-Tahami, Farid

    Techniques are reviewed for the calibration of constitutive relationships for the different phases of the weld. It is shown how the calibration is carried out using property ratios, and a knowledge of the constitutive equations of the parent material. The results of CDM analyses, obtained using the two-dimensional solver Damage XX, are reviewed for: a butt-welded pipe at 565°C and, a welded cylinder-sphere pipe intersection at 590°C. Results are then presented of a three-dimensional CDM solution for a three-degree slice of the welded cylinder-sphere pipe intersection, and shown to be in close agreement with the two-dimensional, Damage XX, solution. Then the paper examines damage growth at a constant temperature of 590°C in a ferritic steel butt-welded pipe subjected to a combined constant internal pressure of 4MPa and a constant global bending moment of 49kNm. The CDM results for a three-dimensional analysis are compared with qualitative experimental results, and good correlation is indicated.

  16. Can f(T) gravity theories mimic ΛCDM cosmic history

    SciTech Connect

    Setare, M.R.; Mohammadipour, N. E-mail: N.Mohammadipour@uok.ac.ir

    2013-01-01

    Recently the teleparallel Lagrangian density described by the torsion scalar T has been extended to a function of T. The f(T) modified teleparallel gravity has been proposed as the natural gravitational alternative for dark energy to explain the late time acceleration of the universe. In order to reconstruct the function f(T) by demanding a background ΛCDM cosmology we assume that, (i) the background cosmic history provided by the flat ΛCDM (the radiation ere with ω{sub eff} = (1/3), matter and de Sitter eras with ω{sub eff} = 0 and ω{sub eff} = −1, respectively) (ii) the radiation dominate in the radiation era with Ω{sub 0r} = 1 and the matter dominate during the matter phases when Ω{sub 0m} = 1. We find the cosmological dynamical system which can obey the ΛCDM cosmic history. In each era, we find a critical lines that, the radiation dominated and the matter dominated are one points of them in the radiation and matter phases, respectively. Also, we drive the cosmologically viability condition for these models. We investigate the stability condition with respect to the homogeneous scalar perturbations in each era and we obtain the stability conditions for the fixed points in each eras. Finally, we reconstruct the function f(T) which mimics cosmic expansion history.

  17. Reconstruction, thermodynamics and stability of the ΛCDM model in f(T,{ T }) gravity

    NASA Astrophysics Data System (ADS)

    Junior, Ednaldo L. B.; Rodrigues, Manuel E.; Salako, Ines G.; Houndjo, Mahouton J. S.

    2016-06-01

    We reconstruct the ΛCDM model for f(T,{ T }) theory, where T is the torsion scalar and { T } the trace of the energy-momentum tensor. The result shows that the action of ΛCDM is a combination of a linear term, a constant (-2{{Λ }}) and a nonlinear term given by the product \\sqrt{-T}{F}g[({T}1/3/16π G) (16π G{ T }+T+8{{Λ }})], with F g being a generic function. We show that to maintain conservation of the energy-momentum tensor, we should impose that {F}g[y] must be linear on the trace { T }. This reconstruction decays in f (T) theory for {F}g\\equiv Q, with Q a constant. Our reconstruction describes the cosmological eras to the present time. The model present stability within the geometric and matter perturbations for the choice {F}g=y, where y=({T}1/3/16π G)(16π G{ T }+T+8{{Λ }}), except for the geometric part in the de Sitter model. We impose the first and second laws of thermodynamics to ΛCDM and find the condition where they are satisfied, that is, {T}A,{G}{{eff}}\\gt 0, however where this is not possible in the cases that we choose, this leads to a breakdown of positive entropy and Misner–Sharp energy.

  18. Experimental search for hidden photon CDM in the eV mass range with a dish antenna

    SciTech Connect

    Suzuki, J.; Horie, T.; Inoue, Y.; Minowa, M.

    2015-09-15

    A search for hidden photon cold dark matter (HP CDM) using a new technique with a dish antenna is reported. From the result of the measurement, we found no evidence for the existence of HP CDM and set an upper limit on the photon-HP mixing parameter χ of ∼6×10{sup −12} for the hidden photon mass m{sub γ}=3.1±1.2 eV.

  19. Bright high z SnIa: A challenge for {lambda}CDM

    SciTech Connect

    Perivolaropoulos, L.; Shafieloo, A.

    2009-06-15

    It has recently been pointed out by Kowalski et. al.[Astrophys. J. 686, 749 (2008).] that there is 'an unexpected brightness of the SnIa data at z>1'. We quantify this statement by constructing a new statistic which is applicable directly on the type Ia supernova (SnIa) distance moduli. This statistic is designed to pick up systematic brightness trends of SnIa data points with respect to a best fit cosmological model at high redshifts. It is based on binning the normalized differences between the SnIa distance moduli and the corresponding best fit values in the context of a specific cosmological model (e.g. {lambda}CDM). These differences are normalized by the standard errors of the observed distance moduli. We then focus on the highest redshift bin and extend its size toward lower redshifts until the binned normalized difference (BND) changes sign (crosses 0) at a redshift z{sub c} (bin size N{sub c}). The bin size N{sub c} of this crossing (the statistical variable) is then compared with the corresponding crossing bin size N{sub mc} for Monte Carlo data realizations based on the best fit model. We find that the crossing bin size N{sub c} obtained from the Union08 and Gold06 data with respect to the best fit {lambda}CDM model is anomalously large compared to N{sub mc} of the corresponding Monte Carlo data sets obtained from the best fit {lambda}CDM in each case. In particular, only 2.2% of the Monte Carlo {lambda}CDM data sets are consistent with the Gold06 value of N{sub c} while the corresponding probability for the Union08 value of N{sub c} is 5.3%. Thus, according to this statistic, the probability that the high redshift brightness bias of the Union08 and Gold06 data sets is realized in the context of a (w{sub 0},w{sub 1})=(-1,0) model ({lambda}CDM cosmology) is less than 6%. The corresponding realization probability in the context of a (w{sub 0},w{sub 1})=(-1.4,2) model is more than 30% for both the Union08 and the Gold06 data sets indicating a much better

  20. Strongly coupled dark energy cosmologies: preserving ΛCDM success and easing low-scale problems - II. Cosmological simulations

    NASA Astrophysics Data System (ADS)

    Macciò, Andrea V.; Mainini, Roberto; Penzo, Camilla; Bonometto, Silvio A.

    2015-10-01

    In this second paper, we present the first N-body cosmological simulations of strongly coupled Dark Energy (SCDEW) models, a class of models that alleviates theoretical issues related to the nature of dark energy (DE). SCDEW models assume a strong coupling between DE and an ancillary cold dark matter (CDM) component together with the presence of an uncoupled warm dark matter (WDM) component. The strong coupling between CDM and DE allows us to preserve small-scale fluctuations even if the warm particle is quite light (≈100 eV). Our large-scale simulations show that, for 1011 < M/M⊙ < 1014, SCDEW haloes exhibit a number density and distribution similar to a standard lambda cold dark matter (ΛCDM) model, even though they have lower concentration parameters. High-resolution simulation of a galactic halo (M ˜ 1012 M⊙) shows ˜60 per cent less substructures than its ΛCDM counterpart, but the same cuspy density profile. On the scale of galactic satellites (M ˜ 109 M⊙), SCDEW haloes dramatically differ from ΛCDM. Due to the high thermal velocities of the WDM component they are almost devoid of any substructures and present strongly cored dark matter density profiles. These density cores extend for several hundreds of parsecs, in very good agreement with Milky Way satellites observations. Strongly coupled models, thanks to their ability to match observations on both large and small scales, might represent a valid alternative to a simple ΛCDM model.

  1. Constraints on Λ(t)CDM models as holographic and agegraphic dark energy with the observational Hubble parameter data

    SciTech Connect

    Zhai, Zhong-Xu; Liu, Wen-Biao; Zhang, Tong-Jie E-mail: tjzhang@bnu.edu.cn

    2011-08-01

    The newly released observational H(z) data (OHD) is used to constrain Λ(t)CDM models as holographic and agegraphic dark energy. By the use of the length scale and time scale as the IR cut-off including Hubble horizon (HH), future event horizon (FEH), age of the universe (AU), and conformal time (CT), we achieve four different Λ(t)CDM models which can describe the present cosmological acceleration respectively. In order to get a comparison between such Λ(t)CDM models and standard ΛCDM model, we use the information criteria (IC), Om(z) diagnostic, and statefinder diagnostic to measure the deviations. Furthermore, by simulating a larger Hubble parameter data sample in the redshift range of 0.1 < z < 2.0, we get the improved constraints and more sufficient comparison. We show that OHD is not only able to play almost the same role in constraining cosmological parameters as SNe Ia does but also provides the effective measurement of the deviation of the DE models from standard ΛCDM model. In the holographic and agegraphic scenarios, the results indicate that the FEH is more preferable than HH scenario. However, both two time scenarios show better approximations to ΛCDM model than the length scenarios.

  2. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  3. Strongly coupled dark energy cosmologies: preserving ΛCDM success and easing low scale problems - I. Linear theory revisited

    NASA Astrophysics Data System (ADS)

    Bonometto, Silvio A.; Mainini, Roberto; Macciò, Andrea V.

    2015-10-01

    In this first paper we discuss the linear theory and the background evolution of a new class of models we dub SCDEW: Strongly Coupled DE, plus WDM. In these models, WDM dominates today's matter density; like baryons, WDM is uncoupled. Dark energy is a scalar field Φ; its coupling to ancillary cold dark matter (CDM), whose today's density is ≪1 per cent, is an essential model feature. Such coupling, in fact, allows the formation of cosmic structures, in spite of very low WDM particle masses (˜100 eV). SCDEW models yield cosmic microwave background and linear large scale features substantially undistinguishable from ΛCDM, but thanks to the very low WDM masses they strongly alleviate ΛCDM issues on small scales, as confirmed via numerical simulations in the second associated paper. Moreover SCDEW cosmologies significantly ease the coincidence and fine tuning problems of ΛCDM and, by using a field theory approach, we also outline possible links with inflationary models. We also discuss a possible fading of the coupling at low redshifts which prevents non-linearities on the CDM component to cause computational problems. The (possible) low-z coupling suppression, its mechanism, and its consequences are however still open questions - not necessarily problems - for SCDEW models. The coupling intensity and the WDM particle mass, although being extra parameters in respect to ΛCDM, are found to be substantially constrained a priori so that, if SCDEW is the underlying cosmology, we expect most data to fit also ΛCDM predictions.

  4. Myotonic Dystrophy: Increased expression of the normal allele in CDM infants muscle

    SciTech Connect

    Radvanyi, H.H.; Gourdon, G.; Junien, C. |

    1994-09-01

    Myotonic dystrophy (DM) is an autosomal dominant multisystemic disorder characterized by a highly variable clinical phenotype. The mutation has been identified as an unstable trinucleotide CTG repeat in the 3{prime} untranslated region of the myotonin-protein kinase (MT-PK) gene. Congenital myotonic dystrophy (CDM), which represents the most severe phenotype, is exclusively maternally inherited. Recent studies, analysis by Northern blots and RT-PCR provided apparently conflicting results on the mutated allele expression in samples from congenitally affected children. The level of expression of the mutant allele depends on the extent of the repeat in the adult form and is no longer expressed when over 800-1300 repeats, whether in adult forms or in CDM. Could this decrease account for the late onset forms? However, the differences between the two phenotypes cannot be explained by the same mechanism. Alternatively, these differences could be due to differences in expression of the normal allele. We analyzed by quantitative RT-PCR the expression of the MT-PK gene in muscle samples from four CDM infants and two aged-matched normal controls. In two of these, the mutant allele (3.3 and 8 kb) was undetectable on Northern blots. We observed an increased expression of the MT-PK gene (10- to 20-fold) in tissues of severely affected congenital patients which can be attributed to the normal allele. Since expression of the normal allele is either normal or slightly decreased in the adult form, the dramatic increase in the congenital form could reflect a disturbance in muscle differentiation. Expression studies of MT-PK at different stages of development and, especially after the 20th week, are therefore required.

  5. Distinguishing interacting dark energy from wCDM with CMB, lensing, and baryon acoustic oscillation data

    NASA Astrophysics Data System (ADS)

    Väliviita, Jussi; Palmgren, Elina

    2015-07-01

    We employ the Planck 2013 CMB temperature anisotropy and lensing data, and baryon acoustic oscillation (BAO) data to constrain a phenomenological wCDM model, where dark matter and dark energy interact. We assume time-dependent equation of state parameter for dark energy, and treat dark matter and dark energy as fluids whose energy-exchange rate is proportional to the dark-matter density. The CMB data alone leave a strong degeneracy between the interaction rate and the physical CDM density parameter today, ωc, allowing a large interaction rate |Γ| ~ H0. However, as has been known for a while, the BAO data break this degeneracy. Moreover, we exploit the CMB lensing potential likelihood, which probes the matter perturbations at redshift z ~ 2 and is very sensitive to the growth of structure, and hence one of the tools for discerning between the ΛCDM model and its alternatives. However, we find that in the non-phantom models (wde>-1), the constraints remain unchanged by the inclusion of the lensing data and consistent with zero interaction, -0.14 < Γ/H0 < 0.02 at 95% CL. On the contrary, in the phantom models (wde<-1), energy transfer from dark energy to dark matter is moderately favoured over the non-interacting model; 0-0.57 < Γ/H0 < -0.1 at 95% CL with CMB+BAO, while addition of the lensing data shifts this to -0.46 < Γ/H0 < -0.01.

  6. The spatial correlation properties of dark galaxy halos in a CDM universe

    NASA Technical Reports Server (NTRS)

    Brainerd, Tereasa G.; Villumsen, Jens V.

    1993-01-01

    We use the Hierarchical Particle Mesh (HPM) N-body code written by J. V. Villumsen (Villumsen, 1989) to investigate the two-point spatial correlation function, xi(r), of dark galaxy halos as a function of halo mass and local environment (i.e. high, low, or average mass density). We assume a standard cold dark matter (CDM) universe (omega = 1, delta = 0, H sub 0 = 50,km/sec/Mpc). Because of the large dynamic ranges in mass and length that can be obtained with the HPM code, it is well-suited to an investigation of this sort.

  7. Exact analytic solution for non-linear density fluctuation in a ΛCDM universe

    NASA Astrophysics Data System (ADS)

    Yoo, Jaiyul; Gong, Jinn-Ouk

    2016-07-01

    We derive the exact third-order analytic solution of the matter density fluctuation in the proper-time hypersurface in a ΛCDM universe, accounting for the explicit time-dependence and clarifying the relation to the initial condition. Furthermore, we compare our analytic solution to the previous calculation in the comoving gauge, and to the standard Newtonian perturbation theory by providing Fourier kernels for the relativistic effects. Our results provide an essential ingredient for a complete description of galaxy bias in the relativistic context.

  8. Stochastic contribution to the growth factor in the {lambda}CDM model

    SciTech Connect

    Ribeiro, A. L. B.; Andrade, A. P. A.; Letelier, P. S.

    2009-01-15

    We study the effect of noise on the evolution of the growth factor of density perturbations in the context of the {lambda}CDM model. Stochasticity is introduced as a Wiener process amplified by an intensity parameter {alpha}. By comparing the evolution of deterministic and stochastic cases for different values of {alpha} we estimate the intensity level necessary to make noise relevant for cosmological tests based on large-scale structure data. Our results indicate that the presence of random forces underlying the fluid description can lead to significant deviations from the nonstochastic solution at late times for {alpha}{>=}10{sup -3}.

  9. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  10. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  11. A unified solution to the small scale problems of the ΛCDM model

    SciTech Connect

    Popolo, A. Del; Lima, J.A.S.; Fabris, Júlio C.; Rodrigues, Davi C. E-mail: limajas@astro.iag.usp.br E-mail: davi.rodrigues@cosmo-ufes.org

    2014-04-01

    We study, by means of the model proposed in Del Popolo (2009), the effect of baryon physics on the small scale problems of the CDM model. We show that, using this model, the cusp/core problem, the missing satellite problem (MSP), the Too Big to Fail (TBTF) problem, and the angular momentum catastrophe can be reconciled with observations. Concerning the cusp/core problem, the interaction among dark matter (DM) and baryonic clumps of 1% the mass of the halo, through dynamical friction (DF), is able to flatten the inner cusp of the density profiles. We moreover assume that haloes form primarily through quiescent accretion, in agreement with the spherical collapse model (SCM)-secondary infall model (SIM) prescriptions. The results of this paper follow from the two assumptions above. Concerning the MSP and TBTF problem, applying to the Via Lactea II (VL2) subhaloes a series of corrections similar to those of Brooks et al. (2013), namely applying a Zolotov et al. (2012)-like correction obtained with our model, and further correcting for the UV heating and tidal stripping, we obtain that the number of massive, luminous satellites is in agreement with the number observed in the MW. The model also produces an angular momentum distribution in agreement with observations, that is with the distribution of the angular spin parameter and angular momentum of the dwarfs studied by van den Bosch, Burkert, and Swaters (2001). In conclusion, the small scale problems of the CDM model can all be solved by introducing baryon physics.

  12. How smooth are particle trajectories in a ΛCDM Universe?

    NASA Astrophysics Data System (ADS)

    Rampf, Cornelius; Villone, Barbara; Frisch, Uriel

    2015-09-01

    It is shown here that in a flat, cold dark matter (CDM)-dominated Universe with positive cosmological constant (Λ), modelled in terms of a Newtonian and collisionless fluid, particle trajectories are analytical in time (representable by a convergent Taylor series) until at least a finite time after decoupling. The time variable used for this statement is the cosmic scale factor, i.e. the `a-time', and not the cosmic time. For this, a Lagrangian-coordinate formulation of the Euler-Poisson equations is employed, originally used by Cauchy for 3D incompressible flow. Temporal analyticity for ΛCDM is found to be a consequence of novel explicit all-order recursion relations for the a-time Taylor coefficients of the Lagrangian displacement field, from which we derive the convergence of the a-time Taylor series. A lower bound for the a-time where analyticity is guaranteed and shell-crossing is ruled out is obtained, whose value depends only on Λ and on the initial spatial smoothness of the density field. The largest time interval is achieved when Λ vanishes, i.e. for an Einstein-de Sitter universe. Analyticity holds also if, instead of the a-time, one uses the linear structure growth D-time, but no simple recursion relations are then obtained. The analyticity result also holds when a curvature term is included in the Friedmann equation for the background, but inclusion of a radiation term arising from the primordial era spoils analyticity.

  13. Non-local gravity and comparison with observational datasets. II. Updated results and Bayesian model comparison with ΛCDM

    NASA Astrophysics Data System (ADS)

    Dirian, Yves; Foffa, Stefano; Kunz, Martin; Maggiore, Michele; Pettorino, Valeria

    2016-05-01

    We present a comprehensive and updated comparison with cosmological observations of two non-local modifications of gravity previously introduced by our group, the so called RR and RT models. We implement the background evolution and the cosmological perturbations of the models in a modified Boltzmann code, using CLASS. We then test the non-local models against the Planck 2015 TT, TE, EE and Cosmic Microwave Background (CMB) lensing data, isotropic and anisotropic Baryonic Acoustic Oscillations (BAO) data, JLA supernovae, H0 measurements and growth rate data, and we perform Bayesian parameter estimation. We then compare the RR, RT and ΛCDM models, using the Savage-Dickey method. We find that the RT model and ΛCDM perform equally well, while the performance of the RR model with respect to ΛCDM depends on whether or not we include a prior on H0 based on local measurements.

  14. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  15. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  16. Piperidine derivatives as nonprostanoid IP receptor agonists.

    PubMed

    Hayashi, Ryoji; Sakagami, Hideki; Koiwa, Masakazu; Ito, Hiroaki; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-05-01

    The discovery of a new class of nonprostanoid prostaglandin I2 receptor (IP receptor) agonists is reported. Among them, the unique piperidine derivative 31b (2-((1-(2-(N-(4-tolyl)benzamido)ethyl)piperidin-4-yl)oxy)acetic acid) was a good IP receptor agonist and was 50-fold more selective for the human IP receptor than for other human prostanoid receptors. This compound showed good pharmacokinetic properties in dog. PMID:26996371

  17. Disruptive Technologies in Workmanship: pH-neutral Flux, CDM ESD Events, HDI PCBs

    NASA Technical Reports Server (NTRS)

    Plante, Jeannette F.

    2010-01-01

    This slide presentation describes what it calls "disruptive technologies", i.e., "Low-end disruption" occurs when the rate at which products improve exceeds the rate at which customers can adopt the new performance. Therefore, at some point the performance of the product overshoots the needs of certain customer segments. At this point, a disruptive technology may enter the market and provide a product which has lower performance than the incumbent but which exceeds the requirements of certain segments, thereby gaining a foothold in the market. This concept is viewed in impacting incumbent technologies Rosin Flux, with a pH-neutral water soluble Flux; electrostatic discharge models being disrupted by the charge device model (CDM) concept; and High Density Interconnect Printed Circuit Boards (HDI PCB).

  18. Non-Gaussian initial conditions in ΛCDM: Newtonian, relativistic, and primordial contributions

    SciTech Connect

    Bruni, Marco; Hidalgo, Juan Carlos; Meures, Nikolai; Wands, David

    2014-04-10

    The goal of the present paper is to set initial conditions for structure formation at nonlinear order, consistent with general relativity, while also allowing for primordial non-Gaussianity. We use the nonlinear continuity and Raychaudhuri equations, which together with the nonlinear energy constraint, determine the evolution of the matter density fluctuation in general relativity. We solve this equations at first and second order in a perturbative expansion, recovering and extending previous results derived in the matter-dominated limit and in the Newtonian regime. We present a second-order solution for the comoving density contrast in a ΛCDM universe, identifying nonlinear contributions coming from the Newtonian growing mode, primordial non-Gaussianity and intrinsic non-Gaussianity, due to the essential nonlinearity of the relativistic constraint equations. We discuss the application of these results to initial conditions in N-body simulations, showing that relativistic corrections mimic a non-zero nonlinear parameter f {sub NL}.

  19. ΛCDM model in f(T) gravity: reconstruction, thermodynamics and stability

    SciTech Connect

    Salako, I.G.; Kpadonou, A.V.; Houndjo, M.J.S.; Tossa, J.; Rodrigues, M.E. E-mail: esialg@gmail.com E-mail: sthoundjo@yahoo.fr

    2013-11-01

    We investigate some cosmological features of the ΛCDM model in the framework of the generalized teleparallel theory of gravity f(T) where T denotes the torsion scalar. Its reconstruction is performed giving rise to an integration constant Q and other input parameters according to which we point out more analysis. Thereby, we show that for some values of this constant, the first and second laws of thermodynamics can be realized in the equilibrium description, for the universe with the temperature inside the horizon equal to that at the apparent horizon. Moreover, still within these suitable values of the constant, we show that the model may be stable using the de Sitter and Power-Law cosmological solutions.

  20. Refining the mouse chromosomal location of Cdm, the major gene associated with susceptibility to cadmium-induced testicular necrosis.

    PubMed

    Dalton, T P; Miller, M L; Wu, X; Menon, A; Cianciolo, E; McKinnon, R A; Smith, P W; Robinson, L J; Nebert, D W

    2000-03-01

    Cadmium (Cd++) is a widespread environmental pollutant and classifed as an IARC 'Category I' human carcinogen. Cd++ can also cause severe renal toxicity and may be involved clinically in cardiovascular disease and osteoporosis. Genetic differences in sensitivity to cadmium toxicity have been noted in humans, whereas, among inbred mouse strains, unequivocal genetic data exist. Resistance to cadmium-induced testicular damage was reported in 1973 to be associated with a single major recessive gene, named Cdm, which has now been localized to mouse chromosome (Chr) 3. Using polymorphic microsatellite markers and semiquantitative histological parameters, we have corroborated the original 1973 data concerning mendelian inheritance and have further refined the region containing the Cdm gene from more than 24 cM to 0.64 cM (estimated 40-80 genes). We phenotyped 26 recombinant inbred lines generated from C57BL/6J (B6, resistant) and DBA/2J (D2, sensitive) inbred mice, and determined that the Cdm gene maps between microsatellite markers D3Mit110 and D3Mit255. Although toxicity to numerous heavy metals is well known, virtually no molecular mechanisms have yet been uncovered either in humans or laboratory animals. Identification and characterization of the mouse Cdm gene should enhance our understanding of heavy metal toxicity by identifying and characterizing, for the first time, a major mammalian gene responsible for susceptibility to diseases caused by heavy metal toxicity. PMID:10762002

  1. The inner structure of ΛCDM haloes - II. Halo mass profiles and low surface brightness galaxy rotation curves

    NASA Astrophysics Data System (ADS)

    Hayashi, E.; Navarro, J. F.; Power, C.; Jenkins, A.; Frenk, C. S.; White, S. D. M.; Springel, V.; Stadel, J.; Quinn, T. R.

    2004-12-01

    We use a set of high-resolution cosmological N-body simulations to investigate the inner mass profile of galaxy-sized cold dark matter (CDM) haloes. These simulations extend the numerical convergence study presented in Paper I of this series, and demonstrate that the mass profile of CDM galaxy haloes can be robustly estimated beyond a minimum converged radius of order rconv~ 1h-1 kpc in our highest-resolution runs. The density profiles of simulated haloes become progressively shallower from the virial radius inwards, and show no sign of approaching a well-defined power law near the centre. At rconv, the density profile is steeper than expected from the formula proposed by Navarro, Frenk & White, which has a ρ~r-1 cusp, but significantly shallower than the steeply divergent ρ~r-1.5 cusp proposed by Moore et al. We perform a direct comparison of the spherically averaged dark matter circular velocity profiles with Hα rotation curves of a sample of low surface brightness (LSB) galaxies. We find that most galaxies in the sample (about 70 per cent) have rotation curves that are consistent with the structure of CDM haloes. Of the remainder, 20 per cent have rotation curves which cannot be fit by any smooth fitting function with few free parameters, and 10 per cent are inconsistent with CDM haloes. However, the latter consist mostly of rotation curves that do not extend to large enough radii to accurately determine their shapes and maximum velocities. We conclude that the inner structure of CDM haloes is not manifestly inconsistent with the rotation curves of LSB galaxies.

  2. Testing ΛCDM cosmology at turnaround: where to look for violations of the bound?

    NASA Astrophysics Data System (ADS)

    Tanoglidis, D.; Pavlidou, V.; Tomaras, T. N.

    2015-12-01

    In ΛCDM cosmology, structure formation is halted shortly after dark energy dominates the mass/energy budget of the Universe. A manifestation of this effect is that in such a cosmology the turnaround radius—the non-expanding mass shell furthest away from the center of a structure— has an upper bound. Recently, a new, local, test for the existence of dark energy in the form of a cosmological constant was proposed based on this turnaround bound. Before designing an experiment that, through high-precision determination of masses and —independently— turnaround radii, will challenge ΛCDM cosmology, we have to answer two important questions: first, when turnaround-scale structures are predicted to be close enough to their maximum size, so that a possible violation of the bound may be observable. Second, which is the best mass scale to target for possible violations of the bound. These are the questions we address in the present work. Using the Press-Schechter formalism, we find that turnaround structures have in practice already stopped forming, and consequently, the turnaround radius of structures must be very close to the maximum value today. We also find that the mass scale of ~ 1013 Msolar characterizes the turnaround structures that start to form in a statistically important number density today —and even at an infinite time in the future, since structure formation has almost stopped. This mass scale also separates turnaround structures with qualitatively different cosmological evolution: smaller structures are no longer readjusting their mass distribution inside the turnaround scale, they asymptotically approach their ultimate abundance from higher values, and they are common enough to have, at some epoch, experienced major mergers with structures of comparable mass; larger structures exhibit the opposite behavior. We call this mass scale the transitional mass scale and we argue that it is the optimal for the purpose outlined above. As a corollary, we

  3. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  4. Introduction of a single isomer beta agonist.

    PubMed

    Rau, J L

    2000-08-01

    The release of levalbuterol offers the first approved single-isomer beta agonist for oral inhalation. Data from in vitro studies support the concept that S albuterol is not inactive and may have properties antagonistic to bronchodilation. There is some variability in the results of clinical studies with the separate isomers of albuterol, which suggests the need for further study. The introduction of levalbuterol into general clinical use in managing asthma and chronic obstructive disease should begin to offer additional information on the effects of a single isomer beta agonist in comparison to previous racemic mixtures. PMID:10963321

  5. A differential CDM model for fatigue of unidirectional metal matrix composites

    NASA Technical Reports Server (NTRS)

    Arnold, S. M.; Kruch, S.

    1992-01-01

    A multiaxial, isothermal, continuum damage mechanics (CDM) model for fatigue of a unidirectional metal matrix composite volume element is presented. The model is phenomenological, stress based, and assumes a single scalar internal damage variable, the evolution of which is anisotropic. The development of the fatigue damage model, (i.e., evolutionary law) is based on the definition of an initially transversely isotropic fatigue limit surface, a static fracture surface, and a normalized stress amplitude function. The anisotropy of these surfaces and function, and therefore the model, is defined through physically meaningful invariants reflecting the local stress and material orientation. This transversely isotropic model is shown, when taken to it's isotropic limit, to directly simplify to a previously developed and validated isotropic fatigue continuum damage model. Results of a nondimensional parametric study illustrate (1) the flexibility of the present formulation in attempting to characterize a class of composite materials, and (2) the capability of the formulation in predicting anticipated qualitative trends in the fatigue behavior of unidirectional metal matrix composites. Also, specific material parameters representing an initial characterization of the composite system SiC/Ti 15-3 and the matrix material (Ti 15-3) are reported.

  6. Is the continuous matter creation cosmology an alternative to ΛCDM?

    SciTech Connect

    Fabris, J.C.; Pacheco, J.A. de Freitas; Piattella, O.F. E-mail: pacheco@oca.eu

    2014-06-01

    The matter creation cosmology is revisited, including the evolution of baryons and dark matter particles. The creation process affects only dark matter and not baryons. The dynamics of the ΛCDM model can be reproduced only if two conditions are satisfied: 1) the entropy density production rate and the particle density variation rate are equal and 2) the (negative) pressure associated to the creation process is constant. However, the matter creation model predicts a present dark matter-to-baryon ratio much larger than that observed in massive X-ray clusters of galaxies, representing a potential difficulty for the model. In the linear regime, a fully relativistic treatment indicates that baryons are not affected by the creation process but this is not the case for dark matter. Both components evolve together at early phases but lately the dark matter density contrast decreases since the background tends to a constant value. This behaviour produces a negative growth factor, in disagreement with observations, being a further problem for this cosmology.

  7. Energy of Einstein's static universe and its implications for the ΛCDM cosmology

    SciTech Connect

    Mitra, Abhas

    2013-03-01

    The total Einstein energy (P{sub 0}) of a homogeneous and isotropic universe can be computed by using an appropriate superpotential (Rosen 1994) and also by a direct method (Mitra 2010). Irrespective of the physical significance of P{sub 0}, its eventual numerical value must be same in both the cases because both are derived from the same Einstein pseudo tensor and by employing the same coordinates. It follows then that the static isotropic and homogeneous universe, i.e., Einstein's static universe (ESU), must have an infinite radius and which tantamounts to a spatially flat case. The physical significance of this result is that the cosmological constant, Λ, is actually zero and ESU is the vacuous Minkowski spacetime. It is the same result which has recently been obtained in a completely independent manner (Mitra, Bhattacharyya and Bhatt 2013). Thus even though, mathematically, one can conceive of a static 3-sphere for the foundation of relativistic cosmology, physically, no such 3-sphere exists. On the other hand, the spatial section of the universe could essentially be an Euclidean space with local curvature spikes due to presence of lumpy matter. Since the ''Dark Energy'' is associated with Λ in the ΛCDM model, the result obtained here suggests that it is an artifact of departure of the lumpy and fractal universe from the ideal Friedmann Robertson Walker model (Jackson et al. 2012, Cowley et al. 2013)

  8. Quantifying substructures in Hubble Frontier Field clusters: comparison with ΛCDM simulations

    NASA Astrophysics Data System (ADS)

    Mohammed, Irshad; Saha, Prasenjit; Williams, Liliya L. R.; Liesenborgs, Jori; Sebesta, Kevin

    2016-04-01

    The Hubble Frontier Fields (HFF) are six clusters of galaxies, all showing indications of recent mergers, which have recently been observed for lensed images. As such they are the natural laboratories to study the merging history of galaxy clusters. In this work, we explore the 2D power spectrum of the mass distribution PM(k) as a measure of substructure. We compare PM(k) of these clusters (obtained using strong gravitational lensing) to that of ΛCDM simulated clusters of similar mass. To compute lensing PM(k), we produced free-form lensing mass reconstructions of HFF clusters, without any light traces mass (LTM) assumption. The inferred power at small scales tends to be larger if (i) the cluster is at lower redshift, and/or (ii) there are deeper observations and hence more lensed images. In contrast, lens reconstructions assuming LTM show higher power at small scales even with fewer lensed images; it appears the small scale power in the LTM reconstructions is dominated by light information, rather than the lensing data. The average lensing derived PM(k) shows lower power at small scales as compared to that of simulated clusters at redshift zero, both dark-matter only and hydrodynamical. The possible reasons are: (i) the available strong lensing data are limited in their effective spatial resolution on the mass distribution, (ii) HFF clusters have yet to build the small scale power they would have at z ˜ 0, or (iii) simulations are somehow overestimating the small scale power.

  9. Inhomogeneous post-inflationary ΛCDM cosmology as a moduli space expansion

    NASA Astrophysics Data System (ADS)

    Wiseman, Toby; Withers, Benjamin

    2011-12-01

    We model the large scale late time universe as a ΛCDM cosmology driven by cosmological constant and perfect dust fluid. Our aim is to find new solutions in the matter and Λ epoch consistent with inflationary initial conditions, namely, that to the far past in the matter era the cosmology tends to a flat Friedmann-Lemaître-Robertson-Walker solution. We identify the moduli degrees of freedom that parametrize the flat Λ-dust Friedmann-Lemaître-Robertson-Walker solution and then promote these moduli to slowly varying functions of the spatial coordinates and show how to solve the Einstein equations in a comoving gradient expansion, controlled by the cosmological constant length scale. Our initial conditions ensure that the approximation remains under control to the far past of the matter era, and to the far future of Λ domination. The solution is fully nonperturbative in the amplitude of the metric deformation, and we explicitly construct it to fourth order in derivatives. A general Λ-dust universe dominated by Λ in the future is characterized by a 3-metric and a stress tensor (with positive trace) defined on the future conformal boundary. The new cosmologies with inflationary initial conditions are characterized only by the boundary 3-metric, the stress tensor being locally determined entirely in terms of that metric.

  10. Indirectly Estimating International Net Migration Flows by Age and Gender: The Community Demographic Model International Migration (CDM-IM) Dataset

    PubMed Central

    Nawrotzki, Raphael J.; Jiang, Leiwen

    2015-01-01

    Although data for the total number of international migrant flows is now available, no global dataset concerning demographic characteristics, such as the age and gender composition of migrant flows exists. This paper reports on the methods used to generate the CDM-IM dataset of age and gender specific profiles of bilateral net (not gross) migrant flows. We employ raw data from the United Nations Global Migration Database and estimate net migrant flows by age and gender between two time points around the year 2000, accounting for various demographic processes (fertility, mortality). The dataset contains information on 3,713 net migrant flows. Validation analyses against existing data sets and the historical, geopolitical context demonstrate that the CDM-IM dataset is of reasonably high quality. PMID:26692590

  11. Constraints from growth-rate data on some coupled dark energy models mimicking a ΛCDM expansion

    NASA Astrophysics Data System (ADS)

    Fay, Stéphane

    2016-05-01

    The ΛCDM expansion could be mimicked by a dark energy coupled to matter. Then, the equation of state bar{w} and coupling bar{Q} of this coupled dark energy could not be constrained by observations of the Hubble function alone. Also, in this paper, we determine the constraints on two such coupled dark energy models considering some current and forecast Euclid-like growth-rate data and assuming the prior on the ΛCDM dark matter density parameter today Ωm0 = 0.295 ± 0.04. The first model is defined by a constant equation of state. We find that at 2σ, bar{w}=-1.02_{-0.22}^{+0.06} and the coupling function bar{Q}_0 today is bar{Q}_0H_0^{-3}=0.057_{-0.148}^{+0.353} with H0 the Hubble constant. The second model is defined by a varying equation of state bar{w}=bar{w}_a-bar{w}_bln (1+z), with z the redshift and (bar{w}_a,bar{w}_b), two constants. We find that at 2σ, bar{w}_a=-0.99_{-0.90}^{+0.17}, bar{w}_b=-0.04_{-1.17}^{+0.31} and bar{Q}_0H_0^{-3}=0.0002_{-0.18}^{+1.35}. These constraints on coupled dark energy agreed with a ΛCDM model but are too poor to discard confidently a coupled dark energy different from vacuum but mimicking a ΛCDM expansion.

  12. Constraints from growth-rate data on some coupled dark energy models mimicking a ΛCDM expansion

    NASA Astrophysics Data System (ADS)

    Fay, Stéphane

    2016-08-01

    The ΛCDM expansion can be mimicked by dark energy coupled to matter. In this case, the equation of state bar{w} and coupling bar{Q} of this coupled dark energy cannot be constrained by observations of the Hubble function alone. In this article, we determine the constraints on two such coupled dark energy models, considering some current and forecast Euclid-like growth-rate data and assuming the prior on the ΛCDM dark matter density parameter today, Ωm0 = 0.295 ± 0.04. The first model is defined by a constant equation of state. We find that, at 2σ, bar{w}=-1.02_{-0.22}^{+0.06} and the coupling function bar{Q}_0 today is bar{Q}_0H_0^{-3}=0.057_{-0.148}^{+0.353}, with H0 the Hubble constant. The second model is defined by a varying equation of state bar{w}=bar{w}_a-bar{w}_bln (1+z), with z the redshift and (bar{w}_a,bar{w}_b) two constants. We find that, at 2σ, bar{w}_a=-0.99_{-0.90}^{+0.17}, bar{w}_b=-0.04_{-1.17}^{+0.31} and bar{Q}_0H_0^{-3}=0.0002_{-0.18}^{+1.35}. These constraints on coupled dark energy agree with a ΛCDM model but are too poor to discard with confidence coupled dark energy different from a vacuum but mimicking a ΛCDM expansion.

  13. Reciprocity of agonistic support in ravens

    PubMed Central

    Fraser, Orlaith N.; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim’s likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  14. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  15. Small molecule TSHR agonists and antagonists.

    PubMed

    Neumann, S; Gershengorn, M C

    2011-04-01

    TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule "drug-like" ligands. Recombinant human TSH (rhTSH, Thyrogen(®)) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential. PMID:21511239

  16. Reciprocity of agonistic support in ravens.

    PubMed

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  17. Discovery of a Supercluster at z ~ 0.91 and Testing the ΛCDM Cosmological Model

    NASA Astrophysics Data System (ADS)

    Kim, Jae-Woo; Im, Myungshin; Lee, Seong-Kook; Edge, Alastair C.; Hyun, Minhee; Kim, Dohyeong; Choi, Changsu; Hong, Jueun; Jeon, Yiseul; Jun, Hyunsung David; Karouzos, Marios; Kim, Duho; Kim, Ji Hoon; Kim, Yongjung; Park, Won-Kee; Taak, Yoon Chan; Yoon, Yongmin

    2016-04-01

    The ΛCDM cosmological model successfully reproduces many aspects of the galaxy and structure formation of the universe. However, the growth of large-scale structures (LSSs) in the early universe is not well tested yet with observational data. Here, we have utilized wide and deep optical–near-infrared data in order to search for distant galaxy clusters and superclusters (0.8 < z < 1.2). From the spectroscopic observation with the Inamori Magellan Areal Camera and Spectrograph (IMACS) on the Magellan telescope, three massive clusters at z ∼ 0.91 are confirmed in the SSA22 field. Interestingly, all of them have similar redshifts within Δ z ∼ 0.01 with velocity dispersions ranging from 470 to 1300 km s‑1. Moreover, as the maximum separation is ∼15 Mpc, they compose a supercluster at z ∼ 0.91, meaning that this is one of the most massive superclusters at this redshift to date. The galaxy density map implies that the confirmed clusters are embedded in a larger structure stretching over ∼100 Mpc. ΛCDM models predict about one supercluster like this in our surveyed volume, consistent with our finding so far. However, there are more supercluster candidates in this field, suggesting that additional studies are required to determine if the ΛCDM cosmological model can successfully reproduce the LSSs at high redshift.

  18. Quantifying substructures in Hubble Frontier Field clusters: comparison with ΛCDM simulations

    DOE PAGESBeta

    Mohammed, Irshad; Saha, Prasenjit; Williams, Liliya L. R.; Liesenborgs, Jori; Sebesta, Kevin

    2016-04-13

    The Hubble Frontier Fields (HFF) are six clusters of galaxies, all showing indications of recent mergers, which have recently been observed for lensed images. As such they are the natural laboratories to study the merging history of galaxy clusters. In this work, we explore the 2D power spectrum of the mass distributionmore » $$P_{\\rm M}(k)$$ as a measure of substructure. We compare $$P_{\\rm M}(k)$$ of these clusters (obtained using strong gravitational lensing) to that of $$\\Lambda$$CDM simulated clusters of similar mass. In order to compute lensing $$P_{\\rm M}(k)$$, we produced free-form lensing mass reconstructions of HFF clusters, without any light traces mass (LTM) assumption. Moreover, the inferred power at small scales tends to be larger if (i)~the cluster is at lower redshift, and/or (ii)~there are deeper observations and hence more lensed images. In contrast, lens reconstructions assuming LTM show higher power at small scales even with fewer lensed images; it appears the small scale power in the LTM reconstructions is dominated by light information, rather than the lensing data. The average lensing derived $$P_{\\rm M}(k)$$ shows lower power at small scales as compared to that of simulated clusters at redshift zero, both dark-matter only and hydrodynamical. The possible reasons are: (i)~the available strong lensing data are limited in their effective spatial resolution on the mass distribution, (ii)~HFF clusters have yet to build the small scale power they would have at $$z\\sim 0$$, or (iii)~simulations are somehow overestimating the small scale power.« less

  19. How rare is the Bullet Cluster (in a ΛCDM universe)?

    NASA Astrophysics Data System (ADS)

    Kraljic, David; Sarkar, Subir

    2015-04-01

    The Bullet Cluster (1E 0657-56) is well-known as providing visual evidence of dark matter but it is potentially incompatible with the standard ΛCDM cosmology due to the high relative velocity of the two colliding clusters. Previous studies have focussed on the probability of such a high relative velocity amongst selected candidate systems. This notion of `probability' is however difficult to interpret and can lead to paradoxical results. Instead, we consider the expected number of Bullet-like systems on the sky up to a specified redshift, which allows for direct comparison with observations. Using a Hubble volume N-body simulation with high resolution we investigate how the number of such systems depends on the masses of the halo pairs, their separation, and collisional angle. This enables us to extract an approximate formula for the expected number of halo-halo collisions given specific collisional parameters. We use extreme value statistics to analyse the tail of the pairwise velocity distribution and demonstrate that it is fatter than the previously assumed Gaussian form. We estimate that the number of dark matter halo pairs as or more extreme than 1E 0657-56 in mass, separation and relative velocity is 1.3+2.0-0.6 up to redshift z=0.3. However requiring the halos to have collided and passed through each other as is observed decreases this number to only 0.1. The discovery of more such systems would thus indeed present a challenge to the standard cosmology.

  20. COSMIC EMULATION: THE CONCENTRATION-MASS RELATION FOR wCDM UNIVERSES

    SciTech Connect

    Kwan, Juliana; Bhattacharya, Suman; Heitmann, Katrin; Habib, Salman

    2013-05-10

    The concentration-mass relation for dark matter-dominated halos is one of the essential results expected from a theory of structure formation. We present a simple prediction scheme, a cosmic emulator, for the concentration-mass (c-M) relation as a function of cosmological parameters for wCDM models. The emulator is constructed from 37 individual models, with three nested N-body gravity-only simulations carried out for each model. The mass range covered by the emulator is 2 Multiplication-Sign 10{sup 12} M{sub Sun} < M < 10{sup 15} M{sub Sun} with a corresponding redshift range of z = 0-1. Over this range of mass and redshift, as well as the variation of cosmological parameters studied, the mean halo concentration varies from c {approx} 2 to c {approx} 8. The distribution of the concentration at fixed mass is Gaussian with a standard deviation of one-third of the mean value, almost independent of cosmology, mass, and redshift over the ranges probed by the simulations. We compare results from the emulator with previously derived heuristic analytic fits for the c-M relation, finding that they underestimate the halo concentration at high masses. Using the emulator to investigate the cosmology dependence of the c-M relation over the currently allowable range of values, we find-not surprisingly-that {sigma}{sub 8} and {omega}{sub m} influence it considerably, but also that the dark energy equation-of-state parameter w has a substantial effect. In general, the concentration of lower-mass halos is more sensitive to changes in cosmological parameters as compared to cluster mass halos. The c-M emulator is publicly available from http://www.hep.anl.gov/cosmology/CosmicEmu.

  1. PREDICTING MERGER-INDUCED GAS MOTIONS IN ΛCDM GALAXY CLUSTERS

    SciTech Connect

    Nagai, Daisuke; Lau, Erwin T.; Avestruz, Camille; Rudd, Douglas H.; Nelson, Kaylea

    2013-11-10

    In the hierarchical structure formation model, clusters of galaxies form through a sequence of mergers and continuous mass accretion, which generate significant random gas motions especially in their outskirts where material is actively accreting. Non-thermal pressure provided by the internal gas motions affects the thermodynamic structure of the X-ray emitting intracluster plasma and introduces biases in the physical interpretation of X-ray and Sunyaev-Zeldovich effect observations. However, we know very little about the nature of gas motions in galaxy clusters. The ASTRO-H X-ray mission, scheduled to launch in 2015, will have a calorimeter capable of measuring gas motions in galaxy clusters at the level of ∼< 100 km s{sup –1}. In this work, we predict the level of merger-induced gas motions expected in the ΛCDM model using hydrodynamical simulations of galaxy cluster formation. We show that the gas velocity dispersion is larger in more massive clusters, but exhibits a large scatter. We show that systems with large gas motions are morphologically disturbed, while early forming, relaxed groups show a smaller level of gas motions. By analyzing mock ASTRO-H observations of simulated clusters, we show that such observations can accurately measure the gas velocity dispersion out to the outskirts of nearby relaxed galaxy clusters. ASTRO-H analysis of merging clusters, on the other hand, requires multi-component spectral fitting and enables unique studies of substructures in galaxy clusters by measuring both the peculiar velocities and the velocity dispersion of gas within individual sub-clusters.

  2. Shapes of Gas, Gravitational Potential, and Dark Matter in ΛCDM Clusters

    NASA Astrophysics Data System (ADS)

    Lau, Erwin T.; Nagai, Daisuke; Kravtsov, Andrey V.; Zentner, Andrew R.

    2011-06-01

    We present analysis of the three-dimensional shape of intracluster gas in clusters formed in cosmological simulations of the ΛCDM cosmology and compare it to the shape of dark matter distribution and the shape of the overall isopotential surfaces. We find that in simulations with radiative cooling, star formation, and stellar feedback (CSF), intracluster gas outside the cluster core (r >~ 0.1r 500) is more spherical compared to non-radiative (NR) simulations, while in the core the gas in the CSF runs is more triaxial and has a distinctly oblate shape. The latter reflects the ongoing cooling of gas, which settles into a thick oblate ellipsoid as it loses thermal energy. The shape of the gas in the inner regions of clusters can therefore be a useful diagnostic of gas cooling. We find that gas traces the shape of the underlying potential rather well outside the core, as expected in hydrostatic equilibrium. At smaller radii, however, the gas and potential shapes differ significantly. In the CSF runs, the difference reflects the fact that gas is partly rotationally supported. Interestingly, we find that in NR simulations the difference between gas and potential shape at small radii is due to random gas motions, which make the gas distribution more spherical than the equipotential surfaces. Finally, we use mock Chandra X-ray maps to show that the differences in shapes observed in a three-dimensional distribution of gas are discernible in the ellipticity of X-ray isophotes. Contrasting the ellipticities measured in simulated clusters against observations can therefore constrain the amount of cooling in the intracluster medium and the presence of random gas motions in cluster cores.

  3. Constraints on CDM cosmology from galaxy power spectrum, CMB and SNIa evolution

    NASA Astrophysics Data System (ADS)

    Ferramacho, L. D.; Blanchard, A.; Zolnierowski, Y.

    2009-05-01

    Aims: We examine the constraints that can be obtained on standard cold dark matter models from the most currently used data set: CMB anisotropies, type Ia supernovae and the SDSS luminous red galaxies. We also examine how these constraints are widened when the equation of state parameter w and the curvature parameter Ωk are left as free parameters. Finally, we investigate the impact on these constraints of a possible form of evolution in SNIa intrinsic luminosity. Methods: We obtained our results from MCMC analysis using the full likelihood of each data set. Results: For the ΛCDM model, our “vanilla” model, cosmological parameters are tightly constrained and consistent with current estimates from various methods. When the dark energy parameter w is free we find that the constraints remain mostly unchanged, i.e. changes are smaller than the 1 sigma uncertainties. Similarly, relaxing the assumption of a flat universe leads to nearly identical constraints on the dark energy density parameter of the universe Ω_Λ , baryon density of the universe Ω_b, the optical depth τ, the index of the power spectrum of primordial fluctuations n_S, with most one sigma uncertainties better than 5%. More significant changes appear on other parameters: while preferred values are almost unchanged, uncertainties for the physical dark matter density Ω_ch^2, Hubble constant H0 and σ8 are typically twice as large. The constraint on the age of the Universe, which is very accurate for the vanilla model, is the most degraded. We found that different methodological approaches on large scale structure estimates lead to appreciable differences in preferred values and uncertainty widths. We found that possible evolution in SNIa intrinsic luminosity does not alter these constraints by much, except for w, for which the uncertainty is twice as large. At the same time, this possible evolution is severely constrained. Conclusions: We conclude that systematic uncertainties for some estimated

  4. Cosmological constant vis-à-vis dynamical vacuum: Bold challenging the ΛCDM

    NASA Astrophysics Data System (ADS)

    Solà, Joan

    2016-08-01

    Next year we will celebrate 100 years of the cosmological term, Λ, in Einstein’s gravitational field equations, also 50 years since the cosmological constant problem was first formulated by Zeldovich, and almost about two decades of the observational evidence that a nonvanishing, positive, Λ-term could be the simplest phenomenological explanation for the observed acceleration of the Universe. This mixed state of affairs already shows that we do no currently understand the theoretical nature of Λ. In particular, we are still facing the crucial question whether Λ is truly a fundamental constant or a mildly evolving dynamical variable. At this point the matter should be settled once more empirically and, amazingly enough, the wealth of observational data at our disposal can presently shed true light on it. In this short review, I summarize the situation of some of these studies. It turns out that the Λ = const. hypothesis, despite being the simplest, may well not be the most favored one when we put it in hard-fought competition with specific dynamical models of the vacuum energy. Recently, it has been shown that the overall fit to the cosmological observables SNIa+BAO+H(z)+LSS+BBN+CMB do favor the class of “running” vacuum models (RVM’s) — in which Λ = Λ(H) is a function of the Hubble rate — against the “concordance” ΛCDM model. The support is at an unprecedented level of ˜ 4σ and is backed up with Akaike and Bayesian criteria leading to compelling evidence in favor of the RVM option and other related dynamical vacuum models. I also address the implications of this framework on the possible time evolution of the fundamental constants of Nature.

  5. HERG1 Channel Agonists and Cardiac Arrhythmia

    PubMed Central

    Sanguinetti, Michael

    2014-01-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  6. HERG1 channel agonists and cardiac arrhythmia.

    PubMed

    Sanguinetti, Michael C

    2014-04-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  7. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  8. Melanocortin 1 Receptor Agonists Reduce Proteinuria

    PubMed Central

    Ebefors, Kerstin; Johansson, Martin E.; Stefánsson, Bergur; Granqvist, Anna; Arnadottir, Margret; Berg, Anna-Lena; Nyström, Jenny; Haraldsson, Börje

    2010-01-01

    Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. Recent reports suggest that treatment with adrenocorticotropic hormone (ACTH) reduces proteinuria, but the mechanism of action is unknown. Here, we identified gene expression of the melanocortin receptor MC1R in podocytes, glomerular endothelial cells, mesangial cells, and tubular epithelial cells. Podocytes expressed most MC1R protein, which colocalized with synaptopodin but not with an endothelial-specific lectin. We treated rats with passive Heymann nephritis (PHN) with MS05, a specific MC1R agonist, which significantly reduced proteinuria compared with untreated PHN rats (P < 0.01). Furthermore, treatment with MC1R agonists improved podocyte morphology and reduced oxidative stress. In summary, podocytes express MC1R, and MC1R agonism reduces proteinuria, improves glomerular morphology, and reduces oxidative stress in nephrotic rats with PHN. These data may explain the proteinuria-reducing effects of ACTH observed in patients with membranous nephropathy, and MC1R agonists may provide a new therapeutic option for these patients. PMID:20507942

  9. THE VELOCITY FUNCTION IN THE LOCAL ENVIRONMENT FROM {lambda}CDM AND {lambda}WDM CONSTRAINED SIMULATIONS

    SciTech Connect

    Zavala, J.; Jing, Y. P.; Faltenbacher, A.; Hoffman, Y.; Gottloeber, S.; Catinella, B.

    2009-08-01

    Using constrained simulations of the local universe for generic cold dark matter (CDM) and for 1 keV warm dark matter (WDM), we investigate the difference in the abundance of dark matter halos in the local environment. We find that the mass function (MF) within 20 h{sup -1} Mpc of the Local Group is {approx}2 times larger than the universal MF in the 10{sup 9}-10{sup 13} h{sup -1} M {sub sun} mass range. Imposing the field of view of the ongoing H I blind survey Arecibo Legacy Fast ALFA (ALFALFA) in our simulations, we predict that the velocity function (VF) in the Virgo-direction region (VdR) exceeds the universal VF by a factor of 3. Furthermore, employing a scheme to translate the halo VF into a galaxy VF, we compare the simulation results with a sample of galaxies from the early catalog release of ALFALFA. We find that our simulations are able to reproduce the VF in the 80-300 km s{sup -1} velocity range, having a value {approx}10 times larger than the universal VF in the VdR. In the low-velocity regime, 35-80 km s{sup -1}, the WDM simulation reproduces the observed flattening of the VF. In contrast, the simulation with CDM predicts a steep rise in the VF toward lower velocities; for V{sub max} = 35 km s{sup -1}, it forecasts {approx}10 times more sources than the ones observed. If confirmed by the complete ALFALFA survey, our results indicate a potential problem for the CDM paradigm or for the conventional assumptions about energetic feedback in dwarf galaxies.

  10. A Comparative Analysis of the Supernova Legacy Survey Sample With ΛCDM and the Rh=ct Universe

    NASA Astrophysics Data System (ADS)

    Wei, Jun-Jie; Wu, Xue-Feng; Melia, Fulvio; Maier, Robert S.

    2015-03-01

    The use of Type Ia supernovae (SNe Ia) has thus far produced the most reliable measurement of the expansion history of the universe, suggesting that ΛCDM offers the best explanation for the redshift-luminosity distribution observed in these events. However, analysis of other kinds of sources, such as cosmic chronometers, gamma-ray bursts, and high-z quasars, conflicts with this conclusion, indicating instead that the constant expansion rate implied by the Rh = ct universe is a better fit to the data. The central difficulty with the use of SNe Ia as standard candles is that one must optimize three or four nuisance parameters characterizing supernova (SN) luminosities simultaneously with the parameters of an expansion model. Hence, in comparing competing models, one must reduce the data independently for each. We carry out such a comparison of ΛCDM and the Rh = ct universe using the SN Legacy Survey sample of 252 SN events, and show that each model fits its individually reduced data very well. However, since Rh = ct has only one free parameter (the Hubble constant), it follows from a standard model selection technique that it is to be preferred over ΛCDM, the minimalist version of which has three (the Hubble constant, the scaled matter density, and either the spatial curvature constant or the dark energy equation-of-state parameter). We estimate using the Bayes Information Criterion that in a pairwise comparison, the likelihood of Rh = ct is ˜90%, compared with only ˜10% for a minimalist form of ΛCDM, in which dark energy is simply a cosmological constant. Compared to Rh = ct, versions of the standard model with more elaborate parametrizations of dark energy are judged to be even less likely. This work is dedicated to the memory of Prof. Tan Lu, who sadly passed away 2014 December 3. Among his many achievements, he is considered to be one of the founders of high-energy astrophysics, and a pioneer in modern cosmology, in China.

  11. Dopamine agonist: pathological gambling and hypersexuality.

    PubMed

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication. PMID:19536937

  12. The low-mass end of the neutral gas mass and velocity width functions of galaxies in ΛCDM

    NASA Astrophysics Data System (ADS)

    Yaryura, C. Y.; Helmi, A.; Abadi, M. G.; Starkenburg, E.

    2016-04-01

    We use the high-resolution Aquarius cosmological dark matter simulations coupled to the semi-analytic model by Starkenburg et al. to study the H I content and velocity width properties of field galaxies at the low-mass end in the context of Λ cold dark matter (ΛCDM). We compare our predictions to the observed Arecibo Legacy Fast ALFA (ALFALFA) survey H I mass and velocity width functions, and find very good agreement without fine-tuning, when considering central galaxies. Furthermore, the properties of the dark matter haloes hosting galaxies, characterized by their peak velocity and circular velocity at two radial disc scalelengths overlap perfectly with the inferred values from observations. This suggests that our galaxies are placed in the right dark matter haloes, and consequently at face value, we do not find any discrepancy with the predictions from the ΛCDM model. Our analysis indicates that previous tensions, apparent when using abundance matching models, arise because this technique cannot be straightforwardly applied for objects with masses Mvir < 1010M⊙.

  13. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  14. Mechanisms of agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Lin, Hong; Strange, Philip G

    2004-12-01

    In this study, we investigated the biochemical mechanisms of agonist action at the G protein-coupled D2 dopamine receptor expressed in Chinese hamster ovary cells. Stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding by full and partial agonists was determined at different concentrations of [35S]GTPgammaS (0.1 and 10 nM) and in the presence of different concentrations of GDP. At both concentrations of [35S]GTPgammaS, increasing GDP decreased the [35S]GTPgammaS binding observed with maximally stimulating concentrations of agonist, with partial agonists exhibiting greater sensitivity to the effects of GDP than full agonists. The relative efficacy of partial agonists was greater at the lower GDP concentrations. Concentration-response experiments were performed for a range of agonists at the two [35S]GTPgammaS concentrations and with different concentrations of GDP. At 0.1 nM [35S]GTPgammaS, the potency of both full and partial agonists was dependent on the GDP concentration in the assays. At 10 nM [35S]GTPgammaS, the potency of full agonists exhibited a greater dependence on the GDP concentration, whereas the potency of partial agonists was virtually independent of GDP. We concluded that at the lower [35S]GTPgammaS concentration, the rate-determining step in G protein activation is the binding of [35S]GTPgammaS to the G protein. At the higher [35S]GTPgammaS concentration, for full agonists, [35S]GTPgammaS binding remains the slowest step, whereas for partial agonists, another (GDP-independent) step, probably ternary complex breakdown, becomes rate-determining. PMID:15340043

  15. FORMING REALISTIC LATE-TYPE SPIRALS IN A {Lambda}CDM UNIVERSE: THE ERIS SIMULATION

    SciTech Connect

    Guedes, Javiera; Madau, Piero; Callegari, Simone; Mayer, Lucio

    2011-12-01

    Simulations of the formation of late-type spiral galaxies in a cold dark matter ({Lambda}CDM) universe have traditionally failed to yield realistic candidates. Here we report a new cosmological N-body/smooth particle hydrodynamic simulation of extreme dynamic range in which a close analog of a Milky Way disk galaxy arises naturally. Named 'Eris', the simulation follows the assembly of a galaxy halo of mass M{sub vir} = 7.9 Multiplication-Sign 10{sup 11} M{sub Sun} with a total of N = 18.6 million particles (gas + dark matter + stars) within the final virial radius, and a force resolution of 120 pc. It includes radiative cooling, heating from a cosmic UV field and supernova explosions (blastwave feedback), a star formation recipe based on a high gas density threshold (n{sub SF} = 5 atoms cm{sup -3} rather than the canonical n{sub SF} = 0.1 atoms cm{sup -3}), and neglects any feedback from an active galactic nucleus. Artificial images are generated to correctly compare simulations with observations. At the present epoch, the simulated galaxy has an extended rotationally supported disk with a radial scale length R{sub d} = 2.5 kpc, a gently falling rotation curve with circular velocity at 2.2 disk scale lengths of V{sub 2.2} = 214 km s{sup -1}, an i-band bulge-to-disk ratio B/D = 0.35, and a baryonic mass fraction within the virial radius that is 30% below the cosmic value. The disk is thin, has a typical H I-to-stellar mass ratio, is forming stars in the region of the {Sigma}{sub SFR}-{Sigma}{sub HI} plane occupied by spiral galaxies, and falls on the photometric Tully-Fisher and the stellar-mass-halo-virial-mass relations. Hot (T > 3 Multiplication-Sign 10{sup 5} K) X-ray luminous halo gas makes up only 26% of the universal baryon fraction and follows a 'flattened' density profile {proportional_to}r{sup -1.13} out to r = 100 kpc. Eris appears then to be the first cosmological hydrodynamic simulation in which the galaxy structural properties, the mass budget in the

  16. Computational modeling toward understanding agonist binding on dopamine 3.

    PubMed

    Zhao, Yaxue; Lu, Xuefeng; Yang, Chao-Yie; Huang, Zhimin; Fu, Wei; Hou, Tingjun; Zhang, Jian

    2010-09-27

    The dopamine 3 (D3) receptor is a promising therapeutic target for the treatment of nervous system disorders, such as Parkinson's disease, and current research interests primarily focus on the discovery/design of potent D3 agonists. Herein, a well-designed computational protocol, which combines pharmacophore identification, homology modeling, molecular docking, and molecular dynamics (MD) simulations, was employed to understand the agonist binding on D3 aiming to provide insights into the development of novel potent D3 agonists. We (1) identified the chemical features required in effective D3 agonists by pharmacophore modeling based upon 18 known diverse D3 agonists; (2) constructed the three-dimensional (3D) structure of D3 based on homology modeling and the pharmacophore hypothesis; (3) identified the binding modes of the agonists to D3 by the correlation between the predicted binding free energies and the experimental values; and (4) investigated the induced fit of D3 upon agonist binding through MD simulations. The pharmacophore models of the D3 agonists and the 3D structure of D3 can be used for either ligand- or receptor-based drug design. Furthermore, the MD simulations further give the insight that the long and flexible EL2 acts as a "door" for agonist binding, and the "ionic lock" at the bottom of TM3 and TM6 is essential to transduce the activation signal. PMID:20695484

  17. Strategies for designing synthetic immune agonists.

    PubMed

    Wu, Tom Y-H

    2016-08-01

    Enhancing the immune system is a validated strategy to combat infectious disease, cancer and allergy. Nevertheless, the development of immune adjuvants has been hampered by safety concerns. Agents that can stimulate the immune system often bear structural similarities with pathogen-associated molecular patterns found in bacteria or viruses and are recognized by pattern recognition receptors (PRRs). Activation of these PRRs results in the immediate release of inflammatory cytokines, up-regulation of co-stimulatory molecules, and recruitment of innate immune cells. The distribution and duration of these early inflammatory events are crucial in the development of antigen-specific adaptive immunity in the forms of antibody and/or T cells capable of searching for and destroying the infectious pathogens or cancer cells. However, systemic activation of these PRRs is often poorly tolerated. Hence, different strategies have been employed to modify or deliver immune agonists in an attempt to control the early innate receptor activation through temporal or spatial restriction. These approaches include physicochemical manipulation, covalent conjugation, formulation and conditional activation/deactivation. This review will describe recent examples of discovery and optimization of synthetic immune agonists towards clinical application. PMID:27213842

  18. Proglumide exhibits delta opioid agonist properties.

    PubMed

    Rezvani, A; Stokes, K B; Rhoads, D L; Way, E L

    1987-01-01

    Recently, it was reported that proglumide, a cholecystokinin (CCK) antagonist, potentiates the analgetic effects of morphine and endogenous opioid peptides and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat. In order to provide additional insight into the mode of action of this agent, we assessed the effect of proglumide in the isolated guinea pig ileum and the mouse, rat and rabbit vas deferens. Furthermore, we studied the in vitro binding affinity of this substance to mouse brain synaptosomes. Our results show that proglumide inhibits, dose dependently, the electrically stimulated twitches in the mouse vas deferens and guinea pig ileum, but not in the rat or rabbit vas deferens. The inhibitory action of proglumide on the mouse vas deferens, but not on the guinea pig ileum, is antagonized by naloxone and by the selective delta-antagonist, ICI 174,864, in a competitive fashion. Other CCK antagonists were found to be devoid of such activity on the mouse vas deferens. In vitro binding studies showed that proglumide displaces D-ala-D-[leucine]5-enkephalin (DADLE), a delta agonist, but not ethylketocyclazocine (EKC), a preferentially selective kappa agonist. The effect of proglumide appeared to be elicited presynaptically since it did not alter the norepinephrine-induced contractions of the mouse vas deferens. Our results suggest that proglumide might exert its opiate-like effects by activation of delta-opioid receptors. PMID:3030338

  19. Chimpanzees Extract Social Information from Agonistic Screams

    PubMed Central

    Slocombe, Katie E.; Kaller, Tanja; Call, Josep; Zuberbühler, Klaus

    2010-01-01

    Chimpanzee (Pan troglodytes) agonistic screams are graded vocal signals that are produced in a context-specific manner. Screams given by aggressors and victims can be discriminated based on their acoustic structure but the mechanisms of listener comprehension of these calls are currently unknown. In this study, we show that chimpanzees extract social information from these vocal signals that, combined with their more general social knowledge, enables them to understand the nature of out-of-sight social interactions. In playback experiments, we broadcast congruent and incongruent sequences of agonistic calls and monitored the response of bystanders. Congruent sequences were in accordance with existing social dominance relations; incongruent ones violated them. Subjects looked significantly longer at incongruent sequences, despite them being acoustically less salient (fewer call types from fewer individuals) than congruent ones. We concluded that chimpanzees categorised an apparently simple acoustic signal into victim and aggressor screams and used pragmatics to form inferences about third-party interactions they could not see. PMID:20644722

  20. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  1. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  2. Estrogen receptor beta agonists in neurobehavioral investigations.

    PubMed

    Choleris, Elena; Clipperton, Amy E; Phan, Anna; Kavaliers, Martin

    2008-07-01

    Neurobehavioral investigations into the functions of estrogen receptor (ER)alpha and ERbeta have utilized 'knockout' mice, phytoestrogens and, more recently, ER-specific agonists. Feeding, sexual, aggressive and social behavior, anxiety, depression, drug abuse, pain perception, and learning (and associated synaptic plasticity) are affected by ERalpha and ERbeta in a manner that is dependent upon the specific behavior studied, gender and developmental stage. Overall, ERalpha and ERbeta appear to function together to foster sociosexual behavior while inhibiting behaviors that, if occurring at the time of behavioral estrous, may compete with reproduction (eg, feeding). Recently developed pharmacological tools have limited selectivity and availability to the research community at large, as they are not commercially available. The development of highly selective, commercially available ERbeta-specific antagonists would greatly benefit preclinical and applied research. PMID:18600582

  3. Non-Benzodiazepine Receptor Agonists for Insomnia.

    PubMed

    Becker, Philip M; Somiah, Manya

    2015-03-01

    Because of proven efficacy, reduced side effects, and less concern about addiction, non-benzodiazepine receptor agonists (non-BzRA) have become the most commonly prescribed hypnotic agents to treat onset and maintenance insomnia. First-line treatment is cognitive-behavioral therapy. When pharmacologic treatment is indicated, non-BzRA are first-line agents for the short-term and long-term management of transient and chronic insomnia related to adjustment, psychophysiologic, primary, and secondary causation. In this article, the benefits and risks of non-BzRA are reviewed, and the selection of a hypnotic agent is defined, based on efficacy, pharmacologic profile, and adverse events. PMID:26055674

  4. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  5. Receptors for /sup 3/H-octopamine in the adult firefly light organ

    SciTech Connect

    Hashemzadeh, H.; Hollingworth, R.M.; Voliva, A.

    1985-08-05

    /sup 3/H-Octopamine binds reversibly and with high affinity to sites on adult firefly light organ membranes. The binding is characterized by multiple affinities. Scatchard analysis supported a two site binding model with a tentative Kd value of about 1 nM for the high affinity component. The more abundant lower affinity site had a Kd value of about 60 nM. Guanyl nucleotides (Gpp(NH)p and GTP) greatly reduced the apparent number of octopamine binding sites. Competition studies with known octopaminergic agonists including the formamidine pesticides chlordimeform (CDM) and N-demethylchlordimeform (DCDM) showed the following rank order of potencies in displacing octopamine: DCDM > octopamine = synephrine > naphazoline > clonidine > CDM. It was also observed that phentolamine was much more active than propranolol in antagonizing OA-binding. These relative activities are similar to the abilities of the same compounds to alter adenylate cyclase activity in light organ homogenates. Together with the effect of GTP on binding, these results suggest that the binding sites are functional octopamine receptors of the light organ. 27 references, 3 figures, 1 table.

  6. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

  7. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pégorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  8. Risk versus benefit considerations for the beta(2)-agonists.

    PubMed

    Kelly, H William

    2006-09-01

    Short-acting beta(2)-agonists are the mainstay of therapy for acute bronchospasm associated with asthma and chronic obstructive pulmonary disease, whereas long-acting beta(2)-agonists are used in maintaining disease control in these respiratory disorders. This review describes and compares the pharmacology of the beta(2)-agonists and explains how these differences translate into differences in efficacy and beta(2)-adrenergic-mediated adverse effects. Questions commonly asked by clinicians regarding the efficacy and safety of short- and long-acting beta(2)-agonists include issues about cardiovascular effects, tolerance to their bronchodilator and bronchoprotective effects, blunting of albuterol response by long-acting beta(2)-agonists, potential masking of worsening asthma control, and the role of long-acting beta(2)-agonists as adjunctive therapy with inhaled corticosteroids in maintaining asthma control. Pharmacogenetics may play a role in determining which patients may be at risk for a reduced response to a beta(2)-agonist. The continued use of racemic albuterol, which contains a mixture of R-albuterol and S-albuterol, has been questioned because of data from preclinical and clinical studies suggesting that S-albuterol causes proinflammatory effects and may increase bronchial hyperreactivity. The preclinical and clinical effects of these two stereoisomers are reviewed. Data describing the efficacy and safety of levalbuterol (R-albuterol) and racemic albuterol are presented. PMID:16945063

  9. Dopamine agonist withdrawal syndrome: implications for patient care.

    PubMed

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID:23686524

  10. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed

    Langmead, Christopher J; Christopoulos, Arthur

    2013-05-01

    The concept of 'super agonism' has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. PMID:23441648

  11. Relamorelin: A Novel Gastrocolokinetic Synthetic Ghrelin Agonist

    PubMed Central

    Camilleri, Michael; Acosta, Andres

    2015-01-01

    Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately 6-fold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a pre-specified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders. PMID:25545036

  12. Selecting agonists from single cells infected with combinatorial antibody libraries.

    PubMed

    Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia; Ruiz, Diana; Wilson, Ian A; Lerner, Richard A

    2013-05-23

    We describe a system for direct selection of antibodies that are receptor agonists. Combinatorial antibody libraries in lentiviruses are used to infect eukaryotic cells that contain a fluorescent reporter system coupled to the receptor for which receptor agonist antibodies are sought. In this embodiment of the method, very large numbers of candidate antibodies expressing lentivirus and eukaryotic reporter cells are packaged together in a format where each is capable of replication, thereby forging a direct link between genotype and phenotype. Following infection, cells that fluoresce are sorted and the integrated genes encoding the agonist antibodies recovered. We validated the system by illustrating its ability to generate rapidly potent antibody agonists that are complete thrombopoietin phenocopies. The system should be generalizable to any pathway where its activation can be linked to production of a selectable phenotype. PMID:23706638

  13. Therapeutic Potential of 5-HT6 Receptor Agonists.

    PubMed

    Karila, Delphine; Freret, Thomas; Bouet, Valentine; Boulouard, Michel; Dallemagne, Patrick; Rochais, Christophe

    2015-10-22

    Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox. PMID:26099069

  14. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    PubMed

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. PMID:20579229

  15. Selective 5-HT2C agonists as potential antidepressants.

    PubMed

    Leysen, D C

    1999-02-01

    The antidepressants currently used need improvement, especially in terms of efficacy, relapse rate and onset of action. In this review the clinical and experimental data which support the rationale for 5-HT2C agonists in the treatment of depression are listed. Next, the results obtained with the non-selective 5-HT2C agonists on the market and in clinical development are described. Finally, the preclinical data on the more selective 5-HT2C agonists are summarized. These recent preclinical results reveal a greater potency and effect size compared to fluoxetine, good tolerability and no evidence of tolerance development. Selective 5-HT2C agonists might become innovative drugs for the treatment of depression, panic, obsessive-compulsive disorder (OCD), some forms of aggression and eating disorders. PMID:16160946

  16. Agonist pharmacology of two Drosophila GABA receptor splice variants.

    PubMed Central

    Hosie, A. M.; Sattelle, D. B.

    1996-01-01

    1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of

  17. Sleep attacks in patients taking dopamine agonists: review

    PubMed Central

    Homann, Carl Nikolaus; Wenzel, Karoline; Suppan, Klaudia; Ivanic, Gerd; Kriechbaum, Norbert; Crevenna, Richard; Ott, Erwin

    2002-01-01

    Objectives To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Design Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. Results 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Conclusion Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information. What is already known on this topicCar crashes in patients with Parkinson's disease have been associated with sleep attacks caused by the dopamine agonists pramipexole and ropiniroleWhether sleep attacks exist, their connection with certain agonists, prevention or treatment, and the justification of legal actions are controversialWhat this study addsSleep attacks as a phenomenon distinct from normal somnolence really do existThey are a class effect of all dopamine drugsEffective prevention and treatment

  18. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  19. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25326839

  20. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25437461

  1. PPAR dual agonists: are they opening Pandora's Box?

    PubMed

    Balakumar, Pitchai; Rose, Madhankumar; Ganti, Subrahmanya S; Krishan, Pawan; Singh, Manjeet

    2007-08-01

    Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in

  2. Mechanisms of inverse agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Strange, Philip G

    2005-05-01

    Mechanisms of inverse agonist action at the D2(short) dopamine receptor have been examined. Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [3H]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. Competition of inverse agonists versus [3H]NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. K(i) values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. K(coupled) and K(uncoupled) were statistically different for the set of compounds tested (ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. These observations were supported by simulations of these competition experiments according to the extended ternary complex model. Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [35S]GTP gamma S binding to varying degrees in concentration-response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (-)-sulpiride was unaffected. These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism. PMID:15735658

  3. Differential effects of AMPK agonists on cell growth and metabolism

    PubMed Central

    Vincent, Emma E.; Coelho, Paula P.; Blagih, Julianna; Griss, Takla; Viollet, Benoit; Jones, Russell G.

    2016-01-01

    As a sensor of cellular energy status, the AMP-activated protein kinase (AMPK) is believed to act in opposition to the metabolic phenotypes favored by proliferating tumor cells. Consequently, compounds known to activate AMPK have been proposed as cancer therapeutics. However, the extent to which the anti-neoplastic properties of these agonists are mediated by AMPK is unclear. Here we examined the AMPK-dependence of six commonly used AMPK agonists (metformin, phenformin, AICAR, 2DG, salicylate and A-769662) and their influence on cellular processes often deregulated in tumor cells. We demonstrate that the majority of these agonists display AMPK-independent effects on cell proliferation and metabolism with only the synthetic activator, A-769662, exerting AMPK-dependent effects on these processes. We find that A-769662 promotes an AMPK-dependent increase in mitochondrial spare respiratory capacity (SRC). Finally, contrary to the view of AMPK activity being tumor suppressive, we find A-769662 confers a selective proliferative advantage to tumor cells growing under nutrient deprivation. Our results indicate that many of the anti-growth properties of these agonists cannot be attributed to AMPK activity in cells, and thus any observed effects using these agonists should be confirmed using AMPK-deficient cells. Ultimately, our data urge caution, not only regarding the type of AMPK agonist proposed for cancer treatment, but also the context in which they are used. PMID:25241895

  4. Perception of specific trigeminal chemosensory agonists

    PubMed Central

    Frasnelli, J; Albrecht, J; Bryant, B; Lundström, JN

    2011-01-01

    The intranasal trigeminal system is a third chemical sense in addition to olfaction and gustation. As opposed to smell and taste, we still lack knowledge on the relationship between receptor binding and perception for the trigeminal system. We therefore investigated the sensitivity of the intranasal trigeminal system towards agonists of the trigeminal receptors TRPM8 and TRPA1 by assessing subjects’ ability to identify which nostril has been stimulated in a monorhinal stimulation design. We summed the number of correct identifications resulting in a lateralization score. Stimuli were menthol (activating TRPM8 receptors), eucalyptol (TRPM8), mustard oil (TRPA1) and two mixtures thereof (menthol/eucalyptol and menthol/mustard oil). In addition, we examined the relationship between intensity and lateralization scores and investigated whether intensity evaluation and lateralization scores of the mixtures show additive effects. All stimuli were correctly lateralized significantly above chance. Across subjects the lateralization scores for single compounds activating the same receptor showed a stronger correlation than stimuli activating different receptors. Although single compounds were isointense, the mixture of menthol and eucalyptol (activating only TRPM8) was perceived as weaker and was lateralized less accurately than the mixture of menthol and mustard oil (activating both TRPM8 and TRPA1) suggesting suppression effects in the former mixture. In conclusion, sensitivity of different subpopulations of trigeminal sensory neurons seems to be related, but only to a certain degree. The large coherence in sensitivity between various intranasal trigeminal stimuli suggests that measuring sensitivity to one single trigeminal chemical stimulus may be sufficient to generally assess the trigeminal system’s chemosensitivity. Further, for stimuli activating the same receptor a mixture suppression effect appears to occur similar to that observed in the other chemosensory

  5. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3′-OH of the 2′-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  6. A unified solution to the small scale problems of the ΛCDM model II: introducing parent-satellite interaction

    SciTech Connect

    Popolo, A. Del; Delliou, M. Le E-mail: delliou@ift.unesp.br

    2014-12-01

    We continue the study of the impact of baryon physics on the small scale problems of the ΛCDM model, based on a semi-analytical model (Del Popolo, 2009). With such model, we show how the cusp/core, missing satellite (MSP), Too Big to Fail (TBTF) problems and the angular momentum catastrophe can be reconciled with observations, adding parent-satellite interaction. Such interaction between dark matter (DM) and baryons through dynamical friction (DF) can sufficiently flatten the inner cusp of the density profiles to solve the cusp/core problem. Combining, in our model, a Zolotov et al. (2012)-like correction, similarly to Brooks et al. (2013), and effects of UV heating and tidal stripping, the number of massive, luminous satellites, as seen in the Via Lactea 2 (VL2) subhaloes, is in agreement with the numbers observed in the MW, thus resolving the MSP and TBTF problems. The model also produces a distribution of the angular spin parameter and angular momentum in agreement with observations of the dwarfs studied by van den Bosch, Burkert, and Swaters (2001)

  7. Exact analytical solution of the linear structure growth rate in {Lambda}CDM cosmology and its cosmological applications

    SciTech Connect

    Zhang Pengjie

    2011-03-15

    We derive the exact analytical solution of the linear structure growth rate in {Lambda}CDM cosmology with flat or curved geometry, under the Newtonian gauge. Unlike the well known solution under the Newtonian limit [D. J. Heath, Mon. Not. R. Astron. Soc. 179, 351 (1977)], our solution takes all general relativistic corrections into account and is hence valid at both the sub- and superhorizon scales. With this exact solution, we evaluate cosmological impacts induced by these relativistic corrections. (1) General relativistic corrections alter the density growth from z=100 to z=0 by 10% at k=0.01 h/Mpc and the impact becomes stronger toward larger scales. We caution the readers that the overdensity is not gauge invariant and the above statement is restrained to the Newtonian gauge. (2) Relativistic corrections introduce a k{sup -2} scale dependence in the density fluctuation. It mimics a primordial non-Gaussianity of the local type with f{sub NL}{sup local{approx}}1. This systematical error may become non-negligible for future all sky deep galaxy surveys. (3) Cosmological simulations with box size greater than 1 Gpc are also affected by these relativistic corrections. We provide a postprocessing recipe to correct for these effects. (4) These relativistic corrections affect the redshift distortion. However, at redshifts and scales relevant to redshift distortion measurements, such effect is negligible.

  8. A Tale of Two Sites: Lessons on Leadership from the Implementation of a Long-term Care Delivery Model (CDM) in Western Canada

    PubMed Central

    Cloutier, Denise; Cox, Amy; Kampen, Ruth; Kobayashi, Karen; Cook, Heather; Taylor, Deanne; Gaspard, Gina

    2016-01-01

    Residential, long-term care serves vulnerable older adults in a facility-based environment. A new care delivery model (CDM) designed to promote more equitable care for residents was implemented in a health region in Western Canada. Leaders and managers faced challenges in implementing this model alongside other concurrent changes. This paper explores the question: How did leadership style influence team functioning with the implementation of the CDM? Qualitative data from interviews with leadership personnel (directors and managers, residential care coordinators and clinical nurse educators), and direct care staff (registered nurses, licensed practical nurses, health care aides, and allied health therapists), working in two different facilities comprise the main sources of data for this study. The findings reveal that leaders with a servant leadership style were better able to create and sustain the conditions to support successful model implementation and higher team functioning, compared to a facility in which the leadership style was less inclusive and proactive, and more resistant to the change. Consequently, staff at the second facility experienced a greater sense of overload with the implementation of the CDM. This study concludes that strong leadership is key to facilitating team work and job satisfaction in a context of change. PMID:27417591

  9. A Tale of Two Sites: Lessons on Leadership from the Implementation of a Long-term Care Delivery Model (CDM) in Western Canada.

    PubMed

    Cloutier, Denise; Cox, Amy; Kampen, Ruth; Kobayashi, Karen; Cook, Heather; Taylor, Deanne; Gaspard, Gina

    2016-01-01

    Residential, long-term care serves vulnerable older adults in a facility-based environment. A new care delivery model (CDM) designed to promote more equitable care for residents was implemented in a health region in Western Canada. Leaders and managers faced challenges in implementing this model alongside other concurrent changes. This paper explores the question: How did leadership style influence team functioning with the implementation of the CDM? Qualitative data from interviews with leadership personnel (directors and managers, residential care coordinators and clinical nurse educators), and direct care staff (registered nurses, licensed practical nurses, health care aides, and allied health therapists), working in two different facilities comprise the main sources of data for this study. The findings reveal that leaders with a servant leadership style were better able to create and sustain the conditions to support successful model implementation and higher team functioning, compared to a facility in which the leadership style was less inclusive and proactive, and more resistant to the change. Consequently, staff at the second facility experienced a greater sense of overload with the implementation of the CDM. This study concludes that strong leadership is key to facilitating team work and job satisfaction in a context of change. PMID:27417591

  10. Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist

    PubMed Central

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg−1), unmasked etorphine (3 mg·kg−1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg−1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg−1) and diazepam (1 mg·kg−1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles

  11. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard

    2012-01-01

    Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6 weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further

  12. Agonists and antagonists for P2 receptors

    PubMed Central

    Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman

    2015-01-01

    Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

  13. Honokiol: A non-adipogenic PPARγ agonist from nature☆

    PubMed Central

    Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.

    2013-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators. Methods We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. Results The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. PMID:23811337

  14. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  15. Radiation therapy generates platelet-activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.

    2016-01-01

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  16. Radiation therapy generates platelet-activating factor agonists.

    PubMed

    Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan; Murphy, Robert C; Konger, Raymond L; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F; Travers, Jeffrey B

    2016-04-12

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  17. Simulated ΛCDM analogues of the thin Plane of Satellites around the Andromeda galaxy are not kinematically coherent structures

    NASA Astrophysics Data System (ADS)

    Buck, Tobias; Dutton, Aaron A.; Macciò, Andrea V.

    2016-05-01

    A large fraction of the dwarf satellites orbiting the Andromeda galaxy are surprisingly aligned in a thin, extended and apparently kinematically coherent planar structure. Such a structure is not easily found in simulations based on the Cold Dark Matter model (ΛCDM). Using 21 high resolution cosmological simulations we analyse the kinematics of planes of satellites similar to the one around Andromeda. We find good agreement when co-rotation is characterized by the line-of-sight velocity. At the same time, when co-rotation is inferred by the angular momenta of the satellites, the planes are in agreement with the plane around our Galaxy. We find such planes to be common in our high concentration haloes. The number of co-rotating satellites obtained from the sign of the line-of-sight velocity shows large variations depending on the viewing angle and is consistent with that obtained from a sample with random velocities. We find that the clustering of angular momentum vectors of the satellites in the plane is a better measure of the kinematic coherence. Thus we conclude that the line-of-sight velocity is not well suited as a proxy for the kinematical coherence of the plane. Analysis of the kinematics of our planes shows a fraction of ˜30% chance aligned satellites. Tracking the satellites in the plane back in time reveals that these planes are a transient feature and not kinematically coherent as would appear at first sight. Thus we expect some of the satellites in the plane around Andromeda to have high velocities perpendicular to the plane.

  18. ΛCDM Halo Models of Galaxy Clustering and Evolution in the PRIMUS Survey at 0

    NASA Astrophysics Data System (ADS)

    Skibba, Ramin A.; Coil, Alison L.; Mendez, Alexander; Blanton, Michael R.; Eisenstein, Daniel; Primus

    2015-01-01

    We utilize ΛCDM halo occupation models of galaxy clustering to investigate the evolving stellar mass and star formation dependent clustering of galaxies in the PRIsm MUlti-object Survey (PRIMUS) from redshifts of z=0.2 to z=1. These clustering measurements provide new constraints on the spatial distribution of galaxies in the 'cosmic web' and on the connections between dark matter halo properties and galaxy properties in the context of the evolving large-scale structure of the universe. Using an analytic model and mock galaxy catalogs, we find a strong correlation between galaxy stellar mass and dark matter halo mass over a wide range of masses, consistent with previous results. However, the stellar-to-halo mass relation (SHMR) and the mass scale where star formation efficiency reaches a maximum appear to evolve more strongly than other models in the literature. Our halo mass constraints obtained from modeling clustering and the stellar mass function are self-consistent only when the COSMOS field, which has relatively strong clustering, is excluded, thus highlighting the importance of 'cosmic variance' effects. We find that the fraction of satellite galaxies in haloes of a given mass increases at higher redshift such that the M1/Mmin ratio decreases from ≈20 to ≈12 at z~1. Considering the evolution of the subhalo mass function, this trend has implications for relations between satellite galaxies and halo substructures and for the growth of intracluster mass. Finally, based on the clustering of star-forming and quiescent galaxies, we argue that the efficiency of star formation quenching of central galaxies evolves significantly over the last eight billion years of cosmic time.

  19. Simulated ΛCDM analogues of the thin plane of satellites around the Andromeda galaxy are not kinematically coherent structures

    NASA Astrophysics Data System (ADS)

    Buck, Tobias; Dutton, Aaron A.; Macciò, Andrea V.

    2016-08-01

    A large fraction of the dwarf satellites orbiting the Andromeda galaxy are surprisingly aligned in a thin, extended and apparently kinematically coherent planar structure. Such a structure is not easily found in simulations based on the cold dark matter model (ΛCDM). Using 21 high-resolution cosmological simulations, we analyse the kinematics of planes of satellites similar to the one around Andromeda. We find good agreement when co-rotation is characterized by the line-of-sight velocity. At the same time, when co-rotation is inferred by the angular momenta of the satellites, the planes are in agreement with the plane around our Galaxy. We find such planes to be common in our high-concentration haloes. The number of co-rotating satellites obtained from the sign of the line-of-sight velocity shows large variations depending on the viewing angle and is consistent with that obtained from a sample with random velocities. We find that the clustering of angular momentum vectors of the satellites in the plane is a better measure of the kinematic coherence. Thus we conclude that the line-of-sight velocity is not well suited as a proxy for the kinematical coherence of the plane. Analysis of the kinematics of our planes shows a fraction of ˜30 per cent chance-aligned satellites. Tracking the satellites in the plane back in time reveals that these planes are a transient feature and not kinematically coherent as would appear at first sight. Thus we expect some of the satellites in the plane around Andromeda to have high velocities perpendicular to the plane.

  20. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed Central

    Langmead, Christopher J; Christopoulos, Arthur

    2013-01-01

    The concept of ‘super agonism’ has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. Linked Article This article is a commentary on Schrage et al., pp. 357–370 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12003 PMID:23441648

  1. Principles of agonist recognition in Cys-loop receptors

    PubMed Central

    Lynagh, Timothy; Pless, Stephan A.

    2014-01-01

    Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term “chemoreceptor” emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies, and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands. PMID:24795655

  2. Alpha-2 agonists as pain therapy in horses.

    PubMed

    Valverde, Alexander

    2010-12-01

    Alpha-2 agonists, such as xylazine, clonidine, romifidine, detomidine, medetomidine, and dexmedetomidine, are potent analgesic drugs that also induce physiologic and behavioral changes, such as hypertension, bradycardia, atrioventricular block, excessive sedation and ataxia, all of which can potentially limit their systemic use as analgesics in some clinical cases. The use of medetomidine and dexmetomidine has been introduced for equine anesthesia/analgesia, and although not approved in this species, their increased specificity for alpha-2 receptors may offer some potential advantages over the traditional alpha-2 agonists. Similarly, other routes of administration and benefits of alpha-2 agonists are recognized in the human and laboratory animal literature, which may prove useful in the equine patient if validated in the near future. This review presents this relevant information. PMID:21056297

  3. Agonist treatment in opioid use: advances and controversy.

    PubMed

    Viswanath, Biju; Chand, Prabhat; Benegal, Vivek; Murthy, Pratima

    2012-06-01

    Opioid dependence is a chronic relapsing condition which requires comprehensive care; pharmacological agents form the mainstay of its long term treatment. The two most popular approaches are the harm reduction method using agonists and the complete abstinence method using antagonists. Currently, particularly from the harm minimization perspective and the low feasibility of an abstinence based approach, there is an increasing trend toward agonist treatment. The use of buprenorphine has gained popularity in view of its safety profile and the availability of the buprenorphine-naloxone combination has made it popular as a take-home treatment. This review outlines the pharmacological advances and controversies in this area. PMID:22813654

  4. Insect Nicotinic Receptor Agonists as Flea Adulticides in Small Animals

    PubMed Central

    Vo, Dai Tan; Hsu, Walter H.; Martin, Richard J.

    2013-01-01

    Fleas are significant ectoparasites of small animals. They can be a severe irritant to animals and serve as a vector for a number of infectious diseases. In this article, we discuss the pharmacological characteristics of four insect nicotinic acetylcholine receptor (nAChR) agonists used as fleacides in dogs and cats, which include three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) and spinosad. Insect nAChR agonists are one of the most important new classes of insecticides, which are used to control sucking insects both on plants and on companion animals. These new compounds provide a new approach for practitioners to safely and effectively eliminate fleas. PMID:20646191

  5. Piperidine derivatives as nonprostanoid IP receptor agonists 2.

    PubMed

    Hayashi, Ryoji; Ito, Hiroaki; Ishigaki, Takeshi; Morita, Yasuhiro; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-06-15

    We searched for a strong and selective nonprostanoid IP agonist bearing piperidine and benzanilide moieties. Through optimization of substituents on the benzanilide moiety, the crucial part of the agonist, 43 (2-((1-(2-(N-(4-tolyl)benzo[d][1,3]dioxole-5-carboxamido)ethyl)piperidin-4-yl)oxy)acetic acid monohydrate monohydrochloride) was discovered and exhibited strong platelet aggregation inhibition (IC50=21nM) and 100-fold selectivity for IP receptor over other PG receptors. The systemic exposure level and bioavailability after oral administration of 43 were also good in dog. PMID:27133594

  6. Pyrrolo- and Pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

    PubMed Central

    Kumar, V.; Clark, M.J.; Traynor, J.R.; Lewis, J.W.; Husbands, S.M.

    2014-01-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  7. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    PubMed

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  8. Dynamical signatures of a ΛCDM-halo and the distribution of the baryons in M 33

    NASA Astrophysics Data System (ADS)

    Corbelli, Edvige; Thilker, David; Zibetti, Stefano; Giovanardi, Carlo; Salucci, Paolo

    2014-12-01

    Aims: We determine the mass distribution of stars, gas, and dark matter in M 33 to test cosmological models of galaxy formation and evolution. Methods: We map the neutral atomic gas content of M 33 using high resolution Very Large Array and Green Bank Telescope observations of the 21 cm HI line emission. A tilted ring model is fitted to the HI datacube to determine the varying spatial orientation of the extended gaseous disk and the rotation curve. We derive the stellar mass surface density map of M 33's optical disk via pixel-SED fitting methods based on population synthesis models that allow for positional changes in star formation history. Stellar and gas maps are used in the dynamical analysis of the rotation curve to constrain the dark halo properties. Results: The disk of M 33 warps from 8 kpc outward without substantial change of its inclination with respect to the line of sight; the line of nodes rotates clockwise toward the direction of M 31. Rotational velocities rise steeply with radius in the inner disk, reaching 100 km s-1 in 4 kpc, then the rotation curve becomes more perturbed and flatter with velocities as high as 120-130 km s-1 out to 2.7 R25. The stellar surface density map highlights a star-forming disk with a varying mass-to-light ratio. At larger radii, a dynamically relevant fraction of the baryons are in gaseous form. A dark matter halo with a Navarro-Frenk-White density profile, as predicted by hierarchical clustering and structure formation in a ΛCDM cosmology, provides the best fits to the rotation curve. Dark matter is relevant at all radii in shaping the rotation curve and the most likely dark halo has a concentration C ≃ 9.5 and a total mass of 4.3(±1.0) × 1011 M⊙. This imples a baryonic fraction of order 0.02 and the evolutionary history of this galaxy should therefore account for loss of a large fraction of its original baryonic content. Appendices are available in electronic form at http://www.aanda.org

  9. REPRODUCING THE STELLAR MASS/HALO MASS RELATION IN SIMULATED {Lambda}CDM GALAXIES: THEORY VERSUS OBSERVATIONAL ESTIMATES

    SciTech Connect

    Munshi, Ferah; Governato, F.; Loebman, S.; Quinn, T.; Brooks, A. M.; Christensen, C.; Shen, S.; Moster, B.; Wadsley, J.

    2013-03-20

    We examine the present-day total stellar-to-halo mass (SHM) ratio as a function of halo mass for a new sample of simulated field galaxies using fully cosmological, {Lambda}CDM, high-resolution SPH + N-body simulations. These simulations include an explicit treatment of metal line cooling, dust and self-shielding, H{sub 2}-based star formation (SF), and supernova-driven gas outflows. The 18 simulated halos have masses ranging from a few times 10{sup 8} to nearly 10{sup 12} M{sub Sun }. At z = 0, our simulated galaxies have a baryon content and morphology typical of field galaxies. Over a stellar mass range of 2.2 Multiplication-Sign 10{sup 3}-4.5 Multiplication-Sign 10{sup 10} M{sub Sun} we find extremely good agreement between the SHM ratio in simulations and the present-day predictions from the statistical abundance matching technique presented in Moster et al. This improvement over past simulations is due to a number systematic factors, each decreasing the SHM ratios: (1) gas outflows that reduce the overall SF efficiency but allow for the formation of a cold gas component; (2) estimating the stellar masses of simulated galaxies using artificial observations and photometric techniques similar to those used in observations; and (3) accounting for a systematic, up to 30% overestimate in total halo masses in DM-only simulations, due to the neglect of baryon loss over cosmic times. Our analysis suggests that stellar mass estimates based on photometric magnitudes can underestimate the contribution of old stellar populations to the total stellar mass, leading to stellar mass errors of up to 50% for individual galaxies. These results highlight that implementing a realistic high density threshold for SF considerably reduces the overall SF efficiency due to more effective feedback. However, we show that in order to reduce the perceived tension between the SF efficiency in galaxy formation models and in real galaxies, it is very important to use proper techniques to

  10. Synthetic RORγt Agonists Enhance Protective Immunity.

    PubMed

    Chang, Mi Ra; Dharmarajan, Venkatasubramanian; Doebelin, Christelle; Garcia-Ordonez, Ruben D; Novick, Scott J; Kuruvilla, Dana S; Kamenecka, Theodore M; Griffin, Patrick R

    2016-04-15

    The T cell specific RORγ isoform RORγt has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and TC17 cells, cells that have demonstrated antitumor efficacy. RORγt controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of RORγt have been shown to increase the basal activity of RORγt enhancing TH17 cell proliferation. Here, we show that activation of RORγt using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, a mechanism that should enhance antitumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment; thus such a molecule would provide a unique approach for the treatment of cancer. PMID:26785144

  11. Amphetamine- type reinforcement by dopaminergic agonists in the rat.

    PubMed

    Yokel, R A; Wise, R A

    1978-07-19

    Intravenous self-administration of d-amphetamine (0.25 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil. The dopaminergic agonists appear to suppress amphetamine intake in the same way as do 'free' amphetamine injections, by extending drug satiation in a given interresponse period. Clonidine, an alpha noradrenergic agonist, did not have similar effects. Apomorphine and piribedil did not increase 14C-amphetamine levels in rat brains, nor did they retard disappearance of 14C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism. Rats responding for amphetamine continued to respond for apomorphine or peribedil when the latter drugs were substituted for the former. Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil. The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine. These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties. PMID:98800

  12. Alkaloid delta agonist BW373U86 increases hypoxic tolerance.

    PubMed

    Bofetiado, D M; Mayfield, K P; D'Alecy, L G

    1996-06-01

    Activation of delta opioid receptors increases survival time during acute, lethal hypoxia in mice. delta Agonists therefore present a promising avenue for therapeutic application to reduce the morbidity and mortality associated with clinical hypoxia in settings such as drowning, head injury apnea, and complicated childbirths. However, most delta agonists now available are peptides, and may have limited clinical utility. In the present study, we evaluate the neuroprotective ability of an alkaloid delta agonist, BW373U86. Alkaloid compounds, due to increased stability and increased systemic distribution, may be more favorable for clinical use. We found that BW373U86, like the peptide delta agonist, DPDPE ([D-Pen2, D-Pen5]-enkephalin), increases survival time of mice during lethal hypoxia. The mechanism of neuroprotection induced by delta receptor activation appears to involve decreasing body temperature. Further, using selective opioid receptor antagonists, it appears that BW373U86 exerts these neuroprotective effects by acting at delta-opioid receptors. PMID:8638797

  13. The Agonistic Approach: Reframing Resistance in Qualitative Research

    ERIC Educational Resources Information Center

    Vitus, Kathrine

    2008-01-01

    The agonistic approach--aimed at embracing opposing perspectives as part of a qualitative research process and acknowledging that process as fundamentally political--sheds light on both the construction of and the resistance to research identities. This approach involves reflexively embedding interview situations into the ethnographic context as a…

  14. [Alpha-2 adrenoreceptor agonists in anaesthesia and intensive care medicine].

    PubMed

    Mavropoulos, G; Minguet, G; Brichant, J F

    2014-02-01

    Alpha-2 adrenoreceptor agonists have long been used in the treatment of arterial hypertension. However, in that indication they have progressively been replaced by antihypertensive drugs with a more interesting therapeutic profile. Nonetheless, pharmacological activation of alpha-2 adrenoreceptors leads to a variety of clinical effects that are of major interest for anaesthesia and intensive care practice. Indeed, the sedative and analgesic properties of alpha-2 adrenoreceptor agonists allow a reduction of hypnotic and opioid needs during general anaesthesia. In addition, they induce a down-regulation of the level of consciousness comparable to that of natural slow-wave sleep during post-anaesthesia and intensive care unit stay. These drugs may also prevent some deleterious effects of the sympathetic discharge in response to surgical stress. Furthermore, alpha-2 adrenoreceptor agonists are potent adjuncts for locoregional anaesthesia. In this article, we will summarize the most frequent applications of alpha-2 adrenoreceptor agonists in anaesthesia and intensive care medicine. We will focus on the clinical data available for the two most representative molecules of this pharmacological class: clonidine and dexmedetomidine. PMID:24683831

  15. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents. PMID:27194194

  16. Physician perceptions of GLP-1 receptor agonists in the UK.

    PubMed

    Matza, Louis S; Curtis, Sarah E; Jordan, Jessica B; Adetunji, Omolara; Martin, Sherry A; Boye, Kristina S

    2016-05-01

    Objectives Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetes for almost a decade, and new treatments in this class have recently been introduced. The purpose of this study was to examine perceptions of GLP-1 receptor agonists among physicians who treat patients with type 2 diabetes in the UK. Methods A total of 670 physicians (226 diabetes specialists; 444 general practice [GP] physicians) completed a survey in 2014. Results Almost all physicians had prescribed GLP-1 receptor agonists (95.4% total sample; 99.1% specialists; 93.5% GP), most frequently to patients whose glucose levels are not adequately controlled with oral medications (85.9% of physicians) and obese/overweight patients (83.7%). Physicians' most common reasons for prescribing a GLP-1 receptor agonist were: associated with weight loss (65.8%), good efficacy (55.7%), less hypoglycemia risk than insulin (55.2%), not associated with weight gain (34.5%), and better efficacy than oral medications (32.7%). Factors that most commonly cause hesitation when prescribing this class were: not considered first line therapy according to guidelines (56.9%), injectable administration (44.6%), cost (36.7%), gastrointestinal side effects (33.4%), and risk of pancreatitis (26.7%). Almost all specialists (99.1%) believed they had sufficient knowledge to prescribe a GLP-1 receptor agonist, compared with 76.1% of GPs. Conclusions Results highlight the widespread use of GLP-1 receptor agonists for treatment of type 2 diabetes in the UK. However, almost a quarter of GPs reported that they do not have enough knowledge to prescribe GLP-1s, suggesting a need for increased dissemination of information to targeted groups of physicians. Study limitations were that the generalizability of the clinician sample is unknown; survey questions required clinicians to select answers from multiple response options rather than generating the responses themselves; and responses to this survey conducted

  17. Activation of endplate nicotinic acetylcholine receptors by agonists.

    PubMed

    Auerbach, Anthony

    2015-10-15

    The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ∼300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by αY190) that behaves similarly at all sites and a coupled pair (led by γW55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of α(1) and one each of β, δ, and either γ (fetal) or ϵ (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at αδ and either αγ or αϵ subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C→O opening rate constant and C↔O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly

  18. Reconciling Dwarf Galaxies with ΛCDM Cosmology: Simulating a Realistic Population of Satellites around a Milky Way–mass Galaxy

    NASA Astrophysics Data System (ADS)

    Wetzel, Andrew R.; Hopkins, Philip F.; Kim, Ji-hoon; Faucher-Giguère, Claude-André; Kereš, Dušan; Quataert, Eliot

    2016-08-01

    Low-mass “dwarf” galaxies represent the most significant challenges to the cold dark matter (CDM) model of cosmological structure formation. Because these faint galaxies are (best) observed within the Local Group (LG) of the Milky Way (MW) and Andromeda (M31), understanding their formation in such an environment is critical. We present first results from the Latte Project: the Milky Way on Feedback in Realistic Environments (FIRE). This simulation models the formation of an MW-mass galaxy to z=0 within ΛCDM cosmology, including dark matter, gas, and stars at unprecedented resolution: baryon particle mass of 7070 {M}ȯ with gas kernel/softening that adapts down to 1 {pc} (with a median of 25{--}60 {pc} at z=0). Latte was simulated using the GIZMO code with a mesh-free method for accurate hydrodynamics and the FIRE-2 model for star formation and explicit feedback within a multi-phase interstellar medium. For the first time, Latte self-consistently resolves the spatial scales corresponding to half-light radii of dwarf galaxies that form around an MW-mass host down to {M}{star}≳ {10}5 {M}ȯ . Latte’s population of dwarf galaxies agrees with the LG across a broad range of properties: (1) distributions of stellar masses and stellar velocity dispersions (dynamical masses), including their joint relation; (2) the mass–metallicity relation; and (3) diverse range of star formation histories, including their mass dependence. Thus, Latte produces a realistic population of dwarf galaxies at {M}{star}≳ {10}5 {M}ȯ that does not suffer from the “missing satellites” or “too big to fail” problems of small-scale structure formation. We conclude that baryonic physics can reconcile observed dwarf galaxies with standard ΛCDM cosmology.

  19. Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists.

    PubMed

    Yang, Ting; Liu, Qian; Cheng, Yaobang; Cai, Wei; Ma, Yingli; Yang, Liuqing; Wu, Qianqian; Orband-Miller, Lisa A; Zhou, Ling; Xiang, Zhijun; Huxdorf, Melanie; Zhang, Wei; Zhang, Jing; Xiang, Jia-Ning; Leung, Stewart; Qiu, Yang; Zhong, Zhong; Elliott, John D; Lin, Xichen; Wang, Yonghui

    2014-01-01

    A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists. PMID:24900774

  20. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    PubMed

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  1. Sex differences in opioid antinociception: kappa and 'mixed action' agonists.

    PubMed

    Craft, R M; Bernal, S A

    2001-08-01

    A number of investigators have shown that male animals are more sensitive than females to the antinociceptive effects of mu-opioid agonists. The present study was conducted to examine sex differences in opioid antinociception in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu-receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine, (-)-bremazocine, (-)-pentazocine, butorphanol and nalbuphine on the 50 or 54 degrees C hotplate and warm water tail withdrawal assays; spontaneous locomotor activity was measured 32-52 min post-injection in the same rats. On the hotplate assay, only butorphanol (54 degrees C) and nalbuphine (50 degrees C) were significantly more potent in males than females. On the tail withdrawal assay, all agonists were significantly more potent or efficacious in males than females at one or both temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses to drug (50 degrees C experiment). These results suggest that (1) sex differences in antinociceptive effects of opioids are not mu-receptor-dependent, as they may occur with opioids known to have significant kappa-receptor-mediated activity; (2) the mechanisms underlying sex differences in kappa-opioid antinociception may be primarily spinal rather than supraspinal; (3) sex differences in antinociceptive effects of opioid agonists are not secondary to sex differences in their sedative effects. PMID:11418226

  2. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore

    SciTech Connect

    Washburn, David G.; Hoang, Tram H.; Campobasso, Nino; Smallwood, Angela; Parks, Derek J.; Webb, Christine L.; Frank, Kelly A.; Nord, Melanie; Duraiswami, Chaya; Evans, Christopher; Jaye, Michael; Thompson, Scott K.

    2009-03-27

    A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXR{alpha} will be disclosed.

  3. Glucagon-Like Peptide-1 Receptor Agonists: Beta-Cell Protection or Exhaustion?

    PubMed

    van Raalte, Daniël H; Verchere, C Bruce

    2016-07-01

    Glucagon-like peptide (GLP)-1 receptor agonists enhance insulin secretion and may improve pancreatic islet cell function. However, GLP-1 receptor (GLP-1R) agonist treatment may have more complex, and sometimes deleterious, effects on beta cells. We discuss the concepts of beta cell protection versus exhaustion for different GLP-1R agonists based on recent data. PMID:27160799

  4. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

    PubMed

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J; Wolber, Gerhard; Mohr, Klaus

    2016-07-29

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site. PMID:27298318

  5. A Potent and Site-Selective Agonist of TRPA1.

    PubMed

    Takaya, Junichiro; Mio, Kazuhiro; Shiraishi, Takuya; Kurokawa, Tatsuki; Otsuka, Shinya; Mori, Yasuo; Uesugi, Motonari

    2015-12-23

    TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation. PMID:26630251

  6. β2-adrenoceptor agonists in the regulation of mitochondrial biogenesis

    PubMed Central

    Peterson, Yuri K.; Cameron, Robert B.; Wills, Lauren P.; Trager, Richard E.; Lindsey, Chris C.; Beeson, Craig C.; Schnellmann, Rick G.

    2014-01-01

    The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of β2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of β2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB. PMID:23954364

  7. A Human Platelet Calcium Calculator Trained by Pairwise Agonist Scanning

    PubMed Central

    Lee, Mei Yan; Diamond, Scott L.

    2015-01-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  8. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    PubMed Central

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor. Abbreviation: AEA arylethanolamine AII 2-(arylimino)imidazolidine AIO 2-(arylimino)oxazolidine AIT 2-(arylimino)thiazolidine APAT 2-(α-phenylethylamino)-2-thiazoline BPAT 2-(β-phenylethylamino)-2-thiazoline CAO 2-(3-chlorobenzylamino)-2-oxazoline DCAO 2-(3,5-dichlorobenzylamino)-2-oxazoline DET5 2-(2,6-diethylphenylimino)-5-methylthiazolidine DET6 2-(2,6-diethylphenylimino)thiazine EGTA ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid GFA genetic function approximation G/PLS genetic partial least squares IND 2-aminomethyl-2-indanol LAH lithium aluminum hydride MCSG maximum common subgroup MCT6 2-(2-methyl-4-chlorophenylimino)thiazine OA octopamine PLS partial least squares QSAR quantitative structure-activity relationship SBAT 2-(substituted benzylamino)-2-thiazoline SD the sum of squared deviations of the dependent variable values from their mean SPIT 3-(substituted phenyl)imidazolidine-2-thione THI 2-amino-1-(2-thiazoyl)ethanol TMS tetramethyl silane PMID:15841226

  9. A human platelet calcium calculator trained by pairwise agonist scanning.

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  10. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K.

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  11. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    PubMed

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline. PMID:20030735

  12. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    PubMed Central

    Keane, Fergus; Navin, Patrick; Brett, Francesca; Dennedy, Michael C

    2016-01-01

    Summary Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH) agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour. Learning points While non-functioning gonadotropinomas represent the most common form of pituitary macroadenoma, functioning gonadotropinomas are exceedingly rare. Acute tumour enlargement, with potential pituitary apoplexy, is a rare but important adverse effect arising from GNRH agonist therapy in the presence of both functioning and non-functioning pituitary gonadotropinomas. GNRH antagonist therapy represents an alternative treatment option for patients with hormonal therapy-requiring prostate cancer, who also have diagnosed with a pituitary gonadotropinoma. PMID:27284452

  13. Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1.

    PubMed

    Aliouane, Lucie; Chao, Sovy; Brizuela, Leyre; Pfund, Emmanuel; Cuvillier, Olivier; Jean, Ludovic; Renard, Pierre-Yves; Lequeux, Thierry

    2014-09-01

    The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported. PMID:25047939

  14. Newspapers and newspaper ink contain agonists for the ah receptor.

    PubMed

    Bohonowych, Jessica E S; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T; Denison, Michael S

    2008-04-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [(3)H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  15. Covalent agonists for studying G protein-coupled receptor activation

    PubMed Central

    Weichert, Dietmar; Kruse, Andrew C.; Manglik, Aashish; Hiller, Christine; Zhang, Cheng; Hübner, Harald; Kobilka, Brian K.; Gmeiner, Peter

    2014-01-01

    Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating Gs-, Gi-, and Gq-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β2-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis. PMID:25006259

  16. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    PubMed

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes. PMID:24038158

  17. Biased signaling: potential agonist and antagonist of PAR2.

    PubMed

    Kakarala, Kavita Kumari; Jamil, Kaiser

    2016-06-01

    Protease activated receptor 2 (PAR2) has emerged as one of the promising therapeutic targets to inhibit rapidly metastasizing breast cancer cells. However, its elusive molecular mechanism of activation and signaling has made it a difficult target for drug development. In this study, in silico methods were used to unfold PAR2 molecular mechanism of signaling based on the concept of GPCR receptor plasticity. Although, there are no conclusive evidences of the presence of specific endogenous ligands for PAR2, the efficacy of synthetic agonist and antagonist in PAR2 signaling has opened up the possibilities of ligand-mediated signaling. Furthermore, it has been proved that ligands specific for one GPCR can induce signaling in GPCRs belonging to other subfamilies. Therefore, the aim of this study was to identify potential agonists and antagonists from the GPCR ligand library (GLL), which may induce biased signaling in PAR2 using the concept of existence of multiple ligand-stabilized receptor conformations. The results of our in silico study suggest that PAR2 may show biased signaling mainly with agonists of serotonin type 1, β-adrenergic type 1,3 and antagonists of substance K (NK1), serotonin type 2, dopamine type 4, and thromboxane receptors. Further, this study also throws light on the putative ligand-specific conformations of PAR2. Thus, the results of this study provide structural insights to putative conformations of PAR2 and also gives initial clues to medicinal chemists for rational drug design targeting this challenging receptor. PMID:26295578

  18. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    PubMed

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  19. Cryptochinones from Cryptocarya chinensis act as farnesoid X receptor agonists.

    PubMed

    Lin, Hsiang-Ru; Chou, Tsung-Hsien; Huang, Din-Wen; Chen, Ih-Sheng

    2014-09-01

    Cryptochinones A-D are tetrahydroflavanones isolated from the leaves of Cryptocarya chinensis, an evergreen tree whose extracts are believed to have a variety of health benefits. The origin of their possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and for hyperglycemia. We studied whether cryptochinones A-D, which are structurally similar to known FXR ligands, may act at this target. Indeed, in mammalian one-hybrid and transient transfection reporter assays, cryptochinones A-D transactivated FXR to modulate promoter action including GAL4, SHP, CYP7A1, and PLTP promoters in dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid (CDCA), an endogenous FXR agonist. Through molecular modeling docking studies we evaluated their ability to bind to the FXR ligand binding pocket. Our results indicate that cryptochinones A-D can behave as FXR agonists. PMID:25127166

  20. Dopamine-deficient mice are hypersensitive to dopamine receptor agonists.

    PubMed

    Kim, D S; Szczypka, M S; Palmiter, R D

    2000-06-15

    Dopamine-deficient (DA-/-) mice were created by targeted inactivation of the tyrosine hydroxylase gene in dopaminergic neurons. The locomotor activity response of these mutants to dopamine D1 or D2 receptor agonists and l-3,4-dihydroxyphenylalanine (l-DOPA) was 3- to 13-fold greater than the response elicited from wild-type mice. The enhanced sensitivity of DA-/- mice to agonists was independent of changes in steady-state levels of dopamine receptors and the presynaptic dopamine transporter as measured by ligand binding. The acute behavioral response of DA-/- mice to a dopamine D1 receptor agonist was correlated with c-fos induction in the striatum, a brain nucleus that receives dense dopaminergic input. Chronic replacement of dopamine to DA-/- mice by repeated l-DOPA administration over 4 d relieved the hypersensitivity of DA-/- mutants in terms of induction of both locomotion and striatal c-fos expression. The results suggest that the chronic presence of dopaminergic neurotransmission is required to dampen the intracellular signaling response of striatal neurons. PMID:10844009

  1. Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer

    PubMed Central

    Shukla, Nikunj M.; Salunke, Deepak B.; Balakrishna, Rajalakshmi; Mutz, Cole A.; Malladi, Subbalakshmi S.; David, Sunil A.

    2012-01-01

    Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen. PMID:22952720

  2. Emerging strategies for exploiting cannabinoid receptor agonists as medicines

    PubMed Central

    Pertwee, Roger G

    2009-01-01

    Medicines that activate cannabinoid CB1 and CB2 receptor are already in the clinic. These are Cesamet® (nabilone), Marinol® (dronabinol; Δ9-tetrahydrocannabinol) and Sativex® (Δ9-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol® can also be prescribed to stimulate appetite, while Sativex® is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB2 receptors; or (v) ‘multi-targeting’. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  3. Highly selective agonists for substance P receptor subtypes.

    PubMed Central

    Wormser, U; Laufer, R; Hart, Y; Chorev, M; Gilon, C; Selinger, Z

    1986-01-01

    The existence of a third tachykinin receptor (SP-N) in the mammalian nervous system was demonstrated by development of highly selective agonists. Systematic N-methylation of individual peptide bonds in the C-terminal hexapeptide of substance P gave rise to agonists which specifically act on different receptor subtypes. The most selective analog of this series, succinyl-[Asp6,Me-Phe8]SP6-11, elicits half-maximal contraction of the guinea pig ileum through the neuronal SP-N receptor at a concentration of 0.5 nM. At least 60,000-fold higher concentrations of this peptide are required to stimulate the other two tachykinin receptors (SP-P and SP-E). The action of selective SP-N agonists in the guinea pig ileum is antagonized by opioid peptides, suggesting a functional counteraction between opiate and SP-N receptors. These results indicate that the tachykinin receptors are distinct entities which may mediate different physiological functions. PMID:2431898

  4. Suppression of atherosclerosis by synthetic REV-ERB agonist

    SciTech Connect

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  5. Development of specific dopamine D-1 agonists and antagonists

    SciTech Connect

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo(a,d)cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo(1,2)cyclohepta(3,4,5d,e)isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC{sub 50} of compound 11 for displacement of {sup 3}H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of {sup 3}H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor.

  6. 2-Triazole-Substituted Adenosines: A New Class of Selective A3 Adenosine Receptor Agonists, Partial Agonists, and Antagonists

    PubMed Central

    Cosyn, Liesbet; Palaniappan, Krishnan K.; Kim, Soo-Kyung; Duong, Heng T.; Gao, Zhan-Guo; Jacobson, Kenneth A.; Van Calenbergh, Serge

    2016-01-01

    “Click chemistry” was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (1–14). Binding affinity at the human A1, A2A, and A3ARs (adenosine receptors) and relative efficacy at the A3AR were determined. Some triazol-1-yl analogues showed A3AR affinity in the low nanomolar range, a high ratio of A3/A2A selectivity, and a moderate-to-high A3/A1 ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A3AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A3AR efficacy. Thus, several 5′-OH derivatives appeared to be selective A3AR antagonists, i.e., 10, with 260-fold binding selectivity in comparison to the A1AR and displaying a characteristic docking mode in an A3AR model. The corresponding 5′-ethyluronamide analogues generally showed increased A3AR affinity and behaved as full agonists, i.e., 17, with 910-fold A3/A1 selectivity. Thus, N6-substituted 2-(1,2,3-triazolyl)-adenosine analogues constitute a novel class of highly potent and selective nucleoside-based A3AR antagonists, partial agonists, and agonists. PMID:17149867

  7. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR.

    PubMed

    Huang, Wendong; Zhang, Jun; Wei, Ping; Schrader, William T; Moore, David D

    2004-10-01

    The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans. PMID:15272053

  8. Different serotonin receptor agonists have distinct effects on sound-evoked responses in inferior colliculus.

    PubMed

    Hurley, Laura M

    2006-11-01

    The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing. PMID:16870843

  9. The Kyoto protocol and payments for tropical forest: An interdisciplinary method for estimating carbon-offset supply and increasing the feasibility of a carbon market under the CDM

    USGS Publications Warehouse

    Pfaff, Alexander S.P.; Kerr, Suzi; Hughes, R. Flint; Liu, Shuguang; Sanchez-Azofeifa, G. Arturo; Schimel, David; Tosi, Joseph; Watson, Vicente

    2000-01-01

    Protecting tropical forests under the Clean Development Mechanism (CDM) could reduce the cost of emissions limitations set in Kyoto. However, while society must soon decide whether or not to use tropical forest-based offsets, evidence regarding tropical carbon sinks is sparse. This paper presents a general method for constructing an integrated model (based on detailed historical, remote sensing and field data) that can produce land-use and carbon baselines, predict carbon sequestration supply to a carbon-offsets market and also help to evaluate optimal market rules. Creating such integrated models requires close collaboration between social and natural scientists. Our project combines varied disciplinary expertise (in economics, ecology and geography) with local knowledge in order to create high-quality, empirically grounded, integrated models for Costa Rica.

  10. Halo Occupation Distributions of Moderate X-ray AGNs formed through Major and Minor Mergers in a Λ-CDM Cosmology

    NASA Astrophysics Data System (ADS)

    Altamirano-Dévora, L.; Miyaji T.; Aceves H.; Castro A.; Cañas R.; Tamayo F.

    2016-04-01

    Motivated by the shape of the halo occupation distribution (HOD) of X-ray selected AGNs in the COSMOS field recently inferred by Allevato et al., we investigated the HOD properties of moderate X-ray luminosity active galactic nuclei (mXAGNs) using a simple model based on the merging activity between dark matter halos (DMHs) in a ΛCDM cosmology. The HODs and number densities of the simulated mXAGNs at z=0.5, under the above scenarios were compared with the results of Allevato et al. We found that the simulated HODs of major and minor mergers, and the observed HODs of mXAGNs are consistent. Our main result is that minor mergers, contrary to what one might expect, can play an important role in the activity of mAGNs.

  11. SMALL-SCALE STRUCTURE IN THE SLOAN DIGITAL SKY SURVEY AND {Lambda}CDM: ISOLATED {approx}L{sub *} GALAXIES WITH BRIGHT SATELLITES

    SciTech Connect

    Tollerud, Erik J.; Boylan-Kolchin, Michael; Barton, Elizabeth J.; Bullock, James S.; Trinh, Christopher Q. E-mail: ebarton@uci.edu E-mail: bullock@uci.edu

    2011-09-01

    We use a volume-limited spectroscopic sample of isolated galaxies in the Sloan Digital Sky Survey to investigate the frequency and radial distribution of luminous (M{sub r} {approx}< -18.3) satellites like the Large Magellanic Cloud (LMC) around {approx}L{sub *} Milky Way (MW) analogs and compare our results object-by-object to {Lambda}CDM predictions based on abundance matching in simulations. We show that 12% of MW-like galaxies host an LMC-like satellite within 75 kpc (projected), and 42% within 250 kpc (projected). This implies {approx}10% have a satellite within the distance of the LMC, and {approx}40% of L{sub *} galaxies host a bright satellite within the virialized extent of their dark matter halos. Remarkably, the simulation reproduces the observed frequency, radial dependence, velocity distribution, and luminosity function of observed secondaries exceptionally well, suggesting that {Lambda}CDM provides an accurate reproduction of the observed universe to galaxies as faint as L {approx} 10{sup 9} L{sub sun} on {approx}50 kpc scales. When stacked, the observed projected pairwise velocity dispersion of these satellites is {sigma} {approx_equal} 160 km s{sup -1}, in agreement with abundance-matching expectations for their host halo masses. Finally, bright satellites around L{sub *} primaries are significantly redder than typical galaxies in their luminosity range, indicating that environmental quenching is operating within galaxy-size dark matter halos that typically contain only a single bright satellite. This redness trend is in stark contrast to the MW's LMC, which is unusually blue even for a field galaxy. We suggest that the LMC's discrepant color might be further evidence that it is undergoing a triggered star formation event upon first infall.

  12. Testing deviations from ΛCDM with growth rate measurements from six large-scale structure surveys at z = 0.06-1

    NASA Astrophysics Data System (ADS)

    Alam, Shadab; Ho, Shirley; Silvestri, Alessandra

    2016-03-01

    We use measurements from the Planck satellite mission and galaxy redshift surveys over the last decade to test three of the basic assumptions of the standard model of cosmology, ΛCDM (Λ cold dark matter): the spatial curvature of the universe, the nature of dark energy and the laws of gravity on large scales. We obtain improved constraints on several scenarios that violate one or more of these assumptions. We measure w0 = -0.94 ± 0.17 (18 per cent measurement) and 1 + wa = 1.16 ± 0.36 (31 per cent measurement) for models with a time-dependent equation of state, which is an improvement over current best constraints. In the context of modified gravity, we consider popular scalar-tensor models as well as a parametrization of the growth factor. In the case of one-parameter f(R) gravity models with a ΛCDM background, we constrain B0 < 1.36 × 10-5 (1σ C.L.), which is an improvement by a factor of 4 on the current best. We provide the very first constraint on the coupling parameters of general scalar-tensor theory and stringent constraint on the only free coupling parameter of Chameleon models. We also derive constraints on extended Chameleon models, improving the constraint on the coupling by a factor of 6 on the current best. The constraints on coupling parameter for Chameleon model rule out the value of β1 = 4/3 required for f(R) gravity. We also measure γ = 0.612 ± 0.072 (11.7 per cent measurement) for growth index parametrization. We improve all the current constraints by combining results from various galaxy redshift surveys in a coherent way, which includes a careful treatment of scale dependence introduced by modified gravity.

  13. Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders.

    PubMed

    Geoffroy, Pierre Alexis; Etain, Bruno; Franchi, Jean-Arthur Micoulaud; Bellivier, Frank; Ritter, Philipp

    2015-01-01

    Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD. PMID:26088111

  14. Comparative endpoint sensitivity of in vitro estrogen agonist assays.

    PubMed

    Dreier, David A; Connors, Kristin A; Brooks, Bryan W

    2015-07-01

    Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less

  15. Pharmacological properties of acid N-thiazolylamide FFA2 agonists

    PubMed Central

    Brown, Andrew J; Tsoulou, Christina; Ward, Emma; Gower, Elaine; Bhudia, Nisha; Chowdhury, Forhad; Dean, Tony W; Faucher, Nicolas; Gangar, Akanksha; Dowell, Simon J

    2015-01-01

    FFA2 is a receptor for short-chain fatty acids. Propionate (C3) and 4-chloro-α-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide (4-CMTB), the prototypical synthetic FFA2 agonist, evoke calcium mobilization in neutrophils and inhibit lipolysis in adipocytes via this G-protein-coupled receptor. 4-CMTB contains an N-thiazolylamide motif but no acid group, and 4-CMTB and C3 bind to different sites on FFA2 and show allosteric cooperativity. Recently, FFA2 agonists have been described that contain both N-thiazolylamide and carboxylate groups, reminiscent of bitopic ligands. These are thought to engage the carboxylate-binding site on FFA2, but preliminary evidence suggests they do not bind to the same site as 4-CMTB even though both contain N-thiazolylamide. Here, we describe the characterization of four FFA2 ligands containing both N-thiazolylamide and carboxylate. (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid (compound 14) exhibits allosteric agonism with 4-CMTB but not C3. Three other compounds agonize FFA2 in [35S]GTPγS-incorporation or cAMP assays but behave as inverse agonists in yeast-based gene-reporter assays, showing orthosteric antagonism of C3 responses but allosteric antagonism of 4-CMTB responses. Thus, the bitopic-like FFA2 ligands engage the orthosteric site but do not compete at the site of 4-CMTB binding on an FFA2 receptor molecule. Compound 14 activates FFA2 on human neutrophils and mouse adipocytes, but appears not to inhibit lipolysis upon treatment of human primary adipocytes in spite of the presence of a functional FFA2 receptor in these cells. Hence, these new ligands may reveal differences in coupling of FFA2 between human and rodent adipose tissues. PMID:26236484

  16. Defining Nicotinic Agonist Binding Surfaces through Photoaffinity Labeling†

    PubMed Central

    Tomizawa, Motohiro; Maltby, David; Medzihradszky, Katalin F.; Zhang, Nanjing; Durkin, Kathleen A.; Presley, Jack; Talley, Todd T.; Taylor, Palmer; Burlingame, Alma L.; Casida, John E.

    2016-01-01

    Nicotinic acetylcholine (ACh) receptor (nAChR) agonists are potential therapeutic agents for neurological dysfunction. In the present study, the homopentameric mollusk ACh binding protein (AChBP), used as a surrogate for the extracellular ligand-binding domain of the nAChR, was specifically derivatized by the highly potent agonist azidoepibatidine (AzEPI) prepared as a photoaffinity probe and radioligand. One EPI-nitrene photoactivated molecule was incorporated in each subunit interface binding site based on analysis of the intact derivatized protein. Tryptic fragments of the modified AChBP were analyzed by collision-induced dissociation and Edman sequencing of radiolabeled peptides. Each specific EPI-nitrene-modified site involved either Tyr195 of loop C on the principal or (+)-face or Met116 of loop E on the complementary or (−)-face. The two derivatization sites were observed in similar frequency, providing evidence of the reactivity of the azido/nitrene probe substituent and close proximity to both residues. [3H]AzEPI binds to the α4β2 nAChR at a single high-affinity site and photoaffinity-labels only the α4 subunit, presumably modifying Tyr225 spatially corresponding to Tyr195 of AChBP. Phe137 of the β2 nAChR subunit, equivalent to Met116 of AChBP, conceivably lacks sufficient reactivity with the nitrene generated from the probe. The present photoaffinity labeling in a physiologically relevant condition combined with the crystal structure of AChBP allows development of precise structural models for the AzEPI interactions with AChBP and α4β2 nAChR. These findings enabled us to use AChBP as a structural surrogate to define the nAChR agonist site. PMID:17614369

  17. AGONISTIC AUTOANTIBODIES AS VASODILATORS IN ORTHOSTATIC HYPOTENSION: A NEW MECHANISM

    PubMed Central

    Li, Hongliang; Kem, David C.; Reim, Sean; Khan, Muneer; Vanderlinde-Wood, Megan; Zillner, Caitlin; Collier, Daniel; Liles, Campbell; Hill, Michael A.; Cunningham, Madeleine W.; Aston, Christopher E.; Yu, Xichun

    2012-01-01

    Agonistic autoantibodies to the β-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to β2-adrenergic and/or M3 muscarinic receptors by enzyme-linked immunosorbent assay in 75% (15 of 20) of patients with significant orthostatic hypotension. Purified serum IgG from all 20 patients and 10 healthy control subjects were examined in a receptor-transfected cell-based cAMP assay for β2 receptor activation and β-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of β2 and M3 receptors in the patient group compared to controls. A dose response was observed for both IgG activation of β2 and M3 receptors and inhibition of their activation with the non-selective β blocker propranolol and muscarinic blocker atropine. The antibody effects on β2 and/or M3 (via production of nitric oxide) receptor-mediated vasodilation were studied in a rat cremaster resistance arteriole assay. Infusion of IgG from patients with documented β2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the β blocker propranolol and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester partially inhibited IgG-induced vasodilation (% of maximal dilatory response: from 57.7±10.4 to 35.3±4.6 and 24.3±5.8, respectively, p<0.01, n=3), indicating antibody activation of vascular β2 and/or M3 receptors may contribute to systemic vasodilation. These data support the concept that circulating agonistic autoantibodies serve as vasodilators and may cause or exacerbate orthostatic hypotension. PMID:22215709

  18. Antinociceptive properties of selective MT(2) melatonin receptor partial agonists.

    PubMed

    López-Canul, Martha; Comai, Stefano; Domínguez-López, Sergio; Granados-Soto, Vinicio; Gobbi, Gabriella

    2015-10-01

    Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5-40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT2 partial agonists were blocked by the pre-treatment with the MT2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT2 melatonin receptor may be a novel target for analgesic drug development. PMID:26162699

  19. Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine.

    PubMed

    Simeon, D; Hollander, E; Stein, D J; DeCaria, C; Cohen, L J; Saoud, J B; Islam, N; Hwang, M

    1995-09-29

    Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization. PMID:8570768

  20. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    PubMed

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight. PMID:26198605

  1. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    NASA Technical Reports Server (NTRS)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  2. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter. PMID:26585147

  3. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    SciTech Connect

    Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  4. Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.

    PubMed

    Sheppeck, James E; Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Nirschl, David; Doweyko, Arthur M; Sack, Jack S; Corbett, Martin J; Malley, Mary F; Gougoutas, Jack Z; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Dodd, John H; Nadler, Steven G; Somerville, John E; Barrish, Joel C

    2013-10-01

    Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. PMID:23953070

  5. Site of action of a pentapeptide agonist at the glucagon-like peptide-1 receptor. Insight into a small molecule agonist-binding pocket

    PubMed Central

    Dong, Maoqing; Pinon, Delia I.; Miller, Laurence J.

    2011-01-01

    The development of small molecule agonists for class B G protein-coupled receptors (GPCRs) has been quite challenging. With proof-of-concept that exenatide, the parenterally administered peptide agonist of the glucagon-like peptide-1 (GLP1) receptor, is an effective treatment for patients with diabetes mellitus, the development of small molecule agonists could have substantial advantages. We previously reported a lead for small molecule GLP1 receptor agonist development representing the pentapeptide NRTFD. In this work, we have prepared an NRTFD derivative incorporating a photolabile benzoylphenylalanine and used it to define its site of action. This peptide probe was a full agonist with potency similar to NRTFD, which bound specifically and saturably to a single, distinct site within the GLP1 receptor. Peptide mapping using cyanogen bromide and endoproteinase Lys-C cleavage of labeled wild type and M397L mutant receptor constructs identified the site of covalent attachment of NRTFD within the third extracellular loop above the sixth transmembrane segment. This region is the same as that identified using an analogous photolabile probe based on secretin receptor sequences, and has been shown in mutagenesis studies to be important for natural agonist action of several members of this family. While these observations suggest that small molecule ligands can act at a site bordering the third extracellular loop to activate this class B GPCR, the relationship of this site to the site of action of the amino-terminal end of the natural agonist peptide is unclear. PMID:22079758

  6. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy

    PubMed Central

    Iribarren, Kristina; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Špíšek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-01-01

    ABSTRACT Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy. PMID:27141345

  7. Synthesis and biological activities of indolizine derivatives as alpha-7 nAChR agonists.

    PubMed

    Xue, Yu; Tang, Jingshu; Ma, Xiaozhuo; Li, Qing; Xie, Bingxue; Hao, Yuchen; Jin, Hongwei; Wang, Kewei; Zhang, Guisen; Zhang, Liangren; Zhang, Lihe

    2016-06-10

    Human α7 nicotinic acetylcholine receptor (nAChR) is a promising therapeutic target for the treatment of schizophrenia accompanied with cognitive impairment. Herein, we report the synthesis and agonistic activities of a series of indolizine derivatives targeting to α7 nAChR. The results show that all synthesized compounds have affinity to α7 nAChR and some give strong agonistic activity, particularly most active agonists show higher potency than control EVP-6124. The docking and structure-activity relationship studies provide insights to develop more potent novel α7 nAChR agonists. PMID:26994846

  8. Dopamine agonist-induced substance addiction: the next piece of the puzzle.

    PubMed

    Evans, Andrew

    2011-02-01

    Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor "off" periods. The recent recognition of a range of "behavioural addictions" that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions. PMID:20980151

  9. Sustained wash-resistant receptor activation responses of GPR119 agonists.

    PubMed

    Hothersall, J Daniel; Bussey, Charlotte E; Brown, Alastair J; Scott, James S; Dale, Ian; Rawlins, Philip

    2015-09-01

    G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses. PMID:26101059

  10. Octopaminergic Modulation of Temporal Frequency Coding in an Identified Optic Flow-Processing Interneuron

    PubMed Central

    Longden, Kit D.; Krapp, Holger G.

    2010-01-01

    Flying generates predictably different patterns of optic flow compared with other locomotor states. A sensorimotor system tuned to rapid responses and a high bandwidth of optic flow would help the animal to avoid wasting energy through imprecise motor action. However, neural processing that covers a higher input bandwidth itself comes at higher energetic costs which would be a poor investment when the animal was not flying. How does the blowfly adjust the dynamic range of its optic flow-processing neurons to the locomotor state? Octopamine (OA) is a biogenic amine central to the initiation and maintenance of flight in insects. We used an OA agonist chlordimeform (CDM) to simulate the widespread OA release during flight and recorded the effects on the temporal frequency coding of the H2 cell. This cell is a visual interneuron known to be involved in flight stabilization reflexes. The application of CDM resulted in (i) an increase in the cell's spontaneous activity, expanding the inhibitory signaling range (ii) an initial response gain to moving gratings (20–60 ms post-stimulus) that depended on the temporal frequency of the grating and (iii) a reduction in the rate and magnitude of motion adaptation that was also temporal frequency-dependent. To our knowledge, this is the first demonstration that the application of a neuromodulator can induce velocity-dependent alterations in the gain of a wide-field optic flow-processing neuron. The observed changes in the cell's response properties resulted in a 33% increase of the cell's information rate when encoding random changes in temporal frequency of the stimulus. The increased signaling range and more rapid, longer lasting responses employed more spikes to encode each bit, and so consumed a greater amount of energy. It appears that for the fly investing more energy in sensory processing during flight is more efficient than wasting energy on under-performing motor control. PMID:21152339

  11. Mapping the agonist binding site of the nicotinic acetylcholine receptor. Orientation requirements for activation by covalent agonist.

    PubMed

    Sullivan, D A; Cohen, J B

    2000-04-28

    To characterize the structural requirements for ligand orientation compatible with activation of the Torpedo nicotinic acetylcholine receptor (nAChR), we used Cys mutagenesis in conjunction with sulfhydryl-reactive reagents to tether primary or quaternary amines at defined positions within the agonist binding site of nAChRs containing mutant alpha- or gamma-subunits expressed in Xenopus oocytes. 4-(N-Maleimido)benzyltrimethylammonium and 2-aminoethylmethanethiosulfonate acted as irreversible antagonists when tethered at alphaY93C, alphaY198C, or gammaE57C, as well as at alphaN94C (2-aminoethylmethanethiosulfonate only). [2-(Trimethylammonium)-ethyl]-methanethiosulfonate (MTSET), which attaches thiocholine to binding site Cys, also acted as an irreversible antagonist when tethered at alphaY93C, alphaN94C, or gammaE57C. However, MTSET modification of alphaY198C resulted in prolonged activation of the nAChR not reversible by washing but inhibitable by subsequent exposure to non-competitive antagonists. Modification of alphaY198C (or any of the other positions tested) by [(trimethylammonium)methyl]methanethiosulfonate resulted only in irreversible inhibition, while modification of alphaY198C by [3-(trimethylammonium)propyl]methanethiosulfonate resulted in irreversible activation of nAChR, but at lower efficacy than by MTSET. Thus changing the length of the tethering arm by less than 1 A in either direction markedly effects the ability of the covalent trimethylammonium to activate the nAChR, and agonist activation depends on a very selective orientation of the quaternary ammonium within the agonist binding site. PMID:10777557

  12. Isothiouronium compounds as gamma-aminobutyric acid agonists.

    PubMed Central

    Allan, R. D.; Dickenson, H. W.; Hiern, B. P.; Johnston, G. A.; Kazlauskas, R.

    1986-01-01

    Analogues of gamma-aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea-pig ileum; [3H]-GABA and [3H]-diazepam binding to rat brain membranes; and GABA uptake and transamination. For the homologous series of omega-isothiouronium alkanoic acids, maximum GABA-mimetic activity was found at 3-[(aminoiminomethyl)thio]propanoic acid. Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites. Both isomers were moderately potent at inhibiting the uptake of [3H]-GABA into rat brain slices. Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites. PMID:3015310

  13. Cold Suppresses Agonist-induced Activation of TRPV1

    PubMed Central

    Chung, M.-K.; Wang, S.

    2011-01-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction. PMID:21666106

  14. Antidiabetic Actions of an Estrogen Receptor β Selective Agonist

    PubMed Central

    Alonso-Magdalena, Paloma; Ropero, Ana B.; García-Arévalo, Marta; Soriano, Sergi; Quesada, Iván; Muhammed, Sarheed J.; Salehi, Albert; Gustafsson, Jan-Ake; Nadal, Ángel

    2013-01-01

    The estrogen receptor β (ERβ) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERβ selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic β-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide–induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic β-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic β-cell mass. We conclude that ERβ agonists should be considered as new targets for the treatment of diabetes. PMID:23349481

  15. Anti-cancer flavonoids are mouse selective STING agonists

    PubMed Central

    Kim, Sujeong; Li, Lingyin; Maliga, Zoltan; Yin, Qian; Wu, Hao; Mitchison, Timothy J.

    2013-01-01

    The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice, but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other anti-tumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the anti-tumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy. PMID:23683494

  16. Aging changes agonist induced contractile responses in permeabilized rat bladder.

    PubMed

    Durlu-Kandilci, N Tugba; Denizalti, Merve; Sahin-Erdemli, Inci

    2015-08-01

    Aging alters bladder functions where a decrease in filling, storage and emptying is observed. These changes cause urinary incontinence, especially in women. The aim of this study is to examine how aging affects the intracellular calcium movements due to agonist-induced contractions in permeabilized female rat bladder. Urinary bladder isolated from young and old female Sprague-Dawley rats were used. Small detrusor strips were permeabilized with β-escin. The contractile responses induced with agonists were compared between young and old groups. Carbachol-induced contractions were decreased in permeabilized detrusor from old rats compared to young group. Heparin and ryanodine decreased carbachol-induced contractions in young rats where only heparin inhibited these contractions in olds. Caffeine-induced contractions but not inositol triphosphate (IP3)-induced contractions were decreased in old group compared to youngs. The cumulative calcium response curves (pCa 8-4) were also decreased in old rats. Carbachol-induced calcium sensitization responses did not alter by age where GTP-β-S and GF-109203X but not Y-27632 inhibited these responses. Carbachol-induced contractions decrease with aging in rat bladder detrusor. It can be postulated as IP3-induced calcium release (IICR) is primarily responsible for the contractions in older rats where the decrease in carbachol contractions in aging may be as a result of a decrease in calcium-induced calcium release (CICR), rather than carbachol-induced calcium sensitization. PMID:26153091

  17. A Sphingosine 1-phosphate receptor 2 selective allosteric agonist

    PubMed Central

    Satsu, Hideo; Schaeffer, Marie-Therese; Guerrero, Miguel; Saldana, Adrian; Eberhart, Christina; Hodder, Peter; Cayanan, Charmagne; Schürer, Stephan; Bhhatarai, Barun; Roberts, Ed; Rosen, Hugh; Brown, Steven J.

    2013-01-01

    Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. PMID:23849205

  18. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists. PMID:19832688

  19. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    SciTech Connect

    Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.

    1985-10-28

    The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with (/sup 3/H)-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT/sub 2/ antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT/sub 2/ type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures.

  20. Suppression of atherosclerosis by synthetic REV-ERB agonist.

    PubMed

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M; Solt, Laura A; Burris, Thomas P

    2015-05-01

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. PMID:25800870

  1. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID:24752777

  2. How does agonistic behaviour differ in albino and pigmented fish?

    PubMed Central

    Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  3. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

    Knight, John M.; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O.; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A.; Milner, Joshua D.; Zhang, Yuan; Mandal, Pijus K.; Luong, Amber; Kheradmand, Farrah

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  4. Cariprazine:New dopamine biased agonist for neuropsychiatric disorders.

    PubMed

    De Deurwaerdère, P

    2016-02-01

    Cariprazine (RGH-188, MP-214, Vraylar[TM]) is a new dopamine receptor ligand developed for the treatment of several neuropsychiatric diseases including schizophrenia and bipolar disorders. Cariprazine displays higher affinity at dopamine D3 receptors and a similar affinity at D2 and 5-HT2B receptors. At variance with some atypical antipsychotics, its affinity at 5-HT1A, 5-HT2A and histamine H1 receptors is modest compared with its three main targets. Cariprazine could correspond to a biased agonist at dopamine receptors, displaying either antagonist or partial agonist properties depending on the signaling pathways linked to D2/D3 receptors. The compound crosses the blood-brain barrier, as revealed by positron emission tomography and pharmacokinetic studies in various species. Two main metabolites result mainly from the activity of CYP34A and display properties similar to those of the parent drug. Behavioral data report that cariprazine is efficacious in animal models addressing positive, negative and cognitive symptoms of schizophrenia with no extrapyramidal side effects. In September 2015, the FDA approved the use of cariprazine for the treatment of schizophrenia and type I bipolar disorder. The efficacy of cariprazine in other neuropsychiatric diseases is currently being evaluated in preclinical and clinical studies. Side effects have been observed in humans, including extrapyramidal side effects and akathisia of mild to moderate intensity. PMID:27092339

  5. Long-Acting Beta Agonists Enhance Allergic Airway Disease.

    PubMed

    Knight, John M; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A; Milner, Joshua D; Zhang, Yuan; Mandal, Pijus K; Luong, Amber; Kheradmand, Farrah; McMurray, John S; Corry, David B

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  6. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification.

    PubMed

    Zaware, Pandurang; Shah, Shailesh R; Pingali, Harikishore; Makadia, Pankaj; Thube, Baban; Pola, Suresh; Patel, Darshit; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Jamili, Jeevankumar; Sairam, Kalapatapu V V M; Giri, Suresh; Patel, Lala; Patel, Harilal; Sudani, Hareshkumar; Patel, Hiren; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh

    2011-01-15

    A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders. PMID:21195611

  7. Impact of Efficacy at the μ-Opioid Receptor on Antinociceptive Effects of Combinations of μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

    PubMed Central

    Maguire, David R.

    2014-01-01

    Cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain. PMID:25194020

  8. 1,4-Benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonists.

    PubMed

    Sherrill, R G; Berman, J M; Birkemo, L; Croom, D K; Dezube, M; Ervin, G N; Grizzle, M K; James, M K; Johnson, M F; Queen, K L; Rimele, T J; Vanmiddlesworth, F; Sugg, E E

    2001-05-01

    A series of 1,4-benzodiazepines, N-1-substituted with an N-isopropyl-N-phenylacetamide moiety, was synthesized and screened for CCK-A agonist activity. In vitro agonist activity on isolated guinea pig gallbladder along with in vivo induction of satiety following intraperitoneal administration in a rat feeding assay was demonstrated. PMID:11354363

  9. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    PubMed

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics. PMID:26675887

  10. Functional desensitization of the β2 adrenoceptor is not dependent on agonist efficacy

    PubMed Central

    Rosethorne, Elizabeth M; Bradley, Michelle E; Kent, Toby C; Charlton, Steven J

    2015-01-01

    Chronic treatment with β2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure. The data show that upon repeat exposure, all agonists produced functional desensitization to the same degree and rate. In addition, β2 adrenoceptor internalization and β-arrestin-2 recruitment were monitored using β2·eGFP visualization and the PathHunter™ β-arrestin-2 assay, respectively. All agonists were capable of causing robust receptor internalization and β-arrestin-2 recruitment, the rate of which was influenced by agonist efficacy, as measured in those assays. In summary, although a relationship exists between agonist efficacy and the rate of both receptor internalization and β-arrestin-2 recruitment, there is no correlation between agonist efficacy and the rate or extent of functional desensitization. PMID:25692019

  11. Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms.

    PubMed

    Randáková, Alena; Dolejší, Eva; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; El-Fakahany, Esam E; Jakubík, Jan

    2015-07-01

    We mutated key amino acids of the human variant of the M1 muscarinic receptor that target ligand binding, receptor activation, and receptor-G protein interaction. We compared the effects of these mutations on the action of two atypical M1 functionally preferring agonists (N-desmethylclozapine and xanomeline) and two classical non-selective orthosteric agonists (carbachol and oxotremorine). Mutations of D105 in the orthosteric binding site and mutation of D99 located out of the orthosteric binding site decreased affinity of all tested agonists that was translated as a decrease in potency in accumulation of inositol phosphates and intracellular calcium mobilization. Mutation of D105 decreased the potency of the atypical agonist xanomeline more than that of the classical agonists carbachol and oxotremorine. Mutation of the residues involved in receptor activation (D71) and coupling to G-proteins (R123) completely abolished the functional responses to both classical and atypical agonists. Our data show that both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site. Furthermore, our data demonstrate a key role of D105 in xanomeline wash-resistant binding and persistent activation of hM1 by wash-resistant xanomeline. PMID:25882246

  12. Prolonging Survival of Corneal Transplantation by Selective Sphingosine-1-Phosphate Receptor 1 Agonist

    PubMed Central

    Gao, Min; Liu, Yong; Xiao, Yang; Han, Gencheng; Jia, Liang; Wang, Liqiang; Lei, Tian; Huang, Yifei

    2014-01-01

    Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1) selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P) receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival. PMID:25216235

  13. Hyperthermia induced by the dopamine D1 receptor agonist SK&F38393 in combination with the dopamine D2 receptor agonist talipexole in the rat.

    PubMed

    Nagashima, M; Yamada, K; Kimura, H; Matsumoto, S; Furukawa, T

    1992-12-01

    The present experiments were performed to investigate the effects of dopamine D1 receptor agonists given alone or in combination with dopamine D2 receptor agonists on body temperature in rats. The selective dopamine D1 receptor agonist, 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SK&F38393), produced hyperthermia. However, the dopamine D2 receptor agonist, B-HT 920 (talipexole), and the newly synthesized dopamine D2 receptor agonist, (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (SND 919), did not change the temperature. Interestingly, the SK&F38393-induced hyperthermia was enhanced by talipexole and SND 919. The drastic hyperthermia induced by combined administration of dopamine D1 and D2 receptor agonists was blocked by either the dopamine D1 receptor antagonist, SCH23390, or the dopamine D2 receptor antagonist, spiperone. On the other hand, treatment with prazosin, yohimbine, propranolol, scopolamine, or methysergide failed to affect the marked hyperthermia. The present results suggest that a functional link between dopamine D1 and D2 receptors may be synergistic in the regulation of body temperature and that concurrent stimulation of both dopamine D1 and D2 receptors thereby produces marked hyperthermia in the rat. PMID:1361996

  14. Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis

    PubMed Central

    Pitari, Giovanni M

    2013-01-01

    Agonists of the transmembrane intestinal receptor guanylyl cyclase C (GCC) have recently attracted interest as promising human therapeutics. Peptide ligands that can specifically induce GCC signaling in the intestine include endogenous hormones guanylin and uroguanylin, diarrheagenic bacterial enterotoxins (ST), and synthetic drugs linaclotide, plecanatide, and SP-333. These agonists bind to GCC at intestinal epithelial surfaces and activate the receptor’s intracellular catalytic domain, an event initiating discrete biological responses upon conversion of guanosine-5′-triphosphate to cyclic guanosine monophosphate. A principal action of GCC agonists in the colon is the promotion of mucosal homeostasis and its dependent barrier function. Herein, GCC agonists are being developed as new medications to treat inflammatory bowel diseases, pathological conditions characterized by mucosal barrier hyperpermeability, abnormal immune reactions, and chronic local inflammation. This review will present important concepts underlying the pharmacology and therapeutic utility of GCC agonists for patients with ulcerative colitis, one of the most prevalent inflammatory bowel disease disorders. PMID:23637522

  15. Voltage dependence of agonist effectiveness at the frog neuromuscular junction: resolution of a paradox.

    PubMed Central

    Dionne, V E; Stevens, C F

    1975-01-01

    1. End-plate currents produced by nerve-released acetylcholine and iontophoretically applied acetylcholine and carbachol have been recorded from voltage-clamped frog cutaneous pectoris neuromuscular junctions made visible with Nomarski differential interference contrast optics. 2. The effectiveness of agonists - that is, the end-plate conductance change produced by a given dose-has been determined as a function of post-junctional membrane potential. 3. As the post-junctional membrane potential is made more negative, nerve-released acetylcholine becomes less effective whereas iontophoretically-applied agonists become more effective. 4. This voltage dependence of agonist effectiveness is mediated neither by end-plate current iontophoresis of agonist into the cleft nor through electric field effects on the esterase. 5. Influences of membrane potential on the opening and closing of end-plate channel gates can account quantitatively for the voltage-dependent effectiveness of both nerve-released and iontophoretically applied agonist. PMID:1081139

  16. The link between non-ergot-derived dopamine agonists and heart failure: how strong is it?

    PubMed

    Lockett, Katrina; DeBacker, Danielle; Cauthon, Kimberly A B

    2015-03-01

    Dopamine agonists are commonly used as initial monotherapy and adjunct treatment for Parkinson's disease. However, the Food and Drug Administration recently linked pramipexole use with an increased risk of heart failure (HF). Several case-control studies demonstrate a possible increased risk of the development of HF in patients taking non-ergot-derived dopamine agonists compared with patients not taking dopamine agonists. In patients taking non-ergot-derived dopamine agonists, the studies associated the risk of increased HF with pramipexole. These studies did not find a possible increased risk with ropinirole, but to date no randomized, controlled trials have been conducted to directly compare ropinirole with pramipexole and the risk of HF. The mechanism by which HF occurs is unknown, but the development of edema after dopamine agonist use could increase the risk of HF. If patients with a history of cardiovascular disease or edema are prescribed pramipexole, additional monitoring for HF signs and symptoms is recommended. PMID:25760663

  17. [Is the LHRH Agonist Recommended for Fertility Preservation ?].

    PubMed

    Kimura, Kosei; Iwamoto, Mitsuhiko; Tanaka, Satoru; Watanabe, Toru; Aihara, Tomohiko; Sugimoto, Takeki; Miyara, Kyuichiro; Hayashi, Mitsuhiro; Kouno, Tsutomu; Baba, Shinichi; Kawashima, Hiroaki; Hashimoto, Naoki; Uchiyama, Kazuhisa

    2015-08-01

    The POEMS reportedan effect of goserelin for fertility preservation. The Clinical Practice Guideline for Breast Cancer by The Japanese Breast Cancer Society indicates that the use of the LHRH agonist (LHRHa) for preventing chemotherapy-induced early menopause is a grade C-1 recommendation, and its use for fertility preservation is a grade C-2 recommendation. Results from previous studies on the effects of LHRHa for fertility preservation have varied owing to differences in chemotherapy regimens, definitions of ovarian failure, and dosages of tamoxifen. In the POEMS, the primary endpoint of ovarian failure at 2 years was significantly lower, and the secondary endpoint of pregnancy outcomes was better in the combination group; however, precise interpretation is difficult because many cases were excluded. Currently, it is not necessary to revise The Clinical Practice Guideline; however, desirable results from future studies may allow the recommendation of a specific dosage of LHRHa for fertility preservation. PMID:26321722

  18. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity

    PubMed Central

    Crane, James; McGowan, Barbara

    2015-01-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  19. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist.

    PubMed

    Kühnen, Peter; Clément, Karine; Wiegand, Susanna; Blankenstein, Oliver; Gottesdiener, Keith; Martini, Lea L; Mai, Knut; Blume-Peytavi, Ulrike; Grüters, Annette; Krude, Heiko

    2016-07-21

    Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2). PMID:27468060

  20. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis

    PubMed Central

    Dietrich, Johannes W.; Landgrafe, Gabi; Fotiadou, Elisavet H.

    2012-01-01

    This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range. PMID:23365787

  1. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity.

    PubMed

    Crane, James; McGowan, Barbara

    2016-03-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  2. Saralasin and Sarile Are AT2 Receptor Agonists

    PubMed Central

    2014-01-01

    Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists. PMID:25313325

  3. Use of Thrombopoietin Receptor Agonists in Childhood Immune Thrombocytopenia

    PubMed Central

    Garzon, Angelica Maria; Mitchell, William Beau

    2015-01-01

    Most children with immune thrombocytopenia (ITP) will have spontaneous remission regardless of therapy, while about 20% will go on to have chronic ITP. In those children with chronic ITP who need treatment, standard therapies for acute ITP may have adverse effects that complicate their long-term use. Thus, alternative treatment options are needed for children with chronic ITP. Thrombopoietin receptor agonists (TPO-RA) have been shown to be safe and efficacious in adults with ITP, and represent a new treatment option for children with chronic ITP. One TPO-RA, eltrombopag, is now approved for children. Clinical trials in children are ongoing and data are emerging on safety and efficacy. This review will focus on the physiology of TPO-RA, their clinical use in children, as well as the long-term safety issues that need to be considered when using these agents. PMID:26322297

  4. Antiinfective applications of toll-like receptor 9 agonists.

    PubMed

    Krieg, Arthur M

    2007-07-01

    The innate immune system detects pathogens by the presence of highly conserved pathogen-expressed molecules, which trigger host immune defenses. Toll-like receptor (TLR) 9 detects unmethylated CpG dinucleotides in bacterial or viral DNA, and can be stimulated for therapeutic applications with synthetic oligodeoxynucleotides containing immune stimulatory "CpG motifs." TLR9 activation induces both innate and adaptive immunity. The TLR9-induced innate immune activation can be applied in the prevention or treatment of infectious diseases, and the adaptive immune-enhancing effects can be harnessed for improving vaccines. This article highlights the current understanding of the mechanism of action of CpG oligodeoxynucleotides, and provides an overview of the preclinical data and early human clinical trial results, applying these TLR9 agonists in the field of infectious diseases. PMID:17607015

  5. Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist

    PubMed Central

    Tai, Sherrica; Nikas, Spyros P.; Shukla, Vidyanand G.; Vemuri, Kiran; Makriyannis, Alexandros; Järbe, Torbjörn U.C.

    2015-01-01

    Rationale Previous reports shows rimonabant's inverse properties may be a limiting factor for treating cannabinoid dependence. To overcome this limitation neutral antagonists were developed, to address mechanisms by which an inverse agonist and neutral antagonist elicit withdrawal. Objective Introduces an animal model to study cannabinoid dependence by incorporating traditional methodologies and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor (CB1R) related physiological/behavioral endpoints. Methods The cannabinergic AM2389 was acutely characterized in the tetrad (locomotor activity, analgesia, inverted screen/catalepsy bar test and temperature); with some comparisons made to Δ9-tetrahydrocannabinol (THC). Tolerance was measured in mice repeatedly administered AM2389. Antagonist-precipitated withdrawal was characterized in cannabinoid-adapted mice induced by either centrally acting antagonists, rimonabant and AM4113, or an antagonist with limited brain penetration, AM6545. Results In the tetrad, AM2389 was more potent and longer acting than THC, suggesting a novel approach for inducing dependence. Repeated administration of AM2389 led to tolerance by attenuating hypothermia that was induced by acute AM2389 administration. Antagonist-precipitated withdrawal signs were induced by rimonabant or AM4113, but not by AM6545. Antagonist-precipitated withdrawal was reversed by reinstating AM2389 or THC. Conclusions These findings suggest cannabinoid-precipitated withdrawal may not be ascribed to the inverse properties of rimonabant, but rather to rapid competition with the agonist at the CB1R. This withdrawal syndrome is likely centrally-mediated, since only the centrally acting CB1R antagonists elicited withdrawal, i.e., such responses were absent after the purported peripherally selective CB1R antagonist AM6545. PMID:25772338

  6. RS 30026: a potent and effective calcium channel agonist.

    PubMed Central

    Patmore, L.; Duncan, G. P.; Clarke, B.; Anderson, A. J.; Greenhouse, R.; Pfister, J. R.

    1990-01-01

    1. A series of dihydropyridine derivatives has been evaluated for calcium channel agonist activity using reversal of nisoldipine-induced inhibition of beating of aggregates of embryonic chick myocytes. This test appears to be specific for calcium channel agonists since isoprenaline and cardiac glycosides are inactive. 2. RS 30026 was the most potent of the series, was significantly more potent than CGP 28392 and of similar potency to Bay K 8644 (pEC50 = 7.45, 6.16 and 7.20, respectively). RS 30026 increased edge movement of individual aggregates, in the absence of nisoldipine, by 50% at 2 nM. 3. Compounds were also evaluated for their effects on guinea-pig papillary muscle and porcine coronary artery rings. RS 30026 displayed positive inotropism at concentrations between 10(-9) and 10(-6) M (pEC200 = 8.21), but was a much more powerful inotrope than Bay K 8644, increasing contractility to 1300% of control at 10(-6) M (compared to 350% of control for Bay K 8644). RS 30026 caused vasoconstriction at concentrations between 10(-10) and 10(-7) M. 4. Calcium channel currents in single embryonic chick myocytes were recorded by whole-cell voltage clamp techniques. RS 30026 (100 nM-500 nM) produced large increases in peak current amplitude and shifted the voltage for threshold and maximal currents to more negative values. RS 30026 (500 nM) also produced large increases in the inward tail currents evoked upon repolarization. The effects of Bay K 8644 (50 and 500 nM) were much less marked.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1694461

  7. Asimadoline, a κ-Opioid Agonist, and Visceral Sensation

    PubMed Central

    Camilleri, Michael

    2009-01-01

    SUMMARY Asimadoline is a potent κ-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the κ receptor, with IC50 of 5.6 nM (guinea pig) and 1.2 nM (human recombinant), and high selectively with κ: μ: δ binding ratios of 1:501:498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in IBS patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 hours post-on-demand treatment with asimadoline was not significantly reduced. Post-hoc analyses suggest asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with asimadoline, 0.5 mg and 1.0 mg, was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date. PMID:18715494

  8. Agonist and antagonist effects of cytisine in vivo.

    PubMed

    Radchenko, Elena V; Dravolina, Olga A; Bespalov, Anton Y

    2015-08-01

    Varenicline, the most successful smoking cessation aid, is a selective partial agonists at α4β2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including cytisine. The present study aimed to characterize behavioral effects of cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not cytisine (0.3-3 mg/kg), lowered ICSS thresholds and cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), stimulated locomotor activity and cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects. PMID:25839895

  9. Could dopamine agonists aid in drug development for anorexia nervosa?

    PubMed

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  10. Gonadotropin-Releasing Hormone Agonist Therapy and Obesity in Girls

    PubMed Central

    Shiasi Arani, Kobra; Heidari, Fatemeh

    2015-01-01

    Background: Depot preparations of gonadotropin-releasing hormone agonists (GnRHa) are the gold standard drugs for the treatment of central precocious puberty. A concern about these drugs is obesity. Objectives: This study aimed to investigate the effect of gonadotropin-releasing hormone agonists (GnRHa) therapy on body mass index (BMI) in girls with central precocious puberty (CPP). Patients and Methods: The girls with onset of puberty before eight years of age or menarche before nine years of age were studied. The weight, height, BMI, and pubertal stage were determined before and at sixth and 12th months of treatment. The GnRHa (Triptorelin) was administered intramuscularly for patients with rapidly progressive forms of CPP. Patients with slowly progressive forms of CPP were considered as control group. Results: From 110 subjects with CPP, 46 girls (41.8%) were considered as intervention and 64 (58.2%) as control groups. The mean age at initial visit was 7.46 ± 1.03 years. The BMI standard deviation scores in both groups was not significantly different at sixth and 12th months of treatment compared with baseline (P = 0.257 and P = 0.839, respectively). The prevalence of obesity was not significantly different between study groups at baseline and at and sixth and 12th months of therapy (P = 0.11, P = 0.068, and P = 0.052, respectively). Conclusions: The GnRHa therapy has no effect on BMI and the prevalence of obesity. PMID:26401141

  11. Recent advances in the development of farnesoid X receptor agonists

    PubMed Central

    Carey, Elizabeth J.; Lindor, Keith D.

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  12. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    PubMed Central

    Frank, Guido K. W.

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  13. Recent advances in the development of farnesoid X receptor agonists.

    PubMed

    Ali, Ahmad H; Carey, Elizabeth J; Lindor, Keith D

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  14. Interaction of a radiolabeled agonist with cardiac muscarinic cholinergic receptors

    SciTech Connect

    Harden, T.K.; Meeker, R.B.; Martin, M.W.

    1983-12-01

    The interaction of a radiolabeled muscarinic cholinergic receptor agonist, (methyl-/sup 3/H)oxotremorine acetate ((/sup 3/H)OXO), with a washed membrane preparation derived from rat heart, has been studied. In binding assays at 4 degrees C, the rate constants for association and dissociation of (/sup 3/H)OXO were 2 X 10(7) M-1 min-1 and 5 X 10(-3) min-1, respectively, Saturation binding isotherms indicated that binding was to a single population of sites with a Kd of approximately 300 pM. The density of (/sup 3/H)OXO binding sites (90-100 fmol/mg of protein) was approximately 75% of that determined for the radiolabeled receptor antagonist (/sup 3/H)quinuclidinyl benzilate. Both muscarinic receptor agonists and antagonists inhibited the binding of (/sup 3/H)OXO with high affinity and Hill slopes of approximately one. Guanine nucleotides completely inhibited the binding of (/sup 3/H)OXO. This effect was on the maximum binding (Bmax) of (/sup 3/H)OXO with no change occurring in the Kd; the order of potency for five nucleotides was guanosine 5'-O-(3-thio-triphosphate) greater than 5'-guanylylimidodiphosphate greater than GTP greater than or equal to guanosine/diphosphate greater than GMP. The (/sup 3/H)OXO-induced interaction of muscarinic receptors with a guanine nucleotide binding protein was stable to solubilization. That is, membrane receptors that were prelabeled with (/sup 3/H)OXO could be solubilized with digitonin, and the addition of guanine nucleotides to the soluble, (/sup 3/H)OXO-labeled complex resulted in dissociation of (/sup 3/H)OXO from the receptor. Pretreatment of membranes with relatively low concentrations of N-ethylmaleimide inhibited (/sup 3/H)OXO binding by 85% with no change in the Kd of (/sup 3/H)OXO, and with no effect on (/sup 3/H)quinuclidinyl benzilate binding.

  15. GITR agonist enhances vaccination responses in lung cancer

    PubMed Central

    Zhu, Li X; Davoodi, Michael; Srivastava, Minu K; Kachroo, Puja; Lee, Jay M; St. John, Maie; Harris-White, Marni; Huang, Min; Strieter, Robert M; Dubinett, Steven; Sharma, Sherven

    2015-01-01

    An immune tolerant tumor microenvironment promotes immune evasion of lung cancer. Agents that antagonize immune tolerance will thus aid the fight against this devastating disease. Members of the tumor necrosis factor receptor (TNFR) family modulate the magnitude, duration and phenotype of immune responsiveness to antigens. Among these, GITR expressed on immune cells functions as a key regulator in inflammatory and immune responses. Here, we evaluate the GITR agonistic antibody (DTA-1) as a mono-therapy and in combination with therapeutic vaccination in murine lung cancer models. We found that DTA-1 treatment of tumor-bearing mice increased: (i) the frequency and activation of intratumoral natural killer (NK) cells and T lymphocytes, (ii) the antigen presenting cell (APC) activity in the tumor, and (iii) systemic T-cell specific tumor cell cytolysis. DTA-1 treatment enhanced tumor cell apoptosis as quantified by cleaved caspase-3 staining in the tumors. DTA-1 treatment increased expression of IFNγ, TNFα and IL-12 but reduced IL-10 levels in tumors. Furthermore, increased anti-angiogenic chemokines corresponding with decreased pro-angiogenic chemokine levels correlated with reduced expression of the endothelial cell marker Meca 32 in the tumors of DTA-1 treated mice. In accordance, there was reduced tumor growth (8-fold by weight) in the DTA-1 treatment group. NK cell depletion markedly inhibited the antitumor response elicited by DTA-1. DTA-1 combined with therapeutic vaccination caused tumor rejection in 38% of mice and a 20-fold reduction in tumor burden in the remaining mice relative to control. Mice that rejected tumors following therapy developed immunological memory against subsequent re-challenge. Our data demonstrates GITR agonist antibody activated NK cell and T lymphocyte activity, and enhanced therapeutic vaccination responses against lung cancer. PMID:26137407

  16. Immobilized thrombin receptor agonist peptide accelerates wound healing in mice.

    PubMed

    Strukova, S M; Dugina, T N; Chistov, I V; Lange, M; Markvicheva, E A; Kuptsova, S; Zubov, V P; Glusa, E

    2001-10-01

    To accelerate the healing processes in wound repair, attempts have been repeatedly made to use growth factors including thrombin and its peptide fragments. Unfortunately, the employment of thrombin is limited because of its high liability and pro-inflammatory actions at high concentrations. Some cellular effects of thrombin in wound healing are mediated by the activation of protease activated receptor-1 (PAR-1). The thrombin receptor agonist peptide (TRAP:SFLLRN) activates this receptor and mimics the effects of thrombin, but TRAP is a relatively weak agonist. We speculated that the encapsulated peptide may be more effective for PAR-1 activation than nonimmobilized peptide and developed a novel method for TRAP encapsulation in hydrogel films based on natural and synthetic polymers. The effects of an encapsulated TRAP in composite poly(N-vinyl caprolactam)-calcium alginate (PVCL) hydrogel films were investigated in a mouse model of wound healing. On day 7 the wound sizes decreased by about 60% under TRAP-chitosan-containing PVCL films, as compared with control films without TRAP. In the case of TRAP-polylysine-containing films no significant decrease in wound sizes was found. The fibroblast/macrophage ratio increased under TRAP-containing films on day 3 and on day 7. The number of proliferating fibroblasts increased to 150% under TRAP-chitosan films on day 7 as compared with control films. The number of [3H]-thymidine labeled endothelial and epithelial cells in granulation tissues was also enhanced. Thus, the immobilized TRAP to PVCL-chitosan hydrogel films were found to promote wound healing following the stimulation of fibroblast and epithelial cell proliferation and neovascularization. Furthermore, TRAP was shown to inhibit the secretion of the inflammatory mediator PAF from stimulated rat peritoneal mast cells due to augmentation of NO release from the mast cells. The encapsulated TRAP is suggested to accelerate wound healing due to the anti-inflammatory effects

  17. Agonist-specific behaviour of the intracellular Ca2+ response in rat hepatocytes.

    PubMed Central

    Chatton, J Y; Cao, Y; Stucki, J W

    1997-01-01

    A variety of agonists stimulate in hepatocytes a response that takes the shape of repetitive cytosolic free Ca2+ transients called Ca2+ oscillations. The shape of spikes and the pattern of oscillations in a given cell differ depending on the agonist of the phosphoinositide pathway that is applied. In this study, the response of individual rat hepatocytes to maximal stimulation by arginine vasopressin (AVP), phenylephrine and ADP was investigated by fluorescence microscopy and flash photolysis. Hepatocytes loaded with Ca2+-sensitive probes were stimulated with a first agonist to evoke a maximal response, and then a second agonist was added. When phenylephrine or ADP was used as the first agonist, AVP applied subsequently could elicit an additional response, which did not happen when AVP was first applied and phenylephrine or ADP was applied later. Cells microinjected with caged myo-inositol 1,4,5-trisphosphate (IP3) were challenged with the different agonists and, when a maximal response was obtained, photorelease of IP3 was triggered. Cells maximally stimulated with AVP did not respond to IP3 photorelease, whereas those stimulated with phenylephrine or ADP responded with a fast Ca2+ spike above the elevated steady-state level, which was followed by an undershoot. In contrast, with all three agonists, IP3 photorelease triggered at the top of an oscillatory Ca2+ transient was able to mobilize additional Ca2+. These experiments indicate that the differential response of cells to agonists is found not only during Ca2+ oscillations but also during maximal agonist stimulation and that potency and efficacy differences exist among agonists. PMID:9371717

  18. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

    PubMed

    Yu, Shan; Li, Sijia; Henke, Adam; Muse, Evan D; Cheng, Bo; Welzel, Gustav; Chatterjee, Arnab K; Wang, Danling; Roland, Jason; Glass, Christopher K; Tremblay, Matthew

    2016-07-01

    Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. PMID:27025962

  19. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs.

    PubMed

    DeVree, Brian T; Mahoney, Jacob P; Vélez-Ruiz, Gisselle A; Rasmussen, Soren G F; Kuszak, Adam J; Edwald, Elin; Fung, Juan-Jose; Manglik, Aashish; Masureel, Matthieu; Du, Yang; Matt, Rachel A; Pardon, Els; Steyaert, Jan; Kobilka, Brian K; Sunahara, Roger K

    2016-07-01

    G-protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other. Upon activation by extracellular agonists, these seven-transmembrane-domain-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades. Crystallographic evidence from a prototypic GPCR, the β2-adrenergic receptor (β2AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide-binding pocket of the G protein α-subunit to catalyse GDP release, the key step required for GTP binding and activation of G proteins. The structure also offers hints about how G-protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G-protein coupling to the β2AR stabilizes a ‘closed’ receptor conformation characterized by restricted access to and egress from the hormone-binding site. Surprisingly, the effects of G protein on the hormone-binding site can be observed in the absence of a bound agonist, where G-protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and inverse agonists. The ability of bound ligands to dissociate from the receptor is also hindered, providing a structural explanation for the G-protein-mediated enhancement of agonist affinity, which has been observed for many GPCR–G-protein pairs. Our data also indicate that, in contrast to agonist binding alone, coupling of a G protein in the absence of an agonist stabilizes large structural changes in a GPCR. The effects of nucleotide-free G protein on ligand-binding kinetics are shared by other members of the superfamily of GPCRs, suggesting that a common mechanism may underlie G-protein-mediated enhancement of agonist affinity. PMID:27362234

  20. The Gravitational Shear-Intrinsic Ellipticity Correlation Functions of Luminous Red Galaxies in Observation and in the ΛCDM Model

    NASA Astrophysics Data System (ADS)

    Okumura, Teppei; Jing, Y. P.

    2009-03-01

    We examine whether the gravitational shear-intrinsic ellipticity (GI) correlation function of the luminous red galaxies (LRGs) can be modeled with the distribution function of a misalignment angle advocated recently by Okumura et al. For this purpose, we have accurately measured the GI correlation for the LRGs in the Data Release 6 (DR6) of the Sloan Digital Sky Survey (SDSS), which confirms the results of Hirata et al. who used the DR4 data. By comparing the GI correlation functions in the simulation and in the observation, we find that the GI correlation can be modeled in the current ΛCDM model if the misalignment follows a Gaussian distribution with a zero mean and a typical misalignment angle σθ = 34.9+1.9 -2.1 degrees. We also find a correlation between the axis ratios and intrinsic alignments of LRGs. This effect should be taken into account in theoretical modeling of the GI and intrinsic ellipticity-ellipticity correlations for weak lensing surveys.

  1. Selective Retinoic Acid Receptor γ Agonists Promote Repair of Injured Skeletal Muscle in Mouse.

    PubMed

    Di Rocco, Agnese; Uchibe, Kenta; Larmour, Colleen; Berger, Rebecca; Liu, Min; Barton, Elisabeth R; Iwamoto, Masahiro

    2015-09-01

    Retinoic acid signaling regulates several biological events, including myogenesis. We previously found that retinoic acid receptor γ (RARγ) agonist blocks heterotopic ossification, a pathological bone formation that mostly occurs in the skeletal muscle. Interestingly, RARγ agonist also weakened deterioration of muscle architecture adjacent to the heterotopic ossification lesion, suggesting that RARγ agonist may oppose skeletal muscle damage. To test this hypothesis, we generated a critical defect in the tibialis anterior muscle of 7-week-old mice with a cautery, treated them with RARγ agonist or vehicle corn oil, and examined the effects of RARγ agonist on muscle repair. The muscle defects were partially repaired with newly regenerating muscle cells, but also filled with adipose and fibrous scar tissue in both RARγ-treated and control groups. The fibrous or adipose area was smaller in RARγ agonist-treated mice than in the control. In addition, muscle repair was remarkably delayed in RARγ-null mice in both critical defect and cardiotoxin injury models. Furthermore, we found a rapid increase in retinoid signaling in lacerated muscle, as monitored by retinoid signaling reporter mice. Together, our results indicate that endogenous RARγ signaling is involved in muscle repair and that selective RARγ agonists may be beneficial to promote repair in various types of muscle injuries. PMID:26205250

  2. Ascorbic acid enables reversible dopamine receptor /sup 3/H-agonist binding

    SciTech Connect

    Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.

    1981-11-16

    The effects of ascorbic acid on dopaminergic /sup 3/H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the /sup 3/H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total /sup 3/H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable /sup 3/H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable /sup 3/H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of /sup 3/H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific /sup 3/H-agonist binding to dopamine receptors.

  3. Did CDM particles of mass 2.47 x 10(-3) eV interact with precursor biopolymers and nucleic acids to initiate and boost lifeforms on Earth?

    PubMed

    Rosen, Gerald

    2011-06-01

    Recent observations and theoretical studies have shown that non-baryonic Cold Dark Matter (CDM), which constitutes about 84% of all matter in the Universe, may feature a complex-scalar-field that carries particles of mass ≅ 2.47 x 10(-3)eV with the associated Compton range m(-1) ≅8.02 x 10(-3) cm, a distance on the scale of extended bionucleic acids and living cells. Such a complex-scalar-field can enter a weak-isospin Lorentz-invariant interaction that generates the flow of right-handed electrons and induces a chirality-imbued quantum chemistry on the m (-1) scale. A phenomenological Volterra-type equation is proposed for the CDM-impacted time development of N, the number of base pairs in the most advanced organism at Earth-age t. The solution to this equation suggests that the boosts in N at t ≅ 1.1 Gyr (advent of the first living prokaryotic cells), at t ≅ 2.9 Gyr (advent of eukaryotic single-celled organisms) and finally at t ≅ 4.0 Gyr (the Cambrian explosion) may be associated with three multi-Myr-duration cosmic showers of the complex-scalar-field CDM particles. If so, the signature of the particles may be detectible in Cambrian rocks. PMID:21057875

  4. Did CDM Particles of Mass 2.47 × 10-3 eV Interact with Precursor Biopolymers and Nucleic Acids to Initiate and Boost Lifeforms on Earth?

    NASA Astrophysics Data System (ADS)

    Rosen, Gerald

    2011-06-01

    Recent observations and theoretical studies have shown that non-baryonic Cold Dark Matter (CDM), which constitutes about 84% of all matter in the Universe, may feature a complex-scalar-field that carries particles of mass m ≅ 2.47 × {10^{{ - 3}}}eV with the associated Compton range {m^{{ - 1}}} ≅ 8.02 × {10^{{ - 3}}}cm, a distance on the scale of extended bionucleic acids and living cells. Such a complex-scalar-field can enter a weak-isospin Lorentz-invariant interaction that generates the flow of right-handed electrons and induces a chirality-imbued quantum chemistry on the m -1 scale. A phenomenological Volterra-type equation is proposed for the CDM-impacted time development of N, the number of base pairs in the most advanced organism at Earth-age t. The solution to this equation suggests that the boosts in N at t ≅ 1.1 Gyr (advent of the first living prokaryotic cells), at t ≅ 2.9 Gyr (advent of eukaryotic single-celled organisms) and finally at t ≅ 4.0 Gyr (the Cambrian explosion) may be associated with three multi-Myr-duration cosmic showers of the complex-scalar-field CDM particles. If so, the signature of the particles may be detectible in Cambrian rocks.

  5. Kinetic determinants of agonist action at the recombinant human glycine receptor

    PubMed Central

    Lewis, Trevor M; Schofield, Peter R; McClellan, Annette M L

    2003-01-01

    The amino acids glycine, β-alanine and taurine are all endogenous agonists of the glycine receptor. In this study, a combination of rapid agonist application onto macropatches and steady-state single-channel recordings was used to compare the actions of glycine, β-alanine and taurine upon homomeric α1 human glycine receptors transiently expressed in human embryonic kidney (HEK 293) cells. The 10–90 % rise times determined from rapid application of 100 μm of each agonist were indistinguishable, indicating each agonist has a similar association rate. At saturating concentrations (30 mm) the rise time for glycine (0.26 ms) was 1.8-fold faster than that for β-alanine (0.47 ms) and 3.9-fold faster than that for taurine (1.01 ms), indicating clear differences in the maximum opening rate between agonists. The relaxation following rapid removal of agonist was fitted with a single exponential for β-alanine (3.0 ms) and taurine (2.2 ms), and two exponential components for glycine with a weighted mean time constant of 27.1 ms. This was consistent with differences in dissociation rates estimated from analysis of bursts, with taurine > β-alanine > glycine. Exponential fits to the open period distributions gave time constants that did not differ between agonists and the geometric distribution for the number of openings per burst indicated that all three agonists had a significant component of single-opening bursts. Based upon these data, we propose a kinetic scheme with three independent open states, where the opening rates are dependent upon the activating agonist, while the closing rates are an intrinsic characteristic of the receptor. PMID:12679369

  6. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    SciTech Connect

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  7. Pairwise agonist scanning-flow cytometry (PAS-FC) measures inside-out signaling and patient-specific response to combinatorial platelet agonists.

    PubMed

    Jaeger, Daniel T L; Diamond, Scott L

    2013-05-01

    Understanding the response of cells to multiple stimuli is vital for predicting donor specific responses and better understanding the signaling pathways involved. This is of particular importance in platelets because exposure of phosphatidylserine (PS) occurs upon costimulation but not with a single agonist. Here, we describe a multiplexed pairwise agonist scanning-flow cytometry (PAS-FC) method of measuring platelet inside-out responses to all pairs of six platelet agonists (convulxin, SFLLRN, AYPGKF, ADP, U46619, and PGE(2)) used at their EC(50) concentrations. These agonists allowed exploration of platelet signaling downstream of GPVI, PAR-1, PAR-4, P2Y(1), P2Y(12), TP, and IP receptors. The three-color flow cytometry method simultaneously measured integrin α(IIb)β(3) activation with PAC-1 antibody, P-selectin exposure (via α granule release) with anti-P-selectin, and PS exposure with annexin V. These responses were consistent across a healthy male donor pool. In duplicate measurements with each donor, 4 of the 10 donors had a sufficiently unique 45-parameter (15 pairs × 3 colors) phenotype to self-cluster (P < 0.001). This method has the potential for efficiently scanning for patient specific responses across a broad agonist-receptor space. PMID:23662898

  8. Analgesic effectiveness of the narcotic agonist-antagonists

    PubMed Central

    Houde, Raymond W.

    1979-01-01

    1 Two fundamentally different types of narcotic-antogonists have been found to be very effective analgesics with relatively low dependence-producing potentials. 2 These two drug classes can be distinguished as being either morphine-like or nalorphine-like on the basis of their subjective and objective effects after single doses and on chronic administration, and by the character of their abstinence syndromes on abrupt withdrawal or on precipitation by other antagonists. 3 To explain differences in side effects associated with their analgesic actions, the existence of three types of receptors has been postulated: a μ receptor which is believed to be associated with euphoria and other typical morphine-like effects and a kappa (χ) and a sigma (σ) receptor which are believed to be associated with the sedative and psychotomimetic effects, respectively, of the nalorphine-like drugs. 4 The antagonist-analgesics of the morphine-type have the characteristics of being agonists of low intrinsic activity but with high affinity for the μ receptor. Representative analgesics of this type are profadol, propiram and buprenorphine. 5 The antagonist-analgesics of the nalorphine-type are drugs which are believed to have varying degrees of affinity and intrinsic activity at all three receptors, but characteristically seem to act merely as competitive antagonists with no intrinsic activity at the μ receptor. Representative analgesics of this type are pentazocine, nalbuphine and butorphanol. 6 There are considerable differences among the individual drugs of each type in terms of their analgesic and narcotic-antagonistic potencies. However, clear differences in analgesic efficacy among any of the antagonist-analgesics remain to be proved. All give evidence of being capable of relieving pain in nondependent patients in situations in which doses of morphine (or its surrogates) usually used would be effective. 7 The major advantages of the partial agonists of the morphine-type over the

  9. Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists

    PubMed Central

    2014-01-01

    The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels. PMID:25313322

  10. Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists.

    PubMed

    Peukert, Stefan; Hughes, Richard; Nunez, Jill; He, Guo; Yan, Zhao; Jain, Rishi; Llamas, Luis; Luchansky, Sarah; Carlson, Adam; Liang, Guiqing; Kunjathoor, Vidya; Pietropaolo, Mike; Shapiro, Jeffrey; Castellana, Anja; Wu, Xiaoping; Bose, Avirup

    2014-10-01

    The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels. PMID:25313322

  11. Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRβ.

    PubMed

    Kick, Ellen; Martin, Richard; Xie, Yinong; Flatt, Brenton; Schweiger, Edwin; Wang, Tie-Lin; Busch, Brett; Nyman, Michael; Gu, Xiao-Hui; Yan, Grace; Wagner, Brandee; Nanao, Max; Nguyen, Lam; Stout, Thomas; Plonowski, Artur; Schulman, Ira; Ostrowski, Jacek; Kirchgessner, Todd; Wexler, Ruth; Mohan, Raju

    2015-01-15

    A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRβ selectivity. The LXRβ selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2μM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist. PMID:25435151

  12. Thromboxane agonist (U46619) potentiates norepinephrine efflux from adrenergic nerves

    SciTech Connect

    Trachte, G.J.

    1986-05-01

    The effect of the synthetic thromboxane/prostaglandin (PG) H2 agonist U46619 on the electrically stimulated rabbit isolated vas deferens was examined to test for thromboxane influences on adrenergic nerves. U46619 effects on force generation, (/sup 3/H) norepinephrine release and norepinephrine-induced contractions were assessed to determine the mechanism of action. U46619 maximally enhanced adrenergic force generation 135 +/- 24% at a concentration of 100 nM. U46619 potentiated maximal contractile effects of exogenously administered norepinephrine 16 +/- 4% and augmented (/sup 3/H)norepinephrine release from electrically stimulated preparations 142 +/- 44%. A competitive thromboxane/PGH2 receptor antagonist, SQ29548, significantly shifted the concentration-response curve for U46619 to the right in a concentration-dependent manner and blocked U46619-induced tritium release. Thus, U46619 appears to potentiate neurotransmitter release by interacting with thromboxane/PGH2 receptors. Because SQ29548 did not prevent the potentiation of norepinephrine contractions by U46619, the postjunctional effect may be independent of thromboxane/PGH2 receptors. We interpret these results to be indicative of both pre- and postjunctional sites of action of U46619. The physiological importance of these thromboxane effects is unknown currently.

  13. Agonistic experience and individual recognition in male Quelea quelea.

    PubMed

    Shawcross, J E; Slater, P J

    1984-01-01

    Male Quelea were moved between groups to assess whether experience of winning or losing in new groups was correlated with their success in competition over food when they were returned to their original groups. No such effect was found. However, differences in time spent feeding after deprivation and in aggressive behaviour were found between groups depending on whether they were made up from high- or low-ranking individuals. In paired encounters there was no evidence that birds threatened unfamiliar individuals more than familiar ones or that they avoided sitting next to them more than familiar birds. This suggests that individual recognition, if it exists at all in these groups, is not important in their agonistic relationships. The rank birds occupied was correlated with beak colour, a probable measure of androgen levels, and with the amount of food consumed after deprivation. The latter result suggests that the same period of deprivation may affect some individuals more than others and this in turn may lead them to compete more for food. PMID:24923828

  14. Agonists and Antagonists of TGF-β Family Ligands.

    PubMed

    Chang, Chenbei

    2016-01-01

    The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling. PMID:27413100

  15. PPARα agonist, fenofibrate, ameliorates age-related renal injury.

    PubMed

    Kim, Eun Nim; Lim, Ji Hee; Kim, Min Young; Kim, Hyung Wook; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-08-01

    The kidney ages quickly compared with other organs. Expression of senescence markers reflects changes in the energy metabolism in the kidney. Two important issues in aging are mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα) is a member of the ligand-activated nuclear receptor superfamily. PPARα plays a major role as a transcription factor that regulates the expression of genes involved in various processes. In this study, 18-month-old male C57BL/6 mice were divided into two groups, the control group (n=7) and the fenofibrate-treated group (n=7) was fed the normal chow plus fenofibrate for 6months. The PPARα agonist, fenofibrate, improved renal function, proteinuria, histological change (glomerulosclerosis and tubular interstitial fibrosis), inflammation, and apoptosis in aging mice. This protective effect against age-related renal injury occurred through the activation of AMPK and SIRT1 signaling. The activation of AMPK and SIRT1 allowed for the concurrent deacetylation and phosphorylation of their target molecules and decreased the kidney's susceptibility to age-related changes. Activation of the AMPK-FOXO3a and AMPK-PGC-1α signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Our results suggest that activation of PPARα and AMPK-SIRT1 signaling may have protective effects against age-related renal injury. Pharmacological targeting of PPARα and AMPK-SIRT1 signaling molecules may prevent or attenuate age-related pathological changes in the kidney. PMID:27130813

  16. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone.

    PubMed

    Watkins, Steven M; Reifsnyder, Peter R; Pan, Huei-ju; German, J Bruce; Leiter, Edward H

    2002-11-01

    Successful therapy for chronic diseases must normalize a targeted aspect of metabolism without disrupting the regulation of other metabolic pathways essential for maintaining health. Use of a limited number of single molecule surrogates for disease, or biomarkers, to monitor the efficacy of a therapy may fail to predict undesirable side effects. In this study, a comprehensive metabolomic assessment of lipid metabolites was employed to determine the specific effects of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone on structural lipid metabolism in a new mouse model of Type 2 diabetes. Dietary supplementation with rosiglitazone (200 mg/kg diet) suppressed Type 2 diabetes in obese (NZO x NON)F1 male mice, but chronic treatment markedly exacerbated hepatic steatosis. The metabolomic data revealed that rosiglitazone i) induced hypolipidemia (by dysregulating liver-plasma lipid exchange), ii) induced de novo fatty acid synthesis, iii) decreased the biosynthesis of lipids within the peroxisome, iv) substantially altered free fatty acid and cardiolipin metabolism in heart, and v) elicited an unusual accumulation of polyunsaturated fatty acids within adipose tissue. These observations suggest that the phenotypes induced by rosiglitazone are mediated by multiple tissue-specific metabolic variables. Because many of the effects of rosiglitazone on tissue metabolism were reflected in the plasma lipid metabolome, metabolomics has excellent potential for developing clinical assessments of metabolic response to drug therapy. PMID:12401879

  17. Therapeutic applications of TRAIL receptor agonists in cancer and beyond.

    PubMed

    Amarante-Mendes, Gustavo P; Griffith, Thomas S

    2015-11-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. PMID:26343199

  18. Minireview: Challenges and opportunities in development of PPAR agonists.

    PubMed

    Wright, Matthew B; Bortolini, Michele; Tadayyon, Moh; Bopst, Martin

    2014-11-01

    The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity. PMID:25148456

  19. Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin-1 receptor in the grey squirrel (Sciurus carolinensis).

    PubMed

    McRobie, Helen R; King, Linda M; Fanutti, Cristina; Symmons, Martyn F; Coussons, Peter J

    2014-06-27

    The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RΔ24) variant. We demonstrate that the MC1RΔ24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RΔ24. We conclude that the deletion in the MC1RΔ24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R. PMID:24879893

  20. The long-acting β2-adrenoceptor agonist, indacaterol, enhances glucocorticoid receptor-mediated transcription in human airway epithelial cells in a gene- and agonist-dependent manner

    PubMed Central

    Joshi, T; Johnson, M; Newton, R; Giembycz, M A

    2015-01-01

    Background and Purpose Inhaled glucocorticoid (ICS)/long-acting β2-adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone-inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)-mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism. Experimental Approach BEAS-2B human airway epithelial cells stably transfected with a 2× glucocorticoid response element luciferase reporter were used to model gene transcription together with an analysis of several glucocorticoid-inducible genes. Key Results Indacaterol augmented glucocorticoid-induced reporter activation in a manner that was positively related to the intrinsic activity of the GR agonist. This effect was demonstrated by an increase in response maxima without a change in GR agonist affinity or efficacy. Indacaterol also enhanced glucocorticoid-inducible gene expression. However, the magnitude of this effect was dependent on both the GR agonist and the gene of interest. Conclusions and Implications These data suggest that indacaterol activates a molecular rheostat, which increases the transcriptional competency of GR in an agonist- and gene-dependent manner without apparently changing the relationship between fractional GR occupancy and response. These findings provide a platform to rationally design ICS/LABA combination therapy that is based on the generation of agonist-dependent gene expression profiles in target and off-target tissues. PMID:25598440

  1. Matter power spectrum covariance matrix from the DEUS-PUR ΛCDM simulations: mass resolution and non-Gaussian errors

    NASA Astrophysics Data System (ADS)

    Blot, L.; Corasaniti, P. S.; Alimi, J.-M.; Reverdy, V.; Rasera, Y.

    2015-01-01

    The upcoming generation of galaxy surveys will probe the distribution of matter in the Universe with unprecedented accuracy. Measurements of the matter power spectrum at different scales and red shifts will provide stringent constraints on the cosmological parameters. However, on non-linear scales this will require an accurate evaluation of the covariance matrix. Here, we compute the covariance matrix of the three-dimensional matter density power spectrum for the concordance ΛCDM cosmology from an ensemble of N-body simulations of the Dark Energy Universe Simulation - Parallel Universe Runs (DEUS-PUR). This consists of 12 288 realizations of a (656 h-1 Mpc)3 simulation box with 2563 particles. We combine this set with an auxiliary sample of 96 simulations of the same volume with 10243 particles. We find the N-body mass resolution effect to be an important source of systematic errors on the covariance at high redshift and small intermediate scales. We correct for this effect by introducing an empirical statistical method which provide an accurate determination of the covariance matrix over a wide range of scales including the baryon oscillations interval. Contrary to previous studies that used smaller N-body ensembles, we find the power spectrum distribution to significantly deviate from expectations of a Gaussian random density field at k ≳ 0.25 h Mpc-1 and z < 0.5. This suggests that for the finite-volume surveys, an unbiased estimate of the ensemble-averaged band power at these scales and red shifts may require a more careful assessment of non-Gaussian errors than previously considered.

  2. Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow.

    PubMed

    Dore, Kim; Aow, Jonathan; Malinow, Roberto

    2015-11-24

    The NMDA receptor (R) plays important roles in brain physiology and pathology as an ion channel. Here we examine the ion flow-independent coupling of agonist to the NMDAR cytoplasmic domain (cd). We measure FRET between fluorescently tagged cytoplasmic domains of GluN1 subunits of NMDARs expressed in neurons. Different neuronal compartments display varying levels of FRET, consistent with different NMDARcd conformations. Agonist binding drives a rapid and transient ion flow-independent reduction in FRET between GluN1 subunits within individual NMDARs. Intracellular infusion of an antibody targeting the GluN1 cytoplasmic domain blocks agonist-driven FRET changes in the absence of ion flow, supporting agonist-driven movement of the NMDARcd. These studies indicate that extracellular ligand binding to the NMDAR can transmit conformational information into the cell in the absence of ion flow. PMID:26553997

  3. Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

    PubMed

    Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Matsui, Tetsuo; Takasu, Toshiyuki; Ohta, Mitsuaki

    2009-06-01

    In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model. PMID:19232786

  4. Potent achiral agonists of the ghrelin (growth hormone secretagogue) receptor. Part I: Lead identification.

    PubMed

    Heightman, Tom D; Scott, Jackie S; Longley, Mark; Bordas, Vincent; Dean, David K; Elliott, Richard; Hutley, Gail; Witherington, Jason; Abberley, Lee; Passingham, Barry; Berlanga, Manuela; de Los Frailes, Maite; Wise, Alan; Powney, Ben; Muir, Alison; McKay, Fiona; Butler, Sharon; Winborn, Kim; Gardner, Christopher; Darton, Jill; Campbell, Colin; Sanger, Gareth

    2007-12-01

    High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats. PMID:17942309

  5. Innate immune responses to microbial agonist stimulations in heterophils and monocytes from young commercial turkeys

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The innate immune system recognizes microbial pathogens and pathogen associated molecular patterns and incites inflammatory immune responses to control the infection. Here, we examined functional innate immune responses of turkey heterophils and monocytes to microbial agonist stimulations by measur...

  6. Clinical use of GnRH agonists in canine and feline species.

    PubMed

    Fontaine, E; Fontbonne, A

    2011-04-01

    GnRH (gonadotrophin releasing hormone) is a key hormone of reproductive function in mammals; agonist forms have been largely developed, and data concerning their use in small animal reproduction are now abundant. GnRH agonists act by a two-step mechanism. First, their agonist properties on the pituitary will cause marked LH (luteinizing hormone) and FSH (follicle-stimulating hormone) secretion into the bloodstream, accompanied by an increase in the concentrations of sex steroid hormones. Then, in case of constant administration, GnRH agonists will lead to pituitary desensitization, and FSH and LH levels will collapse. These two effects have been widely documented, and these compounds have many potential benefits in a clinical context, capitalizing both on their stimulating and sterilizing effects. PMID:20964727

  7. Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist.

    PubMed

    Lin, Hsiang-Ru

    2015-01-01

    Lepidozenolide is a sesquiterpenoid isolated from the liverwort Lepidozia fauriana and its possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and hyperglycemia. In this study, whether lepidozenolide may act as a FXR agonist was determined. Indeed, in mammalian one-hybrid and transient transfection reporter assays, lepidozenolide transactivated FXR to modulate promoter action including GAL4, CYP7A1, and PLTP promoters in a dose-dependent manner, while it exhibited slightly less agonistic activity than chenodeoxycholic acid, an endogenous FXR agonist. Through the molecular modeling docking studies lepidozenolide was shown to bind to FXR ligand binding pocket fairly well. All these results indicate that lepidozenolide acts as a FXR agonist. PMID:25315435

  8. Determination of beta-agonists in swine hair by μFIA and chemiluminescence.

    PubMed

    Chen, Xu; Luo, Yong; Shi, Bo; Gao, Zhigang; Du, Yuguang; Liu, Xianming; Zhao, Weijie; Lin, Bingcheng

    2015-04-01

    β-Agonists are a group of illegal feed additives. In this paper, it was found that the light emission produced by the oxidation of luminol by potassium ferricyanide was enhanced by the β-agonists (ractopamine, salbutamol, and terbutaline). Based on chemiluminescence phenomenon, a novel, rapid, and sensitive microflow injection analysis system on a microfluidic glass chip was established for determination of the β-agonists. The chip was fabricated from two glass plates (64 mm × 32 mm) with microchannels of 200 μm width and 100 μm depth. The detection limits were achieved at 2.0 × 10(-8) mol/L of ractopamine, 1.0 × 10(-8) mol/L of terbutaline and 5.0 × 10(-7) mol/L of salbutamol. In this report, our method was applied for determination of the β-agonists in swine hair from three different sources with satisfactory results. PMID:25546131

  9. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system.

    PubMed

    Engel, Abbi L; Holt, Gregory E; Lu, Hailing

    2011-03-01

    Toll-like receptor (TLR) ligation activates both the innate and adaptive immune systems, and plays an important role in antiviral and anti-tumor immunity. Therefore, a significant amount of effort has been devoted to exploit the therapeutic potential of TLR agonists. Depending on the therapeutic purpose, either as adjuvants to vaccine, chemotherapy or standalone therapy, TLR agonists have been administered via different routes. Both preclinical and clinical studies have suggested that the route of administration has significant effects on pharmacokinetics, and that understanding these effects is critical to the success of TLR agonist drug development. This article will summarize the pharmacokinetics of TLR agonists with different administration routes, with an emphasis on clinical studies of TLR ligands in oncologic applications. PMID:21643519

  10. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system

    PubMed Central

    Engel, Abbi L; Holt, Gregory E; Lu, Hailing

    2011-01-01

    Toll-like receptor (TLR) ligation activates both the innate and adaptive immune systems, and plays an important role in antiviral and anti-tumor immunity. Therefore, a significant amount of effort has been devoted to exploit the therapeutic potential of TLR agonists. Depending on the therapeutic purpose, either as adjuvants to vaccine, chemotherapy or standalone therapy, TLR agonists have been administered via different routes. Both preclinical and clinical studies have suggested that the route of administration has significant effects on pharmacokinetics, and that understanding these effects is critical to the success of TLR agonist drug development. This article will summarize the pharmacokinetics of TLR agonists with different administration routes, with an emphasis on clinical studies of TLR ligands in oncologic applications. PMID:21643519

  11. Aryl sulphonyl amides as potent agonists of the growth hormone secretagogue (ghrelin) receptor.

    PubMed

    Witherington, Jason; Abberley, Lee; Bellenie, Benjamin R; Boatman, Rio; Collis, Katharine; Dean, David K; Gaiba, Alessandra; King, N Paul; Shuker, Nicola; Steadman, Jon G A; Takle, Andrew K; Sanger, Gareth; Butler, Sharon; McKay, Fiona; Muir, Alison; Winborn, Kim; Ward, Robert W; Heightman, Tom D

    2009-02-01

    As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists. PMID:19128969

  12. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

    PubMed Central

    Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

    2013-01-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

  13. Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow

    PubMed Central

    Dore, Kim; Aow, Jonathan; Malinow, Roberto

    2015-01-01

    The NMDA receptor (R) plays important roles in brain physiology and pathology as an ion channel. Here we examine the ion flow-independent coupling of agonist to the NMDAR cytoplasmic domain (cd). We measure FRET between fluorescently tagged cytoplasmic domains of GluN1 subunits of NMDARs expressed in neurons. Different neuronal compartments display varying levels of FRET, consistent with different NMDARcd conformations. Agonist binding drives a rapid and transient ion flow-independent reduction in FRET between GluN1 subunits within individual NMDARs. Intracellular infusion of an antibody targeting the GluN1 cytoplasmic domain blocks agonist-driven FRET changes in the absence of ion flow, supporting agonist-driven movement of the NMDARcd. These studies indicate that extracellular ligand binding to the NMDAR can transmit conformational information into the cell in the absence of ion flow. PMID:26553997

  14. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease

    PubMed Central

    Karner, Charlotta; Cates, Christopher J

    2014-01-01

    Background Long-acting bronchodilators comprising long-acting beta2-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta2-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear. Objectives To assess the relative effects of treatment with tiotropium in addition to long-acting beta2-agonist compared to tiotropium or long-acting beta2-agonist alone in patients with chronic obstructive pulmonary disease. Search methods We searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012. Selection criteria We included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta2-agonist against tiotropium or long-acting beta2-agonist alone for patients with chronic obstructive pulmonary disease. Data collection and analysis Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. Main results Five trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta2-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta2-agonist (formoterol) alone. Two studies used the long-acting beta2-agonist indacaterol, two used formoterol and one used salmeterol. Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long

  15. Changing Patterns of Alpha Agonist Medication Use in Children and Adolescents 2009–2011

    PubMed Central

    Mayne, Stephanie L.; Song, Lihai; Steffes, Jennifer; Liu, Weiwei; McCarn, Banita; Margolis, Benyamin; Grimes, Alan; Gotlieb, Edward; Localio, Russell; Ross, Michelle E.; Grundmeier, Robert W.; Wasserman, Richard; Leslie, Laurel K.

    2015-01-01

    Abstract Objectives: The purpose of this study was to describe rates and patterns of long- and short-acting alpha agonist use for behavioral problems in a primary care population following Food and Drug Administration (FDA) approval of the long-acting alpha agonists guanfacine and clonidine. Methods: Children and adolescents 4–18 years of age, who received an alpha agonist prescription between 2009 and 2011, were identified from a sample of 45 United States primary care practices in two electronic health record-based research networks. Alpha agonist receipt was identified using National Drug Codes and medication names. The proportion of subjects receiving long- and short-acting prescriptions in each year was calculated and examined with respect to reported mental health diagnoses, and whether indications for use were on-label, had evidence from clinical trials, or had no trial evidence. Results: In a cohort of 282,875 subjects, 27,671 (10%) received any psychotropic medication and only 4,227 subjects (1.5%) received at least one prescription for an alpha agonist, most commonly a short-acting formulation (83%). Only 20% of alpha agonist use was on-label (use of long-acting formulations for attention-deficit/hyperactivity disorder [ADHD]). Most subjects (68%) received alpha agonists for indications with evidence of efficacy from clinical trials but no FDA approval, primarily short-acting formulations for ADHD and autism; 12% received alpha agonists for diagnoses lacking randomized clinical trial evidence in children, including sleep disorders and anxiety, or for which there was no documented mental health diagnosis. Rates of long-acting alpha agonist use increased more than 20-fold from 0.2% to 4%, whereas rates of short-acting alpha agonist use grew only slightly between 2009 and 2011 from 10.6% to 11.3%. Conclusions: Alpha agonist use was uncommon in this population, and most subjects received short-acting forms for conditions that were off-label, but with

  16. Effects of oxytocin on serotonin 1B agonist-induced autism-like behavior in mice.

    PubMed

    Lawson, Sarah K; Gray, Andrew C; Woehrle, Nancy S

    2016-11-01

    Social impairments in autism remain poorly understood and without approved pharmacotherapies. Novel animals models are needed to elucidate mechanisms and evaluate novel treatments for the social deficits in autism. Recently, serotonin 1B receptor (5-HT1B) agonist challenge in mice was shown to induce autism-like behaviors including perseveration, reduced prepulse inhibition, and delayed alternation deficits. However, the effects of 5-HT1B agonists on autism-related social behaviors in mice remain unknown. Here, we examine the effects of 5-HT1B agonist challenge on sociability and preference for social novelty in mice. We also examine the effects of 5-HT1B agonist treatment on average rearing duration, a putative rodent measure of non-selective attention. Non-selective attention is an associated feature of autism that is also not well understood. We show that 5-HT1B receptor activation reduces sociability, preference for social novelty, and rearing in mice. In addition, we examine the ability of oxytocin, an off-label treatment for the social impairments in autism, to reverse 5-HT1B agonist-induced social and attention deficits in mice. We show that oxytocin restores social novelty preference in mice treated with a 5-HT1B agonist. We also show that oxytocin attenuates 5-HT1B agonist-induced sociability and rearing deficits in mice. Our results suggest that 5-HT1B agonist challenge provides a useful pharmacological mouse model for aspects of autism, and implicate 5-HT1B in autism social and attention deficits. Moreover, our findings suggest that oxytocin may treat the social deficits in autism through a mechanism involving 5-HT1B. PMID:27439030

  17. Wnt Agonist Attenuates Liver Injury and Improves Survival after Hepatic Ischemia/Reperfusion

    PubMed Central

    Kuncewitch, Michael; Yang, Weng-Lang; Molmenti, Ernesto; Nicastro, Jeffrey; Coppa, Gene F.; Wang, Ping

    2012-01-01

    The Wnt/β-catenin signaling pathway is well characterized in stem cell biology and plays a critical role in liver development, regeneration, and homeostasis. We hypothesized that pharmacological activation of Wnt signaling protects against hepatic ischemia/reperfusion (I/R) injury through its known proliferative and anti-apoptotic properties. Sprague-Dawley rats underwent 70% hepatic ischemia by microvascular clamping of the hilum of the left and median lobes of the liver for 90 min, followed by reperfusion. Wnt agonist (2-amino-4-[3,4-(methylenedioxy)benzylamino]-6-(3-methoxyphenyl)pyrimidine, 5 mg/kg BW) or vehicle (20% DMSO in saline) in 0.5 ml was injected intraperitoneally (i.p.) 1 h prior to ischemia or infused intravenously over 30 min right after ischemia. Blood and tissue samples from the pre-treated groups were collected 24 h after reperfusion, and a survival study was performed. Hepatic expression of β-catenin and its downstream target gene Axin2 were decreased after I/R while Wnt agonist restored their expression to sham levels. Wnt agonist blunted I/R-induced elevations of AST, ALT, and LDH and significantly improved the microarchitecture of the liver. The cell proliferation determined by Ki67 immunostaining significantly increased with Wnt agonist treatment and inflammatory cascades were dampened in Wnt agonist-treated animals, as demonstrated by attenuations in IL-6, myeloperoxdase, iNOS and nitrotyrosine. Wnt agonist also significantly decreased the amount of apoptosis, as evidenced by decreases in both TUNEL staining as well as caspase-3 activity levels. Finally, the 10-day survival rate was increased from 27% in the vehicle group to 73% in the pre-treated Wnt agonist group and 55% in the Wnt agonist post-ischemia treatment group. Thus, we propose that direct Wnt/β-catenin stimulation may represent a novel therapeutic approach in the treatment of hepatic I/R. PMID:23143067

  18. Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

    SciTech Connect

    Thompson, Scott K.; Washburn, David G.; Frazee, James S.; Madauss, Kevin P.; Hoang, Tram H.; Lapinski, Leahann; Grygielko, Eugene T.; Glace, Lindsay E.; Trizna, Walter; Williams, Shawn P.; Duraiswami, Chaya; Bray, Jeffrey D.; Laping, Nicholas J.

    2010-09-03

    Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

  19. WNT AGONIST DECREASES TISSUE DAMAGE AND IMPROVES RENAL FUNCTION AFTER ISCHEMIA-REPERFUSION

    PubMed Central

    Kuncewitch, Michael; Yang, Weng-Lang; Corbo, Lana; Khader, Adam; Nicastro, Jeffrey; Coppa, Gene F.; Wang, Ping

    2014-01-01

    Renal ischemia-reperfusion (IR) injury (IRI) following shock states or transplantation causes tissue damage and delayed graft function, respectively. The Wnt/β-catenin signaling pathway plays a critical role in nephrogenesis. We therefore hypothesized that pharmacological activation of Wnt/β-catenin signaling by Wnt agonist, a synthetic pyrimidine, could protect kidneys from IRI. Adult male rats were subjected to bilateral clamping of the renal pedicles with microvascular clips for 60 min, followed by reperfusion. Wnt agonist (5 mg/kg BW) or vehicle (20% DMSO in saline) was administered intravenously 1 h prior to ischemia. Blood and renal tissues were collected 24 h after IR for evaluation. Renal IR caused a significant reduction of β-catenin and its downstream target gene cyclin D1 by 65% and 39%, respectively, compared to the sham, while Wnt agonist restored them to the sham levels. The number and intensity of cells staining with the proliferation marker Ki67 in ischematized kidneys were enhanced by Wnt agonist. The integrity of the renal histological architecture in the Wnt agonist group was better preserved than the vehicle group. Wnt agonist significantly lowered serum levels of creatinine, AST, and LDH, inhibited the production of IL-6 and IL-1β, and MPO activities. Lastly, Wnt agonist reduced iNOS, nitrotyrosine proteins and 4-hydroxynonenal in the kidneys by 60%, 47% and 21%, respectively, compared to the vehicle. These results indicate that Wnt agonist improves renal regeneration and function while attenuating inflammation and oxidative stress in the kidneys after IR. Thus, pharmacologic stimulation of Wnt/β-catenin signaling provides a beneficial effect on the prevention of renal IRI. PMID:25514428

  20. Do Agonistic Motives Matter More Than Anger? Three Studies of Cardiovascular Risk in Adolescents

    PubMed Central

    Ewart, Craig K.; Elder, Gavin J.; Smyth, Joshua M.; Sliwinski, Martin J.; Jorgensen, Randall S.

    2011-01-01

    Objective Three motivational profiles have been associated with recurring psychological stress in low-income youth and young adults: Striving to control others (agonistic striving), striving to control the self (transcendence striving), and not asserting control (dissipated striving); Agonistic Striving has been associated with elevated ambulatory blood pressure during daily activities. Three studies tested the hypotheses that: (1) Agonistic Striving is associated with poor anger regulation, and (2) Agonistic Striving and poor anger regulation interactively elevate blood pressure. Design Motivational profiles, anger regulation, and ambulatory blood pressure were assessed in a multiethnic sample of 264 urban youth. Main outcome measures (1) Anger regulation/recovery during laboratory challenge; (2) anger / blood pressure during daily activities (48 hours). Results and conclusion Replication of the profiles in distant cities showed they occur with similar frequency across differences of region, race, and gender. Analyses controlling for body size, race, and gender revealed that individuals with the Agonistic Striving profile had higher ambulatory pressure, especially during social encounters. They became more openly angry and aggressive when challenged, but did not exhibit difficulty regulating anger in the laboratory, nor did they feel more angry during monitoring. However, individuals with the Agonistic Striving profile who did display poor anger regulation in the lab had the highest blood pressure; deficient self-regulatory capability amplified the positive association between Agonistic Striving and cardiovascular risk in both genders and all ethnic groups. Although anger is thought to increase cardiovascular risk, present findings suggest that anger and elevated blood pressure are co-effects of agonistic struggles to control others. PMID:21534673

  1. Discovery of Azetidinone Acids as Conformationally-Constrained Dual PPARalpha/gamma Agonists

    SciTech Connect

    Wang, W.; Devasthale, P; Farrelly, D; Gu, L; Harrity, T; Cap, M; Chu, C; Kunselman, L; Morgan, N; et. al.

    2008-01-01

    A novel class of azetidinone acid-derived dual PPAR{alpha}/{gamma} agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARa and PPAR? receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

  2. [Dopamin agonist treatment and fibrotic heart valve disease in hyperprolactinaemia patients].

    PubMed

    Steffensen, Charlotte; Mægbæk, Merete Lund; Laurberg, Peter; Andersen, Marianne; Kistorp, Caroline; Nørrelund, Helene; Dal, Jakob; Jørgensen, Jens Otto Lunde

    2014-01-01

    Treatment with dopamin agonists, particularly cabergoline, is the primary and preferred therapy for prolactinomas and symptomatic hyperprolactinaemia due to its effectiveness and tolerability. However, an association has been demonstrated between fibrotic heart valve disease and high-dose dopamin agonist use in patients with Parkinson's disease in several echocardiographic studies. Such observations have prompted a number of studies of valvular function in cabergoline-treated hyperprolactinaemia patients. These studies have failed to show an increased prevalence of clinically significant valvular regurgitation. PMID:24629610

  3. SUPPRESSION OF THE LUTEINIZING HORMONE SURGE BY CHLORDIMEFORM IN OVARIECTOMIZED, STEROID-PRIMED FEMALE RATS

    EPA Science Inventory

    The midcycle surge of luteinizing hormone (LH) from the pituitary provides the physiological trigger in the mammalian female for the process of ovulation. ccordingly, any agent that compromises the LH surge could function as a reproductive toxicant. ince ovariectomized (OVX) rats...

  4. Evaluation of novel synthetic TLR7/8 agonists as vaccine adjuvants.

    PubMed

    Smith, Alyson J; Li, Yufeng; Bazin, Hélène G; St-Jean, Julien R; Larocque, Daniel; Evans, Jay T; Baldridge, Jory R

    2016-08-01

    Small-molecule adjuvants that boost and direct adaptive immunity provide a powerful means to increase the effectiveness of vaccines. Through rational design several novel imidazoquinoline and oxoadenine TLR7/8 agonists, each with unique molecular modifications, were synthesized and assessed for their ability to augment adaptive immunity. All agonists bound human TLR7 and TLR8 and induced maturation of both human mDCs and pDCs. All agonists prompted production of type I interferon and/or proinflammatory cytokines, albeit with varying potencies. In most in vitro assays, the oxoadenine class of agonists proved more potent than the imidazoquinolines. Therefore, an optimized oxoadenine TLR7/8 agonist that demonstrated maximal activity in the in vitro assays was further assessed in a vaccine study with the CRM197 antigen in a porcine model. Antigen-specific antibody production was greatly enhanced in a dose dependent manner, with antibody titers increased 800-fold compared to titers from pigs vaccinated with the non-adjuvanted vaccine. Moreover, pigs vaccinated with antigen containing the highest dose of adjuvant promoted a 13-fold increase in the percentage of antigen-specific CD3(+)/CD8(+) T cells over pigs vaccinated with antigen alone. Together this work demonstrates the promise of these novel TLR7/8 agonists as effective human vaccine adjuvants. PMID:27402566

  5. Alpha/sub 1/ receptor coupling events initiated by methoxy-substituted tolazoline partial agonists

    SciTech Connect

    Wick, P.; Keung, A.; Deth, R.

    1986-03-01

    A series of mono- and dimethyoxy substituted tolazoline derivatives, known to be partial agonists at the alpha/sub 1/ receptor, were compared with the ..cap alpha../sub 1/ selective full agonist phenylephrine (PE) on isolated strips of rabbit aorta Agonist activity was evaluated in contraction, /sup 45/Ca influx, /sup 45/Ca efflux, and /sup 32/P-Phospholipid labelling studies. Maximum contractile responses for the 2-, 3-, and 3, 5- methoxy substituted tolazoline derivatives (10/sup -5/M) were 53.8, 67.6 and 99.7% of the PE (10/sup -5/M) response respectively. These same partial agonists caused a stimulation of /sup 45/Ca influx to the extent of 64, 86, and 95% of the PE response respectively. In /sup 45/Ca efflux studies, (a measure of the intracellular Ca/sup +2/ release) the tolazolines caused: 30%, 63%, and 78% of the PE stimulated level. /sup 32/P-Phosphatidic acid (PA) labelling was measured as an index of PI turnover after ..cap alpha../sub 1/ receptor stimulation. Compared to PE, the 2-, 3-, and 3,5- methoxy substituted tolazoline derivatives caused 22, 46, and 72% PA labelling. The above values are all in reasonable accord with the rank order or agonist activity shown in maximum contractile responses. The results of this investigation suggest that partial agonists stimulate ..cap alpha.. receptor coupling events at a level which is quantitatively comparable to their potencies in causing contraction of arterial smooth muscle.

  6. β-Adrenoreceptor agonists in the management of pain associated with renal colic: a systematic review

    PubMed Central

    Johnson, Graham David; Fakis, Apostolos; Surtees, Jane; Lennon, Robert Iain

    2016-01-01

    Objectives To determine whether β-adrenoreceptor agonists are effective analgesics for patients with renal colic through a systematic review of the literature. Setting Adult emergency departments or acute assessment units. Participants Human participants with proven or suspected renal colic. Interventions β-adrenoreceptor agonists. Outcome measures Primary: level of pain at 30 min following administration of the β-agonist. Secondary: level of pain at various time points following β-agonist administration; length of hospital stay; analgesic requirement; stone presence, size and position; degree of hydronephrosis. Results 256 records were screened and 4 identified for full-text review. No articles met the inclusion criteria. Conclusions and implications There is no evidence to support or refute the proposed use of β-agonists for analgesia in patients with renal colic. Given the biological plausibility and existing literature base, clinical trials investigating the use of β-adrenoreceptor agonists in the acute setting for treatment of the pain associated with renal colic are recommended. Trial registration number CRD42015016266. PMID:27324714

  7. PPARα-Independent Arterial Smooth Muscle Relaxant Effects of PPARα Agonists

    PubMed Central

    Silswal, Neerupma; Parelkar, Nikhil K.; Wacker, Michael J.; Badr, Mostafa; Andresen, Jon

    2012-01-01

    We sought to determine direct vascular effects of peroxisome proliferator-activated receptor alpha (PPARα) agonists using isolated mouse aortas and middle cerebral arteries (MCAs). The PPARα agonists GW7647, WY14643, and gemfibrozil acutely relaxed aortas held under isometric tension and dilated pressurized MCAs with the following order of potency: GW7647≫WY14643>gemfibrozil. Responses were endothelium-independent, and the use of PPARα deficient mice demonstrated that responses were also PPARα-independent. Pretreating arteries with high extracellular K+ attenuated PPARα agonist-mediated relaxations in the aorta, but not in the MCA. In the aorta, the ATP sensitive potassium (KATP) channel blocker glibenclamide also impaired relaxations whereas the other K+ channel inhibitors, 4-aminopyridine and Iberiotoxin, had no effect. In aortas, GW7647 and WY14643 elevated cGMP levels by stimulating soluble guanylyl cyclase (sGC), and inhibition of sGC with ODQ blunted relaxations to PPARα agonists. In the MCA, dilations were inhibited by the protein kinase C (PKC) activator, phorbol 12,13-dibutyrate, and also by ODQ. Our results demonstrated acute, nonreceptor-mediated relaxant effects of PPARα agonists on smooth muscle of mouse arteries. Responses to PPARα agonists in the aorta involved KATP channels and sGC, whereas in the MCA the PKC and sGC pathways also appeared to contribute to the response. PMID:23008696

  8. Fluorescence characteristics of hydrophobic partial agonist probes of the cholecystokinin receptor.

    PubMed

    Harikumar, Kaleeckal G; Pinon, Delia I; Miller, Laurence J

    2006-04-01

    Fluorescence spectroscopic studies are powerful tools for the evaluation of receptor structure and the dynamic changes associated with receptor activation. Here, we have developed two chemically distinct fluorescent probes of the cholecystokinin (CCK) receptor by attaching acrylodan or a nitrobenzoxadiazole moiety to the amino terminus of a partial agonist CCK analogue. These two probes were able to bind to the CCK receptor specifically and with high affinity, and were able to elicit only submaximal intracellular calcium responses typical of partial agonists. The fluorescence characteristics of these probes were compared with those previously reported for structurally-related full agonist and antagonist probes. Like the previous probes, the partial agonist probes exhibited longer fluorescence lifetimes and increased anisotropy when bound to the receptor than when free in solution. The receptor-bound probes were not easily quenched by potassium iodide, suggesting that the fluorophores were protected from the extracellular aqueous milieu. The fluorescence characteristics of the partial agonist probes were quite similar to those of the analogous full agonist probes and quite distinct from the analogous antagonist probes. These data suggest that the partially activated conformational state of this receptor is more closely related to its fully active state than to its inactive state. PMID:16779661

  9. Three-dimensional common-feature hypotheses for octopamine agonist 2-(arylimino)imidazolidines.

    PubMed

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Taniguchi, Eiji; Eto, Morifusa

    2002-01-01

    Three-dimensional pharmacophore hypotheses were built from a set of 10 octopamine (OA) agonist 2-(Arylimino)imidazolidines (AIIs), 2-(Arylimino)thiazolidines (AITs) and 2-(Arylimino)oxazolidines (AIOs). Among the 10 common-featured models generated by program Catalyst/HipHop, a hypothesis including a ring aromatic (RA), a positive ionizable (PI) and three hydrophobic aliphatic (HpAl) features was considered to be important in evaluating the OA-agonist activity. Active OA agonist 2,6-Et2 AII mapped well onto all the RA, PI and HpAl features of the hypothesis. On the other hand, less active compounds were shown to be difficult to achieve the energetically favorable conformation which is found in the active molecules in order to fit the 3-D common-feature pharmacophore models. Taken together, 2,6-Et2-Ph and foramidine structures are important as OA agonists. The present studies on OA agonists demonstrate that a RA, a PI and three HpAl sites located on the molecule seem to be essential for OA-agonist activity. PMID:11738614

  10. Systemic chemotherapy is modulated by platelet-activating factor-receptor agonists.

    PubMed

    Sahu, Ravi P; Ferracini, Matheus; Travers, Jeffrey B

    2015-01-01

    Chemotherapy is used to treat numerous cancers including melanoma. However, its effectiveness in clinical settings is often hampered by various mechanisms. Previous studies have demonstrated that prooxidative stressor-mediated generation of oxidized lipids with platelet-activating factor-receptor (PAF-R) agonistic activity induces systemic immunosuppression that augments the growth of experimental melanoma tumors. We have recently shown that treatment of murine B16F10 melanoma cells in vitro or tumors implanted into syngeneic mice and treated intratumorally with various chemotherapeutic agents generated PAF-R agonists in a process blocked by antioxidants. Notably, these intratumoral chemotherapy-generated PAF-R agonists augmented the growth of secondary (untreated) tumors in a PAF-R dependent manner. As both localized and systemic chemotherapies are used based on tumor localization/stage and metastases, the current studies were sought to determine effects of PAF-R agonists on systemic chemotherapy against experimental melanoma. Here, we show that systemic chemotherapy with etoposide (ETOP) attenuates the growth of melanoma tumors when given subsequent to the tumor cell implantation. Importantly, this ETOP-mediated suppression of melanoma tumor growth was blocked by exogenous administration of a PAF-R agonist, CPAF. These findings indicate that PAF-R agonists not only negatively affect the ability of localized chemotherapy but also compromise the efficacy of systemic chemotherapy against murine melanoma. PMID:25922565

  11. Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections

    PubMed Central

    Mhashilkar, Amruta S.; Vankayala, Sai L.; Liu, Canhui; Kearns, Fiona; Mehrotra, Priyanka; Tzertzinis, George; Palli, Subba R.; Woodcock, H. Lee; Unnasch, Thomas R.

    2016-01-01

    Background A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. Methodology/ Principal Findings Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites. Conclusions The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites. PMID:27300294

  12. Proteasome involvement in agonist-induced down-regulation of mu and delta opioid receptors.

    PubMed

    Chaturvedi, K; Bandari, P; Chinen, N; Howells, R D

    2001-04-13

    This study investigated the mechanism of agonist-induced opioid receptor down-regulation. Incubation of HEK 293 cells expressing FLAG-tagged delta and mu receptors with agonists caused a time-dependent decrease in opioid receptor levels assayed by immunoblotting. Pulse-chase experiments using [(35)S]methionine metabolic labeling indicated that the turnover rate of delta receptors was accelerated 5-fold following agonist stimulation. Inactivation of functional G(i) and G(o) proteins by pertussis toxin-attenuated down-regulation of the mu opioid receptor, while down-regulation of the delta opioid receptor was unaffected. Pretreatment of cells with inhibitors of lysosomal proteases, calpain, and caspases had little effect on mu and delta opioid receptor down-regulation. In marked contrast, pretreatment with proteasome inhibitors attenuated agonist-induced mu and delta receptor down-regulation. In addition, incubation of cells with proteasome inhibitors in the absence of agonists increased steady-state mu and delta opioid receptor levels. Immunoprecipitation of mu and delta opioid receptors followed by immunoblotting with ubiquitin antibodies suggested that preincubation with proteasome inhibitors promoted accumulation of polyubiquitinated receptors. These data provide evidence that the ubiquitin/proteasome pathway plays a role in agonist-induced down-regulation and basal turnover of opioid receptors. PMID:11152677

  13. How neighborhood disorder increases blood pressure in youth: agonistic striving and subordination

    PubMed Central

    Elder, Gavin J.; Smyth, Joshua M.

    2012-01-01

    Growing evidence links perceptions of neighborhood disorder to adverse health outcomes but little is known about psychological processes that may mediate this association. We tested the hypothesis that two psychological mechanisms—agonistic striving and subordination—mediate the link between perceived neighborhood disorder and hypertension risk in youth. Perceived neighborhood disorder, agonistic striving, subordination experiences, negative affect, obesity, and ambulatory blood pressure during daily activities (48 h) were assessed in a multiethnic sample of 167 low- to middle-income urban adolescents. Path analyses revealed that agonistic striving, subordination, and obesity each independently mediated the association between neighborhood disorder and blood pressure; these variables accounted for 73 % of the shared variance, 42 % of which was explained by agonistic striving. The direct relationship between perceived neighborhood disorder and blood pressure was no longer significant in the presence of these mediators. Negative affect was associated with neighborhood disorder and subordination, but not blood pressure. Agonistic striving proved to be a significant and substantial mediator of the association between perceived neighborhood disorder, blood pressure, and future hypertension risk. New research should seek to clarify the processes by which stressful neighborhoods induce persistent agonistic motives and perceptions of subordination in adolescents. PMID:23229689

  14. Analysis of the agonist activity of fenoldopam (SKF 82526) at the vascular 5-HT2 receptor.

    PubMed Central

    Christie, M. I.; Harper, D.; Smith, G. W.

    1992-01-01

    1. The 5-HT2 receptor agonist activity of fenoldopam (SKF 82526) was characterized in the rabbit isolated aorta preparation. 2. Fenoldopam was an agonist at the vascular 5-HT2 receptor with lower affinity and efficacy than the naturally occurring agonist 5-hydroxytryptamine (5-HT). Fenoldopam had an affinity (pKA) of 5.84 +/- 0.04 and efficacy (tau) of 0.57 +/- 0.04, whereas 5-HT had a pKA of 6.65 +/- 0.12 and tau of 2.66 +/- 0.41. 3. The constrictor effects of fenoldopam and 5-HT were competitively antagonized by the 5-HT2 antagonist, ketanserin, with pKB values of 8.81 +/- 0.11 and 8.83 +/- 0.10 respectively. 4. Prior incubation with fenoldopam produced a concentration-related rightward shift of a subsequent 5-HT concentration-response curve. This inhibition was specific for 5-HT since constrictor responses to angiotensin II were unaffected. 5. This study indicates that the D1 receptor agonist, fenoldopam, acts as an agonist at the vascular 5-HT2 receptor, but with an affinity and efficacy less than that of the naturally occurring agonist, 5-HT. PMID:1361397

  15. Do inhaled beta(2)-agonists have an ergogenic potential in non-asthmatic competitive athletes?

    PubMed

    Kindermann, Wilfried

    2007-01-01

    The prevalence of asthma is higher in elite athletes than in the general population. The risk of developing asthmatic symptoms is the highest in endurance athletes and swimmers. Asthma seems particularly widespread in winter-sport athletes such as cross-country skiers. Asthmatic athletes commonly use inhaled beta(2)-agonists to prevent and treat asthmatic symptoms. However, beta(2)-agonists are prohibited according to the Prohibited List of the World Anti-Doping Agency. An exception can be made only for the substances formoterol, salbutamol, salmeterol and terbutaline by inhalation, as long as a therapeutic use exemption has been applied for and granted. In this context, the question arises of whether beta(2)-agonists have ergogenic benefits justifying the prohibition of these substances. In 17 of 19 randomised placebo-controlled trials in non-asthmatic competitive athletes, performance-enhancing effects of the inhaled beta(2)-agonists formoterol, salbutamol, salmeterol and terbutaline could not be proved. This is particularly true for endurance performance, anaerobic power and strength performance. In three of four studies, even supratherapeutic doses of salbutamol (800-1200 microg) had no ergogenic effect. In contrast to inhaled beta(2)-agonists, oral administration of salbutamol seems to be able to improve the muscle strength and the endurance performance. There appears to be no justification to prohibit inhaled beta(2)-agonists from the point of view of the ergogenic effects. PMID:17241101

  16. The Good, the Bad, and the Ugly: Agonistic Behaviour in Juvenile Crocodilians

    PubMed Central

    Brien, Matthew L.; Lang, Jeffrey W.; Webb, Grahame J.; Stevenson, Colin; Christian, Keith A.

    2013-01-01

    We examined agonistic behaviour in seven species of hatchling and juvenile crocodilians held in small groups (N = 4) under similar laboratory conditions. Agonistic interactions occurred in all seven species, typically involved two individuals, were short in duration (5–15 seconds), and occurred between 1600–2200 h in open water. The nature and extent of agonistic interactions, the behaviours displayed, and the level of conspecific tolerance varied among species. Discrete postures, non-contact and contact movements are described. Three of these were species-specific: push downs by C. johnstoni; inflated tail sweeping by C. novaeguineae; and, side head striking combined with tail wagging by C. porosus. The two long-snouted species (C. johnstoni and G. gangeticus) avoided contact involving the head and often raised the head up out of the way during agonistic interactions. Several behaviours not associated with aggression are also described, including snout rubbing, raising the head up high while at rest, and the use of vocalizations. The two most aggressive species (C. porosus, C. novaeguineae) appeared to form dominance hierarchies, whereas the less aggressive species did not. Interspecific differences in agonistic behaviour may reflect evolutionary divergence associated with morphology, ecology, general life history and responses to interspecific conflict in areas where multiple species have co-existed. Understanding species-specific traits in agonistic behaviour and social tolerance has implications for the controlled raising of different species of hatchlings for conservation, management or production purposes. PMID:24349018

  17. Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B

    PubMed Central

    Vugmeyster, Yulia; Rohde, Cynthia; Perreault, Mylene; Gimeno, Ruth E.; Singh, Pratap

    2013-01-01

    TAM-163, an agonist monoclonal antibody targeting tyrosine receptor kinase-B (TrkB), is currently being investigated as a potential body weight modulatory agent in humans. To support the selection of the dose range for the first-in-human (FIH) trial of TAM-163, we conducted a mechanistic analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) data (e.g., body weight gain) obtained in lean cynomolgus and obese rhesus monkeys following single doses ranging from 0.3 to 60 mg/kg. A target-mediated drug disposition (TMDD) model was used to describe the observed nonlinear PK and Emax approach was used to describe the observed dose-dependent PD effect. The TMDD model development was supported by the experimental determination of the binding affinity constant (9.4 nM) and internalization rate of the drug-target complex (2.08 h−1). These mechanistic analyses enabled linking of exposure, target (TrkB) coverage, and pharmacological activity (e.g., PD) in monkeys, and indicated that ≥ 38% target coverage (time-average) was required to achieve significant body weight gain in monkeys. Based on the scaling of the TMDD model from monkeys to humans and assuming similar relationship between the target coverage and pharmacological activity between monkey and humans, subcutaneous (SC) doses of 1 and 15 mg/kg in humans were projected to be the minimally and the fully pharmacologically active doses, respectively. Based on the minimal anticipated biological effect level (MABEL) approach for starting dose selection, the dose of 0.05 mg/kg (3 mg for a 60 kg human) SC was recommended as the starting dose for FIH trials, because at this dose level < 10% target coverage was projected at Cmax (and all other time points). This study illustrates a rational mechanistic approach for the selection of FIH dose range for a therapeutic protein with a complex model of action. PMID:23529133

  18. Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARγ agonist

    PubMed Central

    Goto, Tsuyoshi; Nagai, Hiroyuki; Egawa, Kahori; Kim, Young-Il; Kato, Sota; Taimatsu, Aki; Sakamoto, Tomoya; Ebisu, Shogo; Hohsaka, Takahiro; Miyagawa, Hiroh; Murakami, Shigeru; Takahashi, Nobuyuki; Kawada, Teruo

    2011-01-01

    The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPARγ (peroxisome-proliferator-activated receptor γ), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPARγ systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPARγ in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)–PPARγ. Direct binding of FPP to PPARγ was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPARγ target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPARγ-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPARγ-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPARγ agonist and regulate gene expression in adipocytes. PMID:21605082

  19. Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARγ agonist.

    PubMed

    Goto, Tsuyoshi; Nagai, Hiroyuki; Egawa, Kahori; Kim, Young-Il; Kato, Sota; Taimatsu, Aki; Sakamoto, Tomoya; Ebisu, Shogo; Hohsaka, Takahiro; Miyagawa, Hiroh; Murakami, Shigeru; Takahashi, Nobuyuki; Kawada, Teruo

    2011-08-15

    The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPARγ (peroxisome-proliferator-activated receptor γ), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPARγ systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPARγ in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)-PPARγ. Direct binding of FPP to PPARγ was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPARγ target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPARγ-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPARγ-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPARγ agonist and regulate gene expression in adipocytes. PMID:21605082

  20. Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists.

    PubMed

    Kang, Yu Mi; Jung, Chang Hee

    2016-06-01

    Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes. PMID:27118277

  1. Metabolic mapping of A3 adenosine receptor agonist MRS5980.

    PubMed

    Fang, Zhong-Ze; Tosh, Dilip K; Tanaka, Naoki; Wang, Haina; Krausz, Kristopher W; O'Connor, Robert; Jacobson, Kenneth A; Gonzalez, Frank J

    2015-09-15

    (1S,2R,3S,4R,5S)-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide (MRS5980) is an A3AR selective agonist containing multiple receptor affinity- and selectivity-enhancing modifications and a therapeutic candidate drug for many inflammatory diseases. Metabolism-related poor pharmacokinetic behavior and toxicities are a major reason for drug R&D failure. Metabolomics with UPLC-MS was employed to profile the metabolism of MRS5980 and MRS5980-induced disruption of endogenous compounds. Recombinant drug-metabolizing enzymes screening experiment were used to determine the enzymes involved in MRS5980 metabolism. Analysis of lipid metabolism-related genes was performed to investigate the reason for MRS5980-induced lipid metabolic disorders. Unsupervised principal components analysis separated the control and MRS5980 treatment groups in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation of feces and urine were oxidized MRS5980, glutathione (GSH) conjugates and cysteine conjugate (degradation product of the GSH conjugates) of MRS5980. The major ions contributing to the group separation of liver samples were phosphatidylcholines. In vitro incubation experiments showed the involvement of CYP3A enzymes in the oxidative metabolism of MRS5980 and direct GSH reactivity of MRS5980. The electrophilic attack by MRS5980 is a minor pathway and did not alter GSH levels in liver or liver histology, and thus may be of minor clinical consequence. Gene expression analysis further showed decreased expression of PC biosynthetic genes choline kinase a and b, which further accelerated conversion of lysophosphatidylcholine to phosphatidylcholines through increasing the expression of lysophosphatidylcholine acyltransferase 3. These data will be useful to guide rational design of drugs targeting A3AR, considering efficacy, metabolic elimination, and

  2. Agonist-induced Ca2+ Sensitization in Smooth Muscle

    PubMed Central

    Artamonov, Mykhaylo V.; Momotani, Ko; Stevenson, Andra; Trentham, David R.; Derewenda, Urszula; Derewenda, Zygmunt S.; Read, Paul W.; Gutkind, J. Silvio; Somlyo, Avril V.

    2013-01-01

    Many agonists, acting through G-protein-coupled receptors and Gα subunits of the heterotrimeric G-proteins, induce contraction of smooth muscle through an increase of [Ca2+]i as well as activation of the RhoA/RhoA-activated kinase pathway that amplifies the contractile force, a phenomenon known as Ca2+ sensitization. Gα12/13 subunits are known to activate the regulator of G-protein signaling-like family of guanine nucleotide exchange factors (RhoGEFs), which includes PDZ-RhoGEF (PRG) and leukemia-associated RhoGEF (LARG). However, their contributions to Ca2+-sensitized force are not well understood. Using permeabilized blood vessels from PRG(−/−) mice and a new method to silence LARG in organ-cultured blood vessels, we show that both RhoGEFs are activated by the physiologically and pathophysiologically important thromboxane A2 and endothelin-1 receptors. The co-activation is the result of direct and independent activation of both RhoGEFs as well as their co-recruitment due to heterodimerization. The isolated recombinant C-terminal domain of PRG, which is responsible for heterodimerization with LARG, strongly inhibited Ca2+-sensitized force. We used photolysis of caged phenylephrine, caged guanosine 5′-O-(thiotriphosphate) (GTPγS) in solution, and caged GTPγS or caged GTP loaded on the RhoA·RhoGDI complex to show that the recruitment and activation of RhoGEFs is the cause of a significant time lag between the initial Ca2+ transient and phasic force components and the onset of Ca2+-sensitized force. PMID:24106280

  3. Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists

    PubMed Central

    Kang, Yu Mi

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes. PMID:27118277

  4. [Functional exploration of brown adipose tissue using beta3 agonists].

    PubMed

    Bertin, R; de Marco, F; Blancher, G; Portet, R

    1994-06-01

    In view to utilize beta 3 adrenoceptor agonists for the investigation of body lipid metabolism, a study of the effects of BRL 37344 on the functional activity of the brown adipose tissue was performed in the Rat. It is known that this tissue is the principal site of heat production for nonshivering thermogenesis mainly due to the oxidation of fatty acids under the control of norepinephrine (NA) released from the sympathetic nervous system. In order to stimulate the activity of the tissue, rats were reared at 16 degrees C. When they were one month old, they were divided in two groups; one group received a surgical sympathectomy of the interscapular brown adipose tissue (TABI) (S group); the other group was sham-operated (T group). The resting metabolism was estimated by the continuous measurement of O2 consumption and CO2 release, at an ambient temperature of 25 degrees C. The animal capacity for nonshivering thermogenesis was determined by increased O2 consumption following i.p. administration of NA or BRL 37344. In the S group a large decrease in TABI NA content and a decrease in resting metabolism were observed. In both groups VO2 was increased by the two drugs; the increase was linearly related to the dose of BRL (between 2.5 to 10 micrograms/kg); but it was 3 times as high in the T group as in the S group. Moreover, the effect of BRL was 40 fold greater than the effect of NA. These results seem to indicate that, in cold reared rats, a part of nonshivering thermogenesis may be mediated by the beta 3 receptors of the brown fat. It may be concluded that the rats born in cold conditions are good models to study the role of beta 3 receptors in the energetic activity of this tissue very profuse in infant but not in adult man. PMID:7994586

  5. GABAA agonist reduces visual awareness: a masking-EEG experiment.

    PubMed

    van Loon, Anouk M; Scholte, H Steven; van Gaal, Simon; van der Hoort, Björn J J; Lamme, Victor A F

    2012-04-01

    Consciousness can be manipulated in many ways. Here, we seek to understand whether two such ways, visual masking and pharmacological intervention, share a common pathway in manipulating visual consciousness. We recorded EEG from human participants who performed a backward-masking task in which they had to detect a masked figure form its background (masking strength was varied across trials). In a within-subject design, participants received dextromethorphan (a N-methyl-d-aspartate receptor antagonist), lorazepam (LZP; a GABA(A) receptor agonist), scopolamine (a muscarine receptor antagonist), or placebo. The behavioral results show that detection rate decreased with increasing masking strength and that of all the drugs, only LZP induced a further decrease in detection rate. Figure-related ERP signals showed three neural events of interest: (1) an early posterior occipital and temporal generator (94-121 msec) that was not influenced by any pharmacological manipulation nor by masking, (2) a later bilateral perioccipital generator (156-211 msec) that was reduced by masking as well as LZP (but not by any other drugs), and (3) a late bilateral occipital temporal generator (293-387 msec) that was mainly affected by masking. Crucially, only the intermediate neural event correlated with detection performance. In combination with previous findings, these results suggest that LZP and masking both reduce visual awareness by means of modulating late activity in the visual cortex but leave early activation intact. These findings provide the first evidence for a common mechanism for these two distinct ways of manipulating consciousness. PMID:22264199

  6. Radiolabelled D2 agonists as prolactinoma imaging agents

    SciTech Connect

    Otto, C.A.

    1989-08-01

    During the past year, further studies on mAChR were conducted. These studies included verification of the difference in pituitary distribution based on ligand charge. The pituitary localization of TRB. A neutral mAChR ligand, was verified. The lack of QNB blockade of TRB uptake was tested by blockage with scopolamine, another mAChR antagonist and by testing the effect in a different strain of rat. Neither scopolamine or change of rat strain had any effect. We concluded that TRB uptake in pituitary is not a receptor-mediated process. Further studies were conducted with an additional quaternized mAChR ligand: MQNB. Pituitary localization of MQNB, like MTRB, could be blocked by pretreatment with QNB. We have tentatively concluded that permanent charge on a mAChR antagonist changes the mechanism of uptake in the pituitary. Time course studies and the effects of DES on myocardial uptake are reported. A brief report on preliminary results of evaluation of quaternized mAChR ligands in the heart is included. In a limited series of such ligands, we have observed a single binding site and a difference in B{sub max} values: QNB competition studies yield larger B{sub max} values than studies with {sup 3}H-NMS. Progress in the synthesis of D{sub 2} agonists includes solving a synthetic problem and preparation of the cold'' analogue of N-0437 using procedures applicable to eventual synthesis with {sup 11}C-CH{sub 3}I. 2 refs., 5 figs., 1 tab.

  7. RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects.

    PubMed

    Kawata, Kohei; Morishita, Ken-ichi; Nakayama, Mariko; Yamada, Shoya; Kobayashi, Toshiki; Furusawa, Yuki; Arimoto-Kobayashi, Sakae; Oohashi, Toshitaka; Makishima, Makoto; Naitou, Hirotaka; Ishitsubo, Erika; Tokiwa, Hiroaki; Tai, Akihiro; Kakuta, Hiroki

    2015-01-22

    We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5. PMID:25486327

  8. Agonist-bound structure of the human P2Y12 receptor

    PubMed Central

    Zhang, Jin; Zhang, Kaihua; Gao, Zhan-Guo; Paoletta, Silvia; Zhang, Dandan; Han, Gye Won; Li, Tingting; Ma, Limin; Zhang, Wenru; Müller, Christa E.; Yang, Huaiyu; Jiang, Hualiang; Cherezov, Vadim; Katritch, Vsevolod; Jacobson, Kenneth A.; Stevens, Raymond C.; Wu, Beili; Zhao, Qiang

    2014-01-01

    The P2Y12 receptor (P2Y12R), one of eight members of the P2YR family expressed in humans, has been identified as one of the most prominent clinical drug targets for inhibition of platelet aggregation. Consequently, extensive mutagenesis and modeling studies of the P2Y12R have revealed many aspects of agonist/antagonist binding1-4. However, the details of agonist and antagonist recognition and function at the P2Y12R remain poorly understood at the molecular level. Here, we report the structures of the human P2Y12R in complex with a full agonist 2-methylthio-adenosine-5′-diphosphate (2MeSADP, a close analogue of endogenous agonist ADP) at 2.5 Å resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5′-triphosphate (2MeSATP) at 3.1 Å resolution. Analysis of these structures, together with the structure of the P2Y12R with antagonist ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283)5, reveals dramatic conformational changes between nucleotide and non-nucleotide ligand complexes in the extracellular regions, providing the first insight into a different ligand binding landscape in the δ-group of class A G protein-coupled receptors (GPCRs). Agonist and non-nucleotide antagonist adopt different orientations in the P2Y12R, with only partially overlapped binding pockets. The agonist-bound P2Y12R structure answers long-standing ambiguities surrounding P2Y12R-agonist recognition, and reveals interactions with several residues that had not been reported to be involved in agonist binding. As a first example of a GPCR where agonist access to the binding pocket requires large scale rearrangements in the highly malleable extracellular region, the structural studies therefore will provide invaluable insight into the pharmacology and mechanisms of action of agonists and different classes of antagonists for the P2Y12R and potentially for other closely related P2YRs. PMID:24784220

  9. Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice

    PubMed Central

    Olson, Katherine E.; Kosloski-Bilek, Lisa M.; Anderson, Kristi M.; Diggs, Breha J.; Clark, Barbara E.; Gledhill, John M.; Shandler, Scott J.; Mosley, R. Lee

    2015-01-01

    Vasoactive intestinal peptide (VIP) mediates a broad range of biological responses by activating two related receptors, VIP receptor 1 and 2 (VIPR1 and VIPR2). Although the use of native VIP facilitates neuroprotection, clinical application of the hormone is limited due to VIP's rapid metabolism and inability to distinguish between VIPR1 and VIPR2 receptors. In addition, activation of both receptors by therapeutics may increase adverse secondary toxicities. Therefore, we developed metabolically stable and receptor-selective agonists for VIPR1 and VIPR2 to improve pharmacokinetic and pharmacodynamic therapeutic end points. Selective agonists were investigated for their abilities to protect mice against MPTP-induced neurodegeneration used to model Parkinson's disease (PD). Survival of tyrosine hydroxylase neurons in the substantia nigra was determined by stereological tests after MPTP intoxication in mice pretreated with either VIPR1 or VIPR2 agonist or after adoptive transfer of splenic cell populations from agonist-treated mice administered to MPTP-intoxicated animals. Treatment with VIPR2 agonist or splenocytes from agonist-treated mice resulted in increased neuronal sparing. Immunohistochemical tests showed that agonist-treated mice displayed reductions in microglial responses, with the most pronounced effects in VIPR2 agonist-treated, MPTP-intoxicated mice. In parallel studies, we observed reductions in proinflammatory cytokine release that included IL-17A, IL-6, and IFN-γ and increases in GM-CSF transcripts in CD4+ T cells recovered from VIPR2 agonist-treated animals. Moreover, a phenotypic shift of effector to regulatory T cells was observed. These results support the use of VIPR2-selective agonists as neuroprotective agents for PD treatment. SIGNIFICANCE STATEMENT Vasoactive intestinal peptide receptor 2 can elicit immune transformation in a model of Parkinson's disease (PD). Such immunomodulatory capabilities can lead to neuroprotection by attenuating

  10. A molecular characterization of the agonist binding site of a nematode cys-loop GABA receptor

    PubMed Central

    Kaji, Mark D; Kwaka, Ariel; Callanan, Micah K; Nusrat, Humza; Desaulniers, Jean-Paul; Forrester, Sean G

    2015-01-01

    Background and Purpose Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and are potential targets for novel anthelmintics (nematicides). However, compared with insect and mammalian receptors, little is known regarding the pharmacological characteristics of nematode Cys-loop GABA receptors. Here we have investigated the agonist binding site of the Cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. Experimental Approach We used two-electrode voltage-clamp electrophysiology to measure channel activation by classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes, along with site-directed mutagenesis and in silico homology modelling. Key Results The sulphonated molecules P4S and taurine had no effect on Hco-UNC-49. Other classical Cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > trans-4-aminocrotonic acid > isoguvacine > imidazole-4-acetic acid (IMA) > (R)-(−)-4-amino-3-hydroxybutyric acid [R(−)-GABOB] > (S)-(+)-4-amino-3-hydroxybutyric acid [S(+)-GABOB] > guanidinoacetic acid > isonipecotic acid > 5-aminovaleric acid (DAVA) (partial agonist) > β-alanine (partial agonist). In silico ligand docking revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response to DAVA and decreased twofold the EC50 for R(−)- and S(+)-GABOB. Conclusions and Implications The pharmacological profile of Hco-UNC-49 differed from that of vertebrate Cys-loop GABA receptors and insect resistance to dieldrin receptors, suggesting differences in the agonist binding pocket. These findings could be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes. PMID:25850584

  11. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice.

    PubMed

    Wagner, Martin; Halilbasic, Emina; Marschall, Hanns-Ulrich; Zollner, Gernot; Fickert, Peter; Langner, Cord; Zatloukal, Kurt; Denk, Helmut; Trauner, Michael

    2005-08-01

    Induction of hepatic phase I/II detoxification enzymes and alternative excretory pumps may limit hepatocellular accumulation of toxic biliary compounds in cholestasis. Because the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate involved enzymes and transporters, we aimed to induce adaptive alternative pathways with different CAR and PXR agonists in vivo. Mice were treated with the CAR agonists phenobarbital and 1,4-bis-[2-(3,5-dichlorpyridyloxy)]benzene, as well as the PXR agonists atorvastatin and pregnenolone-16alpha-carbonitrile. Hepatic bile acid and bilirubin-metabolizing/detoxifying enzymes (Cyp2b10, Cyp3a11, Ugt1a1, Sult2a1), their regulatory nuclear receptors (CAR, PXR, farnesoid X receptor), and bile acid/organic anion and lipid transporters (Ntcp, Oatp1,2,4, Bsep, Mrp2-4, Mdr2, Abcg5/8, Asbt) in the liver and kidney were analyzed via reverse-transcriptase polymerase chain reaction and Western blotting. Potential functional relevance was tested in common bile duct ligation (CBDL). CAR agonists induced Mrp2-4 and Oatp2; PXR agonists induced only Mrp3 and Oatp2. Both PXR and CAR agonists profoundly stimulated bile acid-hydroxylating/detoxifying enzymes Cyp3a11 and Cyp2b10. In addition, CAR agonists upregulated bile acid-sulfating Sult2a1 and bilirubin-glucuronidating Ugt1a1. These changes were accompanied by reduced serum levels of bilirubin and bile acids in healthy and CBDL mice and by increased levels of polyhydroxylated bile acids in serum and urine of cholestatic mice. Atorvastatin significantly increased Oatp2, Mdr2, and Asbt, while other transporters and enzymes were moderately affected. In conclusion, administration of specific CAR or PXR ligands results in coordinated stimulation of major hepatic bile acid/bilirubin metabolizing and detoxifying enzymes and hepatic key alternative efflux systems, effects that are predicted to counteract cholestasis. PMID:15986414

  12. Agonistic onset during development differentiates wild house mouse males (Mus domesticus)

    NASA Astrophysics Data System (ADS)

    Krackow, Sven

    2005-02-01

    Wild house mouse populations have been suggested to locally adapt to varying dispersal regimes by expressing divergent aggressivity phenotypes. This conjecture implies, first, genetic polymorphism for dispersive strategies which is supported by the finding of heritable variation for male dispersal tendency in feral house mice. Secondly, aggressivity is assumed to translate into dispersal rates. This speculation is reinforced by experimental evidence showing that non-agonistic males display lower dispersal propensity than same-aged males that have established agonistic dominance. However, the actual ontogenetic behavioural pattern and its variability among populations remain unknown. Hence, in this study the timing of agonistic onset is quantified within laboratory-reared fraternal pairs, and compared between descendants from two different feral populations. Males from the two populations (G and Z) differed strongly in agonistic development, as Z fraternal pairs had a 50% risk of agonistic onset before 23.5±2.7 days of age, while this took 57.3±5.4 days in males from population G. This difference coincided with significant genetic differentiation between the males of the two populations as determined by 11 polymorphic microsatellite markers. Furthermore, in population G, males from agonistic and amicable fraternal pairs exhibited significant genetic differentiation. These results corroborate the supposition of genetic variability for dispersive strategies in house mice, and identify the ontogenetic timing of agonistic phenotype development as the potential basis for genetic differentiation. This opens a unique opportunity to study the genetic determination of a complex mammalian behavioural syndrome in a life history context, using a simple laboratory paradigm.

  13. PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption.

    PubMed

    Ferguson, Laura B; Most, Dana; Blednov, Yuri A; Harris, R Adron

    2014-11-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior. PMID:25036611

  14. Effects of the serotonin agonists 8-OH-DPAT, buspirone, and DOI on water maze performance.

    PubMed

    Kant, G J; Wylie, R M; Chu, K; Ghosh, S

    1998-03-01

    We have previously reported that the serotonin 5-HT1A agonist 8-OH-DPAT and the 5-HT2c agonist TFMPP impair performance on a water maze. In the present report we extended those studies by examining a second 5-HT1A agonist, buspirone, to see whether its effects paralleled those of 8-OH-DPAT, and by testing the effects of the 5-HT2 agonist DOI. Unlike the open pool Morris water maze, the maze used in these experiments has alleys and doorways. The maze can be easily reconfigured to present rats with both previously learned or new maze challenges. Performance is assessed by time to reach the maze exit platform and the number of wrong doorways entered (errors). At doses that did not affect performance in a previously learned maze, the 5-HT1A agonists 8-OH-DPAT (0.1 mg/kg) and buspirone (1 mg/kg) slowed acquisition of a new maze configuration as measured by both swim time to the exit platform and errors committed. A higher dose of buspirone (10 mg/kg) completely blocked acquisition of a novel maze. In contrast. DOI slowed performance as assessed by swim time on both a well-learned maze as well as acquisition of a new maze, but did not affect error rate on either task, suggesting that this 5-HT2 agonist impaired performance by depressing motor activity. These experiments demonstrate that serotonin agonists, especially the 5-HT1A subtype, can impair learning. PMID:9512079

  15. Differential effects of subtype-specific nicotinic acetylcholine receptor agonists on early and late hippocampal LTP.

    PubMed

    Kroker, Katja S; Rast, Georg; Rosenbrock, Holger

    2011-12-01

    Brain nicotinic acetylcholine receptors are involved in several neuropsychiatric disorders, e.g. Alzheimer's and Parkinson's diseases, Tourette's syndrome, schizophrenia, depression, autism, attention deficit hyperactivity disorder, and anxiety. Currently, approaches selectively targeting the activation of specific nicotinic acetylcholine receptors are in clinical development for treatment of memory impairment of Alzheimer's disease patients. These are α4β2 and α7 nicotinic acetylcholine receptor agonists which are believed to enhance cholinergic and glutamatergic neurotransmission, respectively. In order to gain a better insight into the mechanistic role of these two nicotinic acetylcholine receptors in learning and memory, we investigated the effects of the α4β2 nicotinic acetylcholine receptor agonist TC-1827 and the α7 nicotinic acetylcholine receptor partial agonist SSR180711 on hippocampal long-term potentiation (LTP), a widely accepted cellular experimental model of memory formation. Generally, LTP is distinguished in an early and a late form, the former being protein-synthesis independent and the latter being protein-synthesis dependent. TC-1827 was found to increase early LTP in a bell-shaped dose dependent manner, but did not affect late LTP. In contrast, the α7 nicotinic acetylcholine receptor partial agonist SSR180711 showed enhancing effects on both early and late LTP in a bell-shaped manner. Furthermore, SSR180711 not only increased early LTP, but also transformed it into late LTP, which was not observed with the α4β2 nicotinic acetylcholine receptor agonist. Therefore, based on these findings α7 nicotinic acetylcholine receptor (partial) agonists appear to exhibit stronger efficacy on memory improvement than α4β2 nicotinic acetylcholine receptor agonists. PMID:21968142

  16. Metabotropic glutamate receptor agonists modify the pyloric output of the crustacean stomatogastric ganglion.

    PubMed

    Pérez-Acevedo, Nivia L; Krenz, Wulf D

    2005-11-16

    We have studied the effects of groups I, II, and III metabotropic glutamate receptor (mGluR) agonists and antagonists on pyloric activity in the stomatogastric ganglion (STG) of the Caribbean spiny lobster Panulirus argus. We have found that agonists for all three groups of mGluRs modify the pyloric output. The group I agonist, l-quisqualic acid (l-QA), activated the pyloric central pattern generator (CPG). When the pyloric rhythm was partially suppressed by sucrose-block of input fibers in the stomatogastric nerve (stn), l-QA accelerated the rhythmic activity. In addition, the number of spike discharges was increased in pyloric motoneurons: pyloric (PY), and lateral pyloric (LP). In completely blocked preparations, a slow pyloric rhythm was initiated by l-QA. Groups II and III agonists exerted an inhibitory effect on pyloric activity. The group II agonist, (2S,1'S,2'S)-2-(Carboxycyclopropyl)glycine (L-CCG-I), decreased both the frequency of the pyloric rhythm and the number of spike discharges in the motoneurons: ventricular dilator (VD), PY, and LP. The effects of L-CCG-I were dose-dependent. The group III agonist, l-(+)-2-Amino-4-phosphonobutyric acid (l-AP4), slightly decreased the frequency of the pyloric rhythm and suppressed spike discharges in the VD neuron. All effects of mGluR agonists were reversible. The effect of l-QA was blocked by the broad spectrum mGluR antagonist (S)-Methyl-4-carboxyphenylglycine (MCPG). The inhibitory effect of L-CCG-I was prevented by MCPG and by the group II/III mGluR antagonist (RS)-alpha-Methyl-4-phosphonophenylglycine (MPPG), and was partially blocked by the group II mGluR antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA). The inhibitory effect of l-AP4 was blocked by MPPG and partially blocked by APICA. PMID:16256086

  17. β2-Adrenergic agonists attenuate organic dust-induced lung inflammation.

    PubMed

    Romberger, Debra J; Heires, Art J; Nordgren, Tara M; Poole, Jill A; Toews, Myron L; West, William W; Wyatt, Todd A

    2016-07-01

    Agricultural dust exposure results in significant lung inflammation, and individuals working in concentrated animal feeding operations (CAFOs) are at risk for chronic airway inflammatory diseases. Exposure of bronchial epithelial cells to aqueous extracts of hog CAFO dusts (HDE) leads to inflammatory cytokine production that is driven by protein kinase C (PKC) activation. cAMP-dependent protein kinase (PKA)-activating agents can inhibit PKC activation in epithelial cells, leading to reduced inflammatory cytokine production following HDE exposure. β2-Adrenergic receptor agonists (β2-agonists) activate PKA, and we hypothesized that β2-agonists would beneficially impact HDE-induced adverse airway inflammatory consequences. Bronchial epithelial cells were cultured with the short-acting β2-agonist salbutamol or the long-acting β2-agonist salmeterol prior to stimulation with HDE. β2-Agonist treatment significantly increased PKA activation and significantly decreased HDE-stimulated IL-6 and IL-8 production in a concentration- and time-dependent manner. Salbutamol treatment significantly reduced HDE-induced intracellular adhesion molecule-1 expression and neutrophil adhesion to epithelial cells. Using an established intranasal inhalation exposure model, we found that salbutamol pretreatment reduced airway neutrophil influx and IL-6, TNF-α, CXCL1, and CXCL2 release in bronchoalveolar lavage fluid following a one-time exposure to HDE. Likewise, when mice were pretreated daily with salbutamol prior to HDE exposure for 3 wk, HDE-induced neutrophil influx and inflammatory mediator production were also reduced. The severity of HDE-induced lung pathology in mice repetitively exposed to HDE for 3 wk was also decreased with daily salbutamol pretreatment. Together, these results support the need for future clinical investigations to evaluate the utility of β2-agonist therapies in the treatment of airway inflammation associated with CAFO dust exposure. PMID:27190062

  18. Desensitization of Functional µ-Opioid Receptors Increases Agonist Off-Rate

    PubMed Central

    2014-01-01

    Desensitization of µ-opioid receptors (MORs) develops over 5–15 minutes after the application of some, but not all, opioid agonists and lasts for tens of minutes after agonist removal. The decrease in function is receptor selective (homologous) and could result from 1) a reduction in receptor number or 2) a decrease in receptor coupling. The present investigation used photolysis of two caged opioid ligands to examine the kinetics of MOR-induced potassium conductance before and after MOR desensitization. Photolysis of a caged antagonist, carboxynitroveratryl-naloxone (caged naloxone), blocked the current induced by a series of agonists, and the time constant of decline was significantly decreased after desensitization. The increase in the rate of current decay was not observed after partial blockade of receptors with the irreversible antagonist, β-chlornaltrexamine (β-CNA). The time constant of current decay after desensitization was never more rapid than 1 second, suggesting an increased agonist off-rate rather than an increase in the rate of channel closure downstream of the receptor. The rate of G protein–coupled K+ channel (GIRK) current activation was examined using photolysis of a caged agonist, carboxynitrobenzyl-tyrosine-[Leu5]-enkephalin. After acute desensitization or partial irreversible block of MORs with β-CNA, there was an increase in the time it took to reach a peak current. The decrease in the rate of agonist-induced GIRK conductance was receptor selective and dependent on receptor number. The results indicate that opioid receptor desensitization reduced the number of functional receptor and that the remaining active receptors have a reduced agonist affinity. PMID:24748657

  19. Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells.

    PubMed

    Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C; Hershfeld, Alena; Kenyon, Lawrence C; Deshpande, Deepak A

    2016-02-15

    Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K(+) channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as

  20. Structural insights into Resveratrol’s antagonist and partial agonist actions on estrogen receptor alpha

    PubMed Central

    2013-01-01

    Background Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ERα) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERα) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERα ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERα monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERα in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ERα dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERα are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERα. Conclusions Our Molecular Dynamics simulation of RES-ERα structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity. PMID:24160181

  1. Detection of glucocorticoid receptor agonists in effluents from sewage treatment plants in Japan.

    PubMed

    Suzuki, Go; Sato, Kentaro; Isobe, Tomohiko; Takigami, Hidetaka; Brouwer, Abraham; Nakayama, Kei

    2015-09-15

    Glucocorticoids (GCs) are widely used as anti-inflammatory drugs. Our previous study demonstrated that several GCs such as cortisol and dexamethasone (Dex) were frequently detected in effluents collected from Japanese sewage treatment plants (STPs) in 2012. In this study, we used the GC-Responsive Chemical-Activated LUciferase gene eXpression (GR-CALUX) assay to elucidate GC receptor (GR) agonistic activities of ten pure synthetic GCs and selected STP effluents in Japan for assessment of the risks associated with the presence of GR agonists. The tested GCs demonstrated dose-dependent agonistic effects in the GR-CALUX assay and their EC50 values were calculated for estimation of relative potencies (REPs) compared to Dex. The GR agonistic potency was in the rank of: clobetasol propionate > clobetasone butyrate > betamethasone 17-valerate > difluprednate > betamethasone 17,21-dipropionate > Dex > betamethasone > 6α-methylprednisolone > prednisolone > cortisol. The GR agonistic activity in STP effluents as measured in Dex-equivalent (Dex-EQ) activities ranged from < 3.0-78 ng L(-1) (median: 29 ng L(-1), n = 50). To evaluate the contribution of the target GCs, theoretical Dex-EQs were calculated by multiplying the concentrations of each GC by its respective REP. Our calculation of Dex-EQ contribution for individual GR agonists indicated that the well-known GCs cortisol and Dex should not be given priority for subsequent in vivo testing, monitoring and removal experiments, but rather the highly potent synthetic GCs clobetasol propionate and betamethasone 17-valerate (REP = 28 and 3.1) as well as other unidentified compounds are important GR agonists in STP effluents in Japan. PMID:25965047

  2. Agonist self-inhibition at the nicotinic acetylcholine receptor a nonspecific action

    SciTech Connect

    Forman, S.A.; Firestone, L.L.; Miller, K.W.

    1987-05-19

    Agonist concentration-response relationships at nicotinic postsynaptic receptors were established by measuring /sup 86/Rb/sup +/ efflux from acetylcholine receptor rich native Torpedo membrane vesicles under three different conditions: (1) integrated net ion efflux (in 10 s) from untreated vesicles, (2) integrated net efflux from vesicles in which most acetylcholine sites were irreversibly blocked with ..cap alpha..-bungarotoxin, and (3) initial rates of efflux (5-100 ms) from vesicles that were partially blocked with ..cap alpha..-bungarotoxin. Exposure to acetylcholine, carbamylcholine, suberyldicholine, phenyltrimethylammonium, or (-)-nicotine over 10/sup 8/-fold concentration ranges results in bell-shaped ion flux response curves due to stimulation of acetylcholine receptor channel opening at low concentrations and inhibition of channel function at 60-2000 times higher concentrations. Concentrations of agonists that inhibit their own maximum /sup 86/Rb/sup +/ efflux by 50% (K/sub B/ values) are 110, 211, 3.0, 39, and 8.9 mM, respectively, for the agonists listed above. For acetylcholine and carbamylcholine, K/sub B/ values determined from both 10-s and 15-ms efflux measurements are the same, indicating that the rate of agonist-induced desensitization increases to maximum at concentrations lower than those causing self-inhibition. For all partial and full agonists studied, Hill coefficients for self-inhibition are close to 1.0. Concentrations of agonists up to 8 times K/sub B/ did not change the order parameter reported by a spin-labeled fatty acid incorporated in Torpedo membranes. The authors conclude that agonist self-inhibition cannot be attributed to a general nonspecific membrane perturbation. Instead, these results are consistent with a saturable site of action either at the lipid-protein interface or on the acetylcholine receptor protein itself.

  3. Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties.

    PubMed

    Brust, Andreas; Croker, Daniel E; Colless, Barbara; Ragnarsson, Lotten; Andersson, Åsa; Jain, Kapil; Garcia-Caraballo, Sonia; Castro, Joel; Brierley, Stuart M; Alewood, Paul F; Lewis, Richard J

    2016-03-24

    Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor-ligand interactions similar to KOR agonist dynorphin A (1-8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor. PMID:26859603

  4. Interactions of dopamine agonists with brain D1 receptors labeled by /sup 3/H-antagonists. Evidence for the presence of high and low affinity agonist-binding states

    SciTech Connect

    Leff, S.E.; Hamblin, M.W.; Creese, I.

    1985-02-01

    The interactions of dopaminergic agonists and antagonists with /sup 3/H-antagonist labeled D1 dopamine receptors of rat striatum have been characterized. (/sup 3/H)Flupentixol has been found to selectively label D1 dopamine receptors when its binding to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone. Antagonist//sup 3/H-antagonist competition curves are of uniformly steep slope (nH . 1.0) suggesting the presence of a single D1 dopamine receptor. Agonist//sup 3/H-antagonist competition curves are extremely shallow (nH less than or equal to 0.5) for agonists of high relative efficacy, suggesting the presence of heterogeneous populations of agonist-binding states of the D1 dopamine receptor. Computer-modeling techniques were used to estimate affinities and relative site densities for these heterogeneous binding states. This analysis indicates that the ratio of agonist affinities for low and high affinity agonist-binding states is correlated with agonist relative efficacies in activating adenylate cyclase in membrane homogenates. Under the assay conditions employed, the addition of saturating concentrations of guanine nucleotides reduced, but did not abolish, the relative density of high affinity agonist-binding sites. These binding data can, at least in part, be explained by postulating two states of the D1 dopamine receptor, inducible by agonists but not by antagonists and modulated by guanine nucleotides.

  5. Behavioral and biochemical characterization of benzodiazepine receptor partial agonists in pigeons.

    PubMed

    Witkin, J M; Acri, J B; Wong, G; Gleeson, S; Barrett, J E

    1996-04-01

    The ability of benzodiazepine receptor partial agonists to exhibit full efficacy in preclinical anxiolytic tests, in conjunction with initial clinical results, has suggested the possibility of a reduced clinical side-effect profile compared to benzodiazepine receptor full agonists like diazepam. Because punished behavior of pigeons has been useful in detecting effects of novel anxiolytic drugs, effects of imidazobenzodiazepine and beta-carboline benzodiazepine receptor partial agonists and some related compounds were evaluated in this species. The abilities of these compounds to substitute for the discriminative stimulus effects of the full agonists midazolam also was determined. Intrinsic efficacy was assessed by the degree to which gamma-aminobutyric acid increased ligand potency to displace [(3)H]Ro15-1788 (flumazinil) from membranes of pigeon cerebrum, and ranged from full agonist-like efficacy (Ro 19-5470; 7-(3-cyclopropyl-1,2,4-oxodiazol-5-yl)-5,6-dihydro-5-methyl-4H- imidazo[1,5a]-thieno[3,2-f]diazin-4-one) to minimal gamma-aminobutyric acid potentiations close to that of the antagonist flumazenil (abecarnil and Ro 41-7812; 7-chloro-4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a] -[1,4 ]benzodiazepine-6-one). Punished responding was increased markedly by midazolam and by all partial agonists, except Ro 41-7812 and Ro 42-8773 (7-chloro-3-[3-(cyclopropylmethoxy)-1-propynyl]-4,5-dihyro-5 -methyl-6H-imidaz o[1,5-a][1,4]benzodiazepine-6-one), at doses that did not affect nonpunished responding. In contrast to the full substitution generally observed in mammals, all of the partial agonists produced incomplete substitution (40-70%) in the midazolam drug discrimination procedure in pigeons. A positive relationship was observed between the degree of substitution and intrinsic efficacy. The benzodiazepine antagonists, flumazenil and ZK 93,426 (ethyl-5-isopropoxy-4-methoxymethyl-beta-carboline-3-carboxylate), neither increased punished responding nor

  6. Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors.

    PubMed

    Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi

    2016-01-01

    Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations. PMID:27138239

  7. Agonist mediated conformational changes of solubilized calf forebrain muscarinic acetylcholine receptors.

    PubMed

    Vanderheyden, P; Andre, C; de Backer, J P; Vauquelin, G

    1984-10-01

    Muscarinic receptors in calf forebrain membranes can be identified by the specific binding of the radiolabelled antagonist [3H]dexetimide. These receptors (2.8 pM/mg protein) comprise two non-interconvertible subpopulations with respectively high and low agonist affinity but with the same antagonist affinity. For all the agonists tested the low affinity sites represent 85 +/- 5% of the total receptor population. 0.5% Digitonin solubilized extracts contain 0.8 pM muscarinic receptor/mg protein. In contrast with the membranes, these extracts contain only sites with low agonist affinity. The alkylating reagent N-ethylmaleimide causes an increase of the acetylcholine affinity for the low affinity sites in membranes as well as for the solubilized sites. This effect is time dependent until a maximal 3-fold increase in affinity is attained. The rate of N-ethylmaleimide action is enhanced by the concomitant presence of agonists. In contrast, N-ethylmaleimide does not affect antagonist binding. This suggests that agonists mediate a conformational change of both the membrane bound low affinity muscarinic sites and of the solubilized sites, resulting in their increased susceptibility towards NEM alkylation. PMID:6487351

  8. Evidence for air movement signals in the agonistic behaviour of a nocturnal arachnid (order Amblypygi).

    PubMed

    Santer, Roger D; Hebets, Eileen A

    2011-01-01

    Many arthropods possess filiform hair sensilla (termed trichobothria in arachnids), which are extremely sensitive detectors of medium particle displacement. Electrophysiological evidence in some taxa suggests that these sensilla can detect air particle displacements resulting from intraspecific communication signals. However, it has not yet been shown for any species that the air particle displacements detected by the filiform hairs are themselves perceived as a 'signal' (i.e. that individuals make behavioural decisions based upon the responses of these organs to the displays of conspecifics). We investigate the agonistic behaviour of the whip spider Phrynus marginemaculatus and the role of its trichobothria in receiving agonistic signals. Whip spiders have extremely elongated 'antenniform' first legs, which they vibrate close to their opponents during agonistic interactions, inducing air movements that excite their opponents' trichobothria. We find that ablation of the trichobothria causes significant increases in: (I) contest duration, and (II) the probability of contest escalation past aggressive displays to physical fighting. Therefore, in the absence of air movement-sensitive sensilla, contest assessment is impaired. This suggests that whip spiders exploit true air movement signals during agonistic interactions, and that these are received by the trichobothria. Furthermore, these results indicate that, in whip spiders, such signals help mitigate the cost of agonistic interaction. PMID:21853035

  9. Evidence for Air Movement Signals in the Agonistic Behaviour of a Nocturnal Arachnid (Order Amblypygi)

    PubMed Central

    Santer, Roger D.; Hebets, Eileen A.

    2011-01-01

    Many arthropods possess filiform hair sensilla (termed trichobothria in arachnids), which are extremely sensitive detectors of medium particle displacement. Electrophysiological evidence in some taxa suggests that these sensilla can detect air particle displacements resulting from intraspecific communication signals. However, it has not yet been shown for any species that the air particle displacements detected by the filiform hairs are themselves perceived as a ‘signal’ (i.e. that individuals make behavioural decisions based upon the responses of these organs to the displays of conspecifics). We investigate the agonistic behaviour of the whip spider Phrynus marginemaculatus and the role of its trichobothria in receiving agonistic signals. Whip spiders have extremely elongated ‘antenniform’ first legs, which they vibrate close to their opponents during agonistic interactions, inducing air movements that excite their opponents' trichobothria. We find that ablation of the trichobothria causes significant increases in: (I) contest duration, and (II) the probability of contest escalation past aggressive displays to physical fighting. Therefore, in the absence of air movement-sensitive sensilla, contest assessment is impaired. This suggests that whip spiders exploit true air movement signals during agonistic interactions, and that these are received by the trichobothria. Furthermore, these results indicate that, in whip spiders, such signals help mitigate the cost of agonistic interaction. PMID:21853035

  10. GLP-1 Receptor Agonists: Nonglycemic Clinical Effects in Weight Loss and Beyond

    PubMed Central

    Ryan, Donna; Acosta, Andres

    2015-01-01

    Obective Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for treatment of type 2 diabetes since they mimic the actions of native GLP-1 on pancreatic islet cells, stimulating insulin release, while inhibiting glucagon release, in a glucose-dependent manner. The observation of weight loss has led to exploration of their potential as antiobesity agents, with liraglutide 3.0 mg day−1 approved for weight management in the US on December 23, 2014, and in the EU on March 23, 2015. This review examines the potential nonglycemic effects of GLP-1 receptor agonists. Methods A literature search was conducted to identify preclinical and clinical evidence on nonglycemic effects of GLP-1 receptor agonists. Results GLP-1 receptors are distributed widely in a number of tissues in humans, and their effects are not limited to the well-recognized effects on glycemia. Nonglycemic effects include weight loss, which is perhaps the most widely recognized nonglycemic effect. In addition, effects on the cardiovascular, neurologic, and renal systems and on taste perception may occur independently of weight loss. Conclusions GLP-1 receptor agonists may provide other nonglycemic clinical effects besides weight loss. Understanding these effects is important for prescribers in using GLP-1 receptor agonists for diabetic patients, but also if approved for chronic weight management. PMID:25959380

  11. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

    PubMed

    Sun, Yiyi; Zang, Zhihe; Zhong, Ling; Wu, Min; Su, Qing; Gao, Xiurong; Zan, Wang; Lin, Dong; Zhao, Yan; Zhang, Zhonglin

    2013-01-01

    Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (-)-arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases. PMID:23691032

  12. Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series.

    PubMed

    Barker, Mike; Clackers, Margaret; Copley, Royston; Demaine, Derek A; Humphreys, Davina; Inglis, Graham G A; Johnston, Michael J; Jones, Haydn T; Haase, Michael V; House, David; Loiseau, Richard; Nisbet, Lesley; Pacquet, Francois; Skone, Philip A; Shanahan, Stephen E; Tape, Dan; Vinader, Victoria M; Washington, Melanie; Uings, Iain; Upton, Richard; McLay, Iain M; Macdonald, Simon J F

    2006-07-13

    The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described. PMID:16821781

  13. PPARδ agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair

    PubMed Central

    Pang, Maoyin; de la Monte, Suzanne M.; Longato, Lisa; Tong, Ming; He, Jiman; Chaudhry, Rajeeve; Duan, Kevin; Ouh, Jiyun; Wands, Jack R.

    2009-01-01

    Background/Aims Chronic ethanol exposure impairs liver regeneration due to inhibition of insulin signaling and oxidative injury. PPAR agonists function as insulin sensitizers and anti-inflammatory agents. We investigated whether treatment with a PPARδ agonist could restore hepatic insulin sensitivity, survival signaling, and regenerative responses vis-a-vis chronic ethanol feeding. Methods Adult rats were fed isocaloric liquid diets containing 0% or 37% ethanol, and administered a PPARδ agonist by i.p. injection. We used liver tissue to examine histopathology, gene expression, oxidative stress, insulin signaling, and regenerative responses to 2/3 hepatectomy. Results Chronic ethanol feeding caused insulin resistance, increased oxidative stress, lipid peroxidation, DNA damage, and hepatocellular injury in liver. These effects were associated with reduced insulin receptor binding and affinity, impaired survival signaling through PI3K/Akt/GSK3β, and reduced expression of insulin responsive genes mediating energy metabolism and tissue remodeling. PPARδ agonist treatment reduced ethanol-mediated hepatic injury, oxidative stress, lipid peroxidation, and insulin resistance, increased signaling through PI3K/Akt/GSK3β, and enhanced the regenerative response to partial hepatectomy. Conclusions PPARδ agonist administration may attenuate the severity of chronic ethanol-induced liver injury and ethanol’s adverse effects on the hepatic repair by restoring insulin responsiveness, even in the context of continued high-level ethanol consumption. PMID:19398227

  14. Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα + γ Agonists

    PubMed Central

    Oleksiewicz, Martin B.; Southgate, Jennifer; Iversen, Lars; Egerod, Frederikke L.

    2008-01-01

    Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds. PMID:19197366

  15. Identification of Adiponectin Receptor Agonist Utilizing a Fluorescence Polarization Based High Throughput Assay

    PubMed Central

    Sun, Yiyi; Zang, Zhihe; Zhong, Ling; Wu, Min; Su, Qing; Gao, Xiurong; Zan, Wang; Lin, Dong; Zhao, Yan; Zhang, Zhonglin

    2013-01-01

    Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (-)-arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases. PMID:23691032

  16. Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors

    PubMed Central

    Koshimizu, Taka-aki; Kashiwazaki, Aki; Taniguchi, Junichi

    2016-01-01

    Reducing Na+ in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na+-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na+ sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na+ increased cell surface [3H]AVP binding and decreased receptor internalization. Substitution of Na+ by Cs+ or NH4+ inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na+ over Cs+. Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations. PMID:27138239

  17. Reconstitution of high-affinity opioid agonist binding in brain membranes

    SciTech Connect

    Remmers, A.E.; Medzihradsky, F. )

    1991-03-15

    In synaptosomal membranes from rat brain cortex, the {mu} selective agonist ({sup 3}H)dihydromorphine in the absence of sodium, and the nonselective antagonist ({sup 3}H)naltrexone in the presence of sodium, bound to two populations of opioid receptor sites with K{sub d} values of 0.69 and 8.7 nM for dihydromorphine, and 0.34 and 5.5 nM for naltrexone. The addition of 5 {mu}M guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)) strongly reduced high-affinity agonist but not antagonist binding. Exposure of the membranes to high pH reduced the number of GTP({gamma}-{sup 35}S) binding sites by 90% and low K{sub m}, opioid-sensitive GTPase activity by 95%. In these membranes, high-affinity agonist binding was abolished and modulation of residual binding by GTP({gamma}S) was diminished. Alkali treatment of the glioma cell membranes prior to fusion inhibited most of the low K{sub m} GTPase activity and prevented the reconstitution of agonist binding. The results show that high-affinity opioid agonist binding reflects the ligand-occupied receptor - guanine nucleotide binding protein complex.

  18. Identification of dual PPARα/γ agonists and their effects on lipid metabolism.

    PubMed

    Gao, Quanqing; Hanh, Jacky; Váradi, Linda; Cairns, Rose; Sjöström, Helena; Liao, Vivian W Y; Wood, Peta; Balaban, Seher; Ong, Jennifer Ai; Lin, Hsuan-Yu Jennifer; Lai, Felcia; Hoy, Andrew J; Grewal, Thomas; Groundwater, Paul W; Hibbs, David E

    2015-12-15

    The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%±3.5 and 54.1%±3.7 at 50μM and 100μM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid β-oxidation in HuH7 hepatocytes. PMID:26616289

  19. Structure-Activity Relationship and Signaling of New Chimeric CXCR4 Agonists.

    PubMed

    Mona, Christine E; Besserer-Offroy, Élie; Cabana, Jérôme; Lefrançois, Marilou; Boulais, Philip E; Lefebvre, Marie-Reine; Leduc, Richard; Lavigne, Pierre; Heveker, Nikolaus; Marsault, Éric; Escher, Emanuel

    2016-08-25

    The CXCR4 receptor binds with meaningful affinities only CXCL12 and synthetic antagonists/inverse agonists. We recently described high affinity synthetic agonists for this chemokine receptor, obtained by grafting the CXCL12 N-terminus onto the inverse agonist T140. While those chimeric molecules behave as agonists for CXCR4, their binding and activation mode are unknown. The present SAR of those CXCL12-oligopeptide grafts reveals the key determinants involved in CXCR4 activation. Position 3 (Val) controls affinity, whereas position 7 (Tyr) acts as an efficacy switch. Chimeric molecules bearing aromatic residues in position 3 possess high binding affinities for CXCR4 and are Gαi full agonists with robust chemotactic properties. Fine-tuning of electron-poor aromatic rings in position 7 enhances receptor activation. To rationalize these results, a homology model of a receptor-ligand complex was built using the published crystal structures of CXCR4. Molecular dynamics simulations reveal further details accounting for the observed SAR for this series. PMID:27434274

  20. A combined ligand and structure based approach to design potent PPAR-alpha agonists

    NASA Astrophysics Data System (ADS)

    Dhoke, Gaurao V.; Gangwal, Rahul P.; Sangamwar, Abhay T.

    2012-11-01

    A combined ligand and structure based pharmacophore modeling approach was employed to reveal structural and chemical features necessary for PPAR-alpha agonistic activity. The best HypoGen pharmacophore model Hypo1 for PPAR-alpha agonists contains two hydrogen-bond acceptor (HBA), two general hydrophobic (H), and one negative ionizable (NI) feature. In addition, one structure based pharmacophore model was developed using LigandScout3.0, which has identified additional three hydrophobic features. Further, molecular docking studies of all agonists showed hydrogen bond interactions with important amino acids (Ser280, Tyr314 and Tyr464) and these interactions were compared with Hypo1, which shows that the Hypo1 has a good predictive ability. The screened virtual hits from Hypo1 were subjected to the Lipinski's rule of five, structure based pharmacophore screening and molecular docking analysis. Finally, three novel compounds with diverse scaffolds were selected as possible candidates for the designing of potent PPAR-alpha agonists. Combination of these two approaches results in designing an ideal pharmacophore model, which provides a powerful tool for the discovery of novel PPAR-alpha agonists.

  1. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver.

    PubMed

    Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

    2016-01-01

    Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis. PMID:26770990

  2. 3D-Pharmacophore Identification for κ-Opioid Agonists Using Ligand-Based Drug-Design Techniques

    NASA Astrophysics Data System (ADS)

    Yamaotsu, Noriyuki; Hirono, Shuichi

    A selective κ-opioid receptor (KOR) agonist might act as a powerful analgesic without the side effects of μ-opioid receptor-selective drugs such as morphine. The eight classes of known KOR agonists have different chemical structures, making it difficult to construct a pharmacophore model that takes them all into account. Here, we summarize previous efforts to identify the pharmacophore for κ-opioid agonists and propose a new three-dimensional pharmacophore model that encompasses the κ-activities of all classes. This utilizes conformational sampling of agonists by high-temperature molecular dynamics and pharmacophore extraction through a series of molecular superpositions.

  3. Detection of retinoic acid receptor agonistic activity and identification of causative compounds in municipal wastewater treatment plants in Japan.

    PubMed

    Sawada, Kazuko; Inoue, Daisuke; Wada, Yuichiro; Sei, Kazunari; Nakanishi, Tsuyoshi; Ike, Michihiko

    2012-02-01

    Retinoic acid (RA) receptor (RAR) agonists are potential toxicants that can cause teratogenesis in vertebrates. To determine the occurrence of RAR agonists in municipal wastewater treatment plants (WWTPs), we examined the RARα agonistic activities of influent and effluent samples from several municipal WWTPs in Osaka, Japan, using a yeast two-hybrid assay. Significant RARα agonistic activity was detected in all the influent samples investigated, suggesting that municipal wastewater consistently contains RAR agonists. Fractionations using high-performance liquid chromatography, directed by the bioassay, found several bioactive peaks from influent samples. The RAR agonists, all-trans RA (atRA), 13-cis RA (13cRA), 4-oxo-atRA, and 4-oxo-13cRA, possibly arising from human urine, were identified by liquid chromatography ion trap time-of-flight mass spectrometry. Quantification of the identified compounds in municipal WWTPs confirmed that they were responsible for the majority of RARα agonistic activity in WWTP influents, and also revealed they were readily removed from wastewater by activated sludge treatment. Simultaneous measurement of the RARα agonistic activity revealed that although total activity typically declined concomitant with the reduction of the four identified compounds, it remained high after the decline of RAs and 4-oxo-RAs in one WWTP, suggesting the occurrence of unidentified RAR agonists during the activated sludge treatment. PMID:22095885

  4. Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists.

    PubMed

    Kajita, Daisuke; Nakamura, Masaharu; Matsumoto, Yotaro; Ishikawa, Minoru; Hashimoto, Yuichi; Fujii, Shinya

    2015-08-15

    We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPARα agonist, and evaluated their PPARα/δ/γ agonistic activity. We found that diethylsilyl derivative 20 exhibited PPARα/δ agonistic activity, and we also obtained a PPARδ-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds. PMID:26071639

  5. Errors in the measurement of agonist potency-ratios produced by uptake processes: a general model applied to beta-adrenoceptor agonists.

    PubMed Central

    Kenakin, T. P.

    1980-01-01

    1. The sensitization of guinea-pig atria and trachea to noradrenaline, isoprenaline, and salbutamol, produced by an inhibitor of neuronal (cocaine) and extraneuronal (metanephrine) uptake, was studied quantitatively. The data were compared to a theoretical model. 2. Cocaine produced near maximal sensitization to noradrenaline in guinea-pig atria (5 fold) at concentrations which produced only partial sensitization in guinea-pig trachea (4.7 fold sensitization of a maximum 11 fold). These results agreed with the model which predicts that there is a direct relationship between the amount of uptake inhibitor required to produce full sensitization and the magnitude of maximal sensitization demonstrable in the tissue. This makes extrapolation of uptake inhibition concentrations from tissue to tissue a potentially erroneous practice. 3. In normal trachea, salbutamol is 20 times more potent than noradrenaline but this difference is abolished (to 0.9 times) by cocaine (100 microM). This reduction of potency-ratio is due to the selective cocaine-induced sensitization of trachea to noradrenaline and raises a serious objection to the classification of salbutamol as a beta 2 selective agonist. 4. Metanephrine produced very little sensitization of trachea to isoprenaline. Experiments with salbutamol showed metanephrine to be a simple competitive antagonist of beta-adrenoceptors (pKb = 4.3) and that this receptor antagonism masked sensitization to isoprenaline. 5. A theoretical model indicates that an inhibitor of agonist uptake requires a remarkable degree of selectivity for the uptake mechanism (i.e. Kb for receptors 10(4) x KI for uptake sites) to demonstrate tissue sensitization to the agonist. This analysis and the data with metanephrine indicate that a sinistral shift of the concentration-response curve is a poor indicator of the importance of uptake mechanisms in an isolated tissue. 6. An alternate method to determine the importance of agonist-uptake effects on

  6. Beta-adrenergic agonists increase lung liquid clearance in anesthetized sheep.

    PubMed Central

    Berthiaume, Y; Staub, N C; Matthay, M A

    1987-01-01

    We did experiments to determine whether beta-adrenergic agonists increase lung liquid clearance in anesthetized ventilated adult sheep and, if so, whether the increase is mediated by beta receptors and what mechanism is involved. We instilled 100 ml of autologous serum either alone or with a beta-adrenergic agonist (terbutaline, 10(-5) M, or epinephrine, 5.5 X 10(-6) M) into one lower lobe. After 4 h both terbutaline and epinephrine increased lung liquid clearance. The increase in lung liquid clearance was inhibited when propranolol (a beta blocker) or amiloride (a sodium channel blocker) was added to the terbutaline. Increased clearance was not explained by changes in pulmonary hemodynamics, pulmonary blood flow, or lung lymph flow. We conclude that beta-adrenergic agonists increase lung liquid clearance in anesthetized intact adult sheep. This increase is mediated through beta receptors and probably depends on increased active transport of sodium across the alveolar barrier. Images PMID:2879851

  7. Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons

    NASA Technical Reports Server (NTRS)

    Zheng, F.; Gallagher, J. P.

    1992-01-01

    We have previously reported that, in the rat dorsolateral septal nucleus (DLSN), metabotropic glutamate receptor (met-GluR) agonists evoked a slow depolarization accompanied by an increase in membrane conductance and burst firing. We have speculated that the burst firing elicited by met-GluR agonists may be due to activation or enhancement of a non-specific cation current, which exists in some DLSN neurons. Now we report that a slow afterdepolarization (sADP) mediated by a non-specific cation current was potentiated by both 1S,3R-ACPD and quisqualate. In addition, met-GluR agonists unmask a sADP in DLSN neurons which did not show a sADP under control conditions. Our data suggest that a non-specific cation current can be potentiated by activation of the met-GluR.

  8. Search for new type of PPARγ agonist-like anti-diabetic compounds from medicinal plants.

    PubMed

    Matsuda, Hisashi; Nakamura, Seikou; Yoshikawa, Masayuki

    2014-01-01

    Potent ligands of peroxisome proliferator-activated receptor γ (PPARγ) such as thiazolidinediones (pioglitazone, troglitazone, etc.) improve insulin sensitivity by increasing the levels of adiponectin, an important adipocytokine associated with insulin sensitivity in adipose tissue. Several constituents from medicinal plants were recently reported to show PPARγ agonist-like activity in 3T3-L1 cells, but did not show agonistic activity at the receptor site different from thiazolidinediones. Our recent studies on PPARγ agonist-like constituents, such as hydrangenol and hydrangeic acid from the processed leaves of Hydrangea macrophylla var. thunbergii, piperlonguminine and retrofractamide A from the fruit of Piper chaba, and tetramethylkaempferol and pentamethylquercetin from the rhizomes of Kaempferia parviflora, are reviewed. PMID:24882400

  9. Incorporation of Phosphonate into Benzonaphthyridine Toll-like Receptor 7 Agonists for Adsorption to Aluminum Hydroxide.

    PubMed

    Cortez, Alex; Li, Yongkai; Miller, Andrew T; Zhang, Xiaoyue; Yue, Kathy; Maginnis, Jillian; Hampton, Janice; Hall, De Shon; Shapiro, Michael; Nayak, Bishnu; D'Oro, Ugo; Li, Chun; Skibinski, David; Mbow, M Lamine; Singh, Manmohan; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M; Wu, Tom Y-H

    2016-06-23

    Small molecule Toll-like receptor 7 (TLR7) agonists have been used as vaccine adjuvants by enhancing innate immune activation to afford better adaptive response. Localized TLR7 agonists without systemic exposure can afford good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific) is not required for immune priming. To enhance colocalization of antigen and adjuvant, benzonaphthyridine (BZN) TLR7 agonists are chemically modified with phosphonates to allow adsorption onto aluminum hydroxide (alum), a formulation commonly used in vaccines for antigen stabilization and injection site deposition. The adsorption process is facilitated by enhancing aqueous solubility of BZN analogs to avoid physical mixture of two insoluble particulates. These BZN-phosphonates are highly adsorbed onto alum, which significantly reduced systemic exposure and increased local retention post injection. This report demonstrates a novel approach in vaccine adjuvant design using phosphonate modification to afford adsorption of small molecule immune potentiator (SMIP) onto alum, thereby enhancing co-delivery with antigen. PMID:27270029

  10. DEVELOPMENT AND IN VITRO CHARACTERIZATION OF A NOVEL BIFUNCTIONAL MU-AGONIST/DELTA-ANTAGONIST OPIOID TETRAPEPTIDE

    PubMed Central

    Purington, Lauren C.; Sobczyk-Kojiro, Katarzyna; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.

    2011-01-01

    The development of tolerance to and dependence on opioid analgesics greatly reduces their long-term usefulness. Previous studies have demonstrated that co-administration of a mu opioid receptor (MOR) agonist and delta opioid receptor (DOR) antagonist can decrease MOR agonist induced tolerance and dependence development after chronic exposure. Clinically, a single ligand displaying multiple efficacies (e.g. MOR agonism concurrently with DOR antagonism) would be of increased value over two drugs administered simultaneously. Guided by modeling of receptor-ligand complexes we have developed a series of potent non-selective opioid tetrapeptides that have differing efficacy at MOR and DOR. In particular, our lead peptide (KSK-103) binds with equal affinity to MOR and DOR but acts as a MOR agonist with similar efficacy but greater potency than morphine and a DOR antagonist in cellular assays measuring both G protein stimulation and adenylyl cyclase inhibition. PMID:21958158

  11. 2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor.

    PubMed

    Takahashi, Bitoku; Funami, Hideaki; Iwaki, Takehiko; Maruoka, Hiroshi; Nagahira, Asako; Koyama, Makoto; Kamiide, Yoshiyuki; Matsuo, Tsuyoshi; Muto, Tsuyoshi; Annoura, Hirokazu

    2015-07-01

    New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects. PMID:25981690

  12. Label-Free Cell Phenotypic Identification of D-Luciferin as an Agonist for GPR35.

    PubMed

    Hu, Heidi; Deng, Huayun; Fang, Ye

    2016-01-01

    D-Luciferin (also known as beetle or firefly luciferin) is one of the most widely used bioluminescent reporters for monitoring in vitro or in vivo luciferase activity. The identification of several natural phenols and thieno[3,2-b]thiophene-2-carboxylic acid derivatives as agonists for GPR35, an orphan G protein-coupled receptor, had motivated us to examine the pharmacological activity of D-Luciferin, given that it also contains phenol and carboxylic acid moieties. Here, we describe label-free cell phenotypic assays that ascertain D-Luciferin as a partial agonist for GPR35. The agonistic activity of D-Luciferin at the GPR35 shall evoke careful interpretation of biological data when D-Luciferin or its analogues are used as probes. PMID:27424891

  13. Clinical use of deslorelin (GnRH agonist) in companion animals: a review.

    PubMed

    Lucas, X

    2014-10-01

    Over the years, many contraceptive medications have been developed for companion animals, but many secondary adverse effects have limited their use. A major advancement was achieved with the use of gonadotropin-releasing hormone (GnRH) analogues, mainly GnRH agonists, which mimic the effects of native GnRH. The development of effective low-dose, slow-release implants with potent agonists such as deslorelin (Suprelorin®, Virbac) have allowed their use to become widespread in recent years, with many potential benefits in companion animals. While the major application of deslorelin was initially male contraception, due to its two differing actions, either the stimulation of oestrus or the sterilization of fertility, its use has been increasing in the bitch as well. The aim of this study is to review the applications of deslorelin GnRH agonist implants in companion animal, such as dogs, cats and some exotic pets. PMID:25277434

  14. Quantitative Measure of Receptor Agonist and Modulator Equi-Response and Equi-Occupancy Selectivity

    PubMed Central

    Zhang, Rumin; Kavana, Michael

    2016-01-01

    G protein-coupled receptors (GPCRs) are an important class of drug targets. Quantitative analysis by global curve fitting of properly designed dose-dependent GPCR agonism and allosterism data permits the determination of all affinity and efficacy parameters based on a general operational model. We report here a quantitative and panoramic measure of receptor agonist and modulator equi-response and equi-occupancy selectivity calculated from these parameters. The selectivity values help to differentiate not only one agonist or modulator from another, but on-target from off-target receptor or functional pathway as well. Furthermore, in conjunction with target site free drug concentrations and endogenous agonist tones, the allosterism parameters and selectivity values may be used to predict in vivo efficacy and safety margins. PMID:27116909

  15. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

    PubMed

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat). PMID:24462665

  16. Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.

    PubMed

    Asaki, Tetsuo; Kuwano, Keiichi; Morrison, Keith; Gatfield, John; Hamamoto, Taisuke; Clozel, Martine

    2015-09-24

    Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogues is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agonist potency were optimized through modification of the linear side chain. Compound 12b (MRE-269, ACT-333679) was identified as a potent and highly selective prostacyclin receptor agonist. Replacement of the terminal carboxyl group with an N-acylsulfonamide group yielded parent compound 26a (selexipag, NS-304, ACT-293987), which is orally active and provides sustained plasma exposure of 12b. Compound 26a was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial. PMID:26291199

  17. Nitric oxide donor beta2-agonists: furoxan derivatives containing the fenoterol moiety and related furazans.

    PubMed

    Buonsanti, M Federica; Bertinaria, Massimo; Stilo, Antonella Di; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2007-10-01

    The structure of fenoterol, a beta2-adrenoceptor agonist used in therapy, has been joined with furoxan NO-donor moieties to give new NO-donor beta2-agonists. The furazan analogues, devoid of the property to release NO, were also synthesized for comparison. All the compounds retained beta2-agonistic activity at micromolar or submicromolar concentration when tested on guinea pig tracheal rings precontracted with carbachol. Among the furoxan derivatives, the NO contribution to trachea relaxation was evident with product 15b at micromolar concentrations. All the new NO-donor hybrids were able to dilate rat aortic strips precontracted with phenylephrine. Both furoxan and furazan derivatives displayed antioxidant activity greater than that of fenoterol. PMID:17845020

  18. Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist

    PubMed Central

    2015-01-01

    GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, as a potent and orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats. PMID:25815144

  19. PPAR{alpha} agonists up-regulate organic cation transporters in rat liver cells

    SciTech Connect

    Luci, Sebastian; Geissler, Stefanie; Koenig, Bettina; Koch, Alexander; Stangl, Gabriele I.; Hirche, Frank; Eder, Klaus . E-mail: klaus.eder@landw.uni-halle.de

    2006-11-24

    It has been shown that clofibrate treatment increases the carnitine concentration in the liver of rats. However, the molecular mechanism is still unknown. In this study, we observed for the first time that treatment of rats with the peroxisome proliferator activated receptor (PPAR)-{alpha} agonist clofibrate increases hepatic mRNA concentrations of organic cation transporters (OCTNs)-1 and -2 which act as transporters of carnitine into the cell. In rat hepatoma (Fao) cells, treatment with WY-14,643 also increased the mRNA concentration of OCTN-2. mRNA concentrations of enzymes involved in carnitine biosynthesis were not altered by treatment with the PPAR{alpha} agonists in livers of rats and in Fao cells. We conclude that PPAR{alpha} agonists increase carnitine concentrations in livers of rats and cells by an increased uptake of carnitine into the cell but not by an increased carnitine biosynthesis.

  20. Pharmacological and Therapeutic Effects of A3 Adenosine Receptor (A3AR) Agonists

    PubMed Central

    Fishman, Pnina; Bar-Yehuda, Sara; Liang, Bruce T.; Jacobson, Kenneth A.

    2011-01-01

    The Gi-coupled A3 adenosine receptor (A3AR) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A3AR as a potential therapeutic target. Highly selective A3AR agonists have been synthesized and molecular recognition in the binding site has been characterized. The present review summarizes preclinical and clinical human studies demonstrating that A3AR agonists induce specific anti-inflammatory and anticancer effects via a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways. Currently, A3AR agonists are being developed for the treatment of inflammatory diseases including rheumatoid arthritis and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis. PMID:22033198

  1. Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.

    PubMed

    Weichert, Dietmar; Stanek, Markus; Hübner, Harald; Gmeiner, Peter

    2016-06-15

    Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders. PMID:27132867

  2. Influence of idazoxan on the dopamine D2 receptor agonist-induced behavioural effects in rats.

    PubMed

    Ferrari, F; Giuliani, D

    1993-11-30

    The behavioural effects in rats of the dopamine D2 receptor agonists, lisuride, B-HT 920 and SND 919, were variously influenced by pre-treatment with the selective alpha 2-adrenoceptor antagonist, idazoxan (2 mg/kg), depending on the nature of the effect in question and the doses of agonist employed. The influence of idazoxan on drug-induced stretching-yawning, penile erection, sedation, stereotyped behaviour, aggressiveness and mounting is described and tentatively interpreted in neurochemical terms, account being taken of the activity of respective alpha 2-adrenoceptor antagonist and dopamine receptor agonists used, at alpha 2-adrenoceptors and at different dopamine D2 receptor subtypes, pre- and postsynaptically located. PMID:7907024

  3. The potency of different serotonergic agonists in counteracting opioid evoked cardiorespiratory disturbances

    PubMed Central

    Dutschmann, M.; Waki, H.; Manzke, T.; Simms, A. E.; Pickering, A. E.; Richter, D. W.; Paton, J. F. R.

    2009-01-01

    Serotonin receptor (5-HTR) agonists that target 5-HT4(a)R and 5-HT1AR can reverse μ-opioid receptor (μ-OR)-evoked respiratory depression. Here, we have tested whether such rescuing by serotonin agonists also applies to the cardiovascular system. In working heart–brainstem preparations in situ, we have recorded phrenic nerve activity, thoracic sympathetic chain activity (SCA), vascular resistance and heart rate (HR) and in conscious rats, diaphragmatic electromyogram, arterial blood pressure (BP) and HR via radio-telemetry. In addition, the distribution of 5-HT4(a)R and 5-HT1AR in ponto-medullary cardiorespiratory networks was identified using histochemistry. Systemic administration of the μ-OR agonist fentanyl in situ decreased HR, vascular resistance, SCA and phrenic nerve activity. Subsequent application of the 5-HT1AR agonist 8-OH-DPAT further enhanced bradycardia, but partially compensated the decrease in vascular resistance, sympathetic activity and restored breathing. By contrast, the 5-HT4(a)R agonist RS67333 further decreased vascular resistance, HR and sympathetic activity, but partially rescued breathing. In conscious rats, administration of remifentanyl caused severe respiratory depression, a decrease in mean BP accompanied by pronounced bradyarrhythmia. 8-OH-DPAT restored breathing and prevented the bradyarrhythmia; however, BP and HR remained below baseline. In contrast, RS67333 further suppressed cardiovascular functions in vivo and only partially recovered breathing in some cases. The better recovery of μ-OR cardiorespiratory disturbance by 5-HT1AR than 5-HT4(a)R is supported by the finding that 5-HT1AR was more densely expressed in key brainstem nuclei for cardiorespiratory control compared with 5-HT4(a)R. We conclude that during treatment of severe pain, 5-HT1AR agonists may provide a useful tool to counteract opioid-mediated cardiorespiratory disturbances. PMID:19651661

  4. Recovery of brain biomarkers following peroxisome proliferator-activated receptor agonist neuroprotective treatment before ischemic stroke

    PubMed Central

    2014-01-01

    Background Lipid lowering agent such as agonists of peroxisome proliferator-activated receptors (PPAR) are suggested as neuroprotective agents and may protect from the sequelae of brain ischemic stroke. Although the demonstration is not clearly established in human, the underlying molecular mechanism may be of interest for future therapeutic purposes. To this end, we have used our well established rodent model of ischemia-reperfusion pre-treated or not with fenofibrate or atorvastatin and performed a differential proteomics analyses of the brain and analysed the protein markers which levels returned to “normal” following pre-treatments with PPARα agonists. Results In order to identify potential therapeutic targets positively modulated by pre-treatment with the PPARα agonists, two-dimensional gel electrophoresis proteome profiles between control, ischemia-reperfusion and pre-treated or not, were compared. The polypeptide which expression was altered following ischemia – reperfusion but whose levels remain unchanged after pre-treatment were characterized by mass spectrometry and further investigated by Western-blotting and immunohistochemistry. A series of 28 polypeptides were characterized among which the protein disulfide isomerase reduction – a protein instrumental to the unfolded protein response system - was shown to be reduced following PPARα agonists treatment while it was strongly increased in ischemia-reperfusion. Conclusions Pre-treatment with PPARα agonist or atorvastatin show potential neuroprotective effects by inhibiting the PDI overexpression in conjunction with the preservation of other neuronal markers, several of which are associated with the regulation of protein homeostasis, signal transduction and maintenance of synaptic plasticity. This proteomic study therefore suggests that neuroprotective effect of PPARα agonists supposes the preservation of the expression of several proteins essential for the maintenance of protein homeostasis

  5. Peroxisome Proliferator-Activated Receptor Agonist Treatment of Alcohol-Induced Hepatic Insulin Resistance

    PubMed Central

    de la Monte, Suzanne M.; Pang, Maoyin; Chaudhry, Rajeeve; Duan, Kevin; Longato, Lisa; Carter, Jade; Ouh, Jiyun; Wands, Jack R.

    2011-01-01

    Chronic ethanol exposure impairs insulin signaling in the liver. Peroxisome-proliferator activated receptor (PPAR) agonists function as insulin sensitizers and are used to treat type 2 diabetes mellitus. We examined the therapeutic effectiveness of PPAR agonists in reducing alcoholic hepatitis and hepatic insulin resistance in a model of chronic ethanol feeding. Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% (control) or 37% ethanol (caloric content; 9.2% v/v) for 8 weeks. After 3 weeks on the diets, the rats were treated with vehicle, or a PPAR-α, PPAR-δ, or PPAR-γ agonist twice weekly by i.p. injection. Livers were harvested for histopathological, gene expression (RT-PCR), protein (Western and ELISA), and receptor binding studies. Ethanol-fed rats developed steatohepatitis with disordered hepatic chord architecture, increased hepatocellular apoptosis, reduced binding to the insulin, IGF-1, and IGF-2 receptors, and decreased expression of glyceraldehyde-3-phosphate dehydrogenase and aspartyl-(asparaginyl)-β-hydroxylase (mediates remodeling), which are regulated by insulin/IGF signaling. PPAR-α, PPAR-δ, or PPAR-γ agonist treatments reduced the severity of ethanol-mediated liver injury, including hepatic architectural disarray and steatosis. In addition, PPAR-δ and PPAR-γ agonists reduced insulin/IGF resistance and increased insulin/IGF-responsive gene expression. In conclusion, PPAR agonists may help reduce the severity of chronic ethanol-induced liver injury and insulin/IGF resistance, even in the context of continued high-level ethanol consumption. PMID:21426453

  6. Early postnatal stress alters place conditioning to both mu- and kappa-opioid agonists.

    PubMed

    Michaels, Clifford C; Holtzman, Stephen G

    2008-04-01

    Clinical literature has established a link between early childhood incidents of neglect and trauma and adult problems with substance abuse. In rats, such early life stress has been modeled using a maternal separation (MS) paradigm in which rat pups were removed from their mothers for a few hours daily during the first two postnatal weeks. In this study, we used the MS model to investigate the effects of early postnatal stress on place conditioning to both mu- and kappa-opioid agonists in male and female Long-Evans rats. Offspring of both rearing conditions [MS or nonhandled (NH)] were conditioned using a biased procedure to saline, the mu-opioid agonist morphine (3.0, 5.6, and 10 mg/kg s.c.), or the kappa-opioid agonist spiradoline (0.3, 1.0, and 3.0 mg/kg) for 3 days, followed by a drug-free place-conditioning test 24 h later. Saline was administered in the morning, 30 min before confinement in one compartment, whereas morphine or spiradoline was administered in a similar manner 6 h later in the opposite compartment. MS offspring spent significantly more time in the morphine-paired compartment than NH offspring, indicating a greater place preference for the mu-opioid agonist. In the case of spiradoline, NH offspring spent significantly less time in the spiradoline-paired compartment, indicating a greater aversion to the kappa-opioid agonist in these animals than in MS offspring. These findings indicate that early postnatal stress can significantly alter the rewarding or aversive value of mu- and kappa-opioid agonists when measured using place conditioning. PMID:18203949

  7. Agonist binding and function at the human alpha(2A)-adrenoceptor: allosteric modulation by amilorides.

    PubMed

    Leppik, R A; Birdsall, N J

    2000-11-01

    It has been found previously that amilorides act via an allosteric site on the alpha(2A)-adrenergic receptor to strongly inhibit antagonist binding. In this study, allosteric modulation of agonist binding and function at the alpha(2A)-adrenergic receptor was explored. The dissociation rate of the agonist [(3)H]UK14304 from alpha(2A)-receptors was decreased by the amilorides in a concentration-dependent manner. This contrasts with the increases in (3)H-antagonist dissociation rate found previously. The agonist-amiloride analog interaction data could be fitted to equations derived from the ternary complex allosteric model. The calculated log affinities of the amilorides at the [(3)H]UK14304-occupied receptor increased with the size of the 5-N-alkyl side chain and ranged from 2.4 for amiloride to 4.2 for 5-(N,N-hexamethylene)-amiloride. The calculated negative cooperativities cover a narrow range, in sharp contrast to the broad range found for antagonist-amiloride analog interactions. The effects of the amilorides on the agonist actions of UK14304, epinephrine, and norepinephrine were explored using a [(35)S]GTPgammaS functional assay, and the parameters calculated for the cooperativities and affinities of the UK14304-amiloride analog interactions, using the equation derived from the ternary complex allosteric model, were in good agreement with those derived from the kinetic studies. Therefore both the binding and functional data provide further support for the existence of a well defined allosteric site on the human alpha(2A)-adrenergic receptor. The binding mode of the amilorides at the agonist-occupied and antagonist-occupied receptor differs markedly but, within each group, the structure of either the agonist or the antagonist examined has only a slight effect on the allosteric interactions. PMID:11040058

  8. Flow-injection chemiluminescence method to detect a β2 adrenergic agonist.

    PubMed

    Zhang, Guangbin; Tang, Yuhai; Shang, Jian; Wang, Zhongcheng; Yu, Hua; Du, Wei; Fu, Qiang

    2015-02-01

    A new method for the detection of β2 adrenergic agonists was developed based on the chemiluminescence (CL) reaction of β2 adrenergic agonist with potassium ferricyanide-luminol CL. The effect of β2 adrenergic agonists including isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine on the CL intensity of potassium ferricyanide-luminol was discovered. Detection of the β2 adrenergic agonist was carried out in a flow system. Using uniform design experimentation, the influence factors of CL were optimized. The optimal experimental conditions were 1 mmol/L of potassium ferricyanide, 10 µmol/L of luminol, 1.2 mmol/L of sodium hydroxide, a flow speed of 2.6 mL/min and a distance of 1.2 cm from 'Y2 ' to the flow cell. The linear ranges and limit of detection were 10-100 and 5 ng/mL for isoprenaline hydrochloride, 20-100 and 5 ng/mL for salbutamol sulfate, 8-200 and 1 ng/mL for terbutaline sulfate, 20-100 and 4 ng/mL for ractopamine, respectively. The proposed method allowed 200 injections/h with excellent repeatability and precision. It was successfully applied to the determination of three β2 adrenergic agonists in commercial pharmaceutical formulations with recoveries in the range of 96.8-98.5%. The possible CL reaction mechanism of potassium ferricyanide-luminol-β2 adrenergic agonist was discussed from the UV/vis spectra. PMID:24830367

  9. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor.

    PubMed

    Gough, Michael J; Ruby, Carl E; Redmond, William L; Dhungel, Birat; Brown, Alexis; Weinberg, Andrew D

    2008-07-01

    Acquisition of full T-cell effector function and memory differentiation requires appropriate costimulatory signals, including ligation of the costimulatory molecule OX40 (TNFRSF4, CD134). Tumors often grow despite the presence of tumor-specific T cells and establish an environment with weak costimulation and immune suppression. Administration of OX40 agonists has been shown to significantly increase the survival of tumor-bearing mice and was dependent on the presence of both CD4 and CD8 T cells during tumor-specific priming. To understand how OX40 agonists work in mice with established tumors, we developed a model to study changes in immune cell populations within the tumor environment. We show here that systemic administration of OX40 agonist antibodies increased the proportion of CD8 T cells at the tumor site in three different tumor models. The function of the CD8 T cells at the tumor site was also increased by administration of OX40 agonist antibody, and we observed an increase in the proportion of antigen-specific CD8 T cells within the tumor. Despite decreases in the proportion of T regulatory cells at the tumor site, T regulatory cell function in the spleen was unaffected by OX40 agonist antibody therapy. Interestingly, administration of OX40 agonist antibody caused significant changes in the tumor stroma, including decreased macrophages, myeloid-derived suppressor cells, and decreased expression of transforming growth factor-beta. Thus, therapies targeting OX40 dramatically changed the tumor environment by enhancing the infiltration and function of CD8 T cells combined with diminished suppressive influences within the tumor. PMID:18593921

  10. Estrogen receptor agonists alleviate cardiac and renal oxidative injury in rats with renovascular hypertension.

    PubMed

    Özdemir Kumral, Zarife Nigâr; Kolgazi, Meltem; Üstünova, Savaş; Kasımay Çakır, Özgür; Çevik, Özge Dağdeviren; Şener, Göksel; Yeğen, Berrak Ç

    2016-01-01

    Although endogenous estrogen is known to offer cardiac and vascular protection, the involvement of estrogen receptors in mediating the protective effect of estrogen on hypertension-induced cardiovascular and renal injury is not fully explained. We aimed to investigate the effects of estrogen receptor (ER) agonists on oxidative injury, cardiovascular and renal functions of rats with renovascular hypertension (RVH). Female Sprague-Dawley rats were randomly divided as control and RVH groups, and RVH groups had either ovariectomy (OVX) or sham-OVX. Sham-OVX-RVH and OVX-RVH groups received either ERβ agonist diarylpropiolnitrile (1 mg/kg/day) or ERα agonist propyl pyrazole triol (1 mg/kg/day) for 6 weeks starting at the third week following the surgery. At the end of the 9(th) week, systolic blood pressures were recorded, cardiac functions were determined, and the contraction/relaxation responses of aortic rings were obtained. Serum creatinine levels, tissue malondialdehyde, glutathione, superoxide dismutase, catalase levels, and myeloperoxidase activity in heart and kidney samples were analyzed, and Na(+), K(+)-ATPase activity was measured in kidney samples. In both sham-OVX and OVX rats, both agonists reduced blood pressure and reversed the impaired contractile performance of the heart, while ERβ agonist improved renal functions in both the OVX and non-OVX rats. Both agonists reduced neutrophil infiltration, lipid peroxidation, and elevated antioxidant levels in the heart, but a more ERβ-mediated protective effect was observed in the kidney. Our data suggest that activation of ERβ might play a role in preserving the function of the stenotic kidney and delaying the progression of renal injury, while both receptors mediate similar cardioprotective effects. PMID:27399230

  11. Thermostabilisation of an agonist-bound conformation of the human adenosine A(2A) receptor.

    PubMed

    Lebon, Guillaume; Bennett, Kirstie; Jazayeri, Ali; Tate, Christopher G

    2011-06-10

    The adenosine A(2A) receptor (A(2A)R) is a G-protein-coupled receptor that plays a key role in transmembrane signalling mediated by the agonist adenosine. The structure of A(2A)R was determined recently in an antagonist-bound conformation, which was facilitated by the T4 lysozyme fusion in cytoplasmic loop 3 and the considerable stabilisation conferred on the receptor by the bound inverse agonist ZM241385. Unfortunately, the natural agonist adenosine does not sufficiently stabilise the receptor for the formation of diffraction-quality crystals. As a first step towards determining the structure of A(2A)R bound to an agonist, the receptor was thermostabilised by systematic mutagenesis in the presence of the bound agonist [(3)H]5'-N-ethylcarboxamidoadenosine (NECA). Four thermostabilising mutations were identified that when combined to give mutant A(2A)R-GL26, conferred a greater than 200-fold decrease in its rate of unfolding compared to the wild-type receptor. Pharmacological analysis suggested that A(2A)R-GL26 is stabilised in an agonist-bound conformation because antagonists bind with up to 320-fold decreased affinity. None of the thermostabilising mutations are in the ZM241385 binding pocket, suggesting that the mutations affect ligand binding by altering the conformation of the receptor rather than through direct interactions with ligands. A(2A)R-GL26 shows considerable stability in short-chain detergents, which has allowed its purification and crystallisation. PMID:21501622

  12. Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands.

    PubMed

    Takayama, Hiromitsu; Ishikawa, Hayato; Kurihara, Mika; Kitajima, Mariko; Aimi, Norio; Ponglux, Dhavadee; Koyama, Fumi; Matsumoto, Kenjiro; Moriyama, Tomoyuki; Yamamoto, Leonard T; Watanabe, Kazuo; Murayama, Toshihiko; Horie, Syunji

    2002-04-25

    Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compounds for mu-, delta-, and kappa-receptors were determined in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivatives of mitragynine, i.e., mitragynine pseudoindoxyl (2) and 7-hydroxymitragynine (12), were found as opioid agonists with higher potency than morphine in the experiment with guinea pig ileum. In addition, 2 induced an analgesic activity in the tail flick test in mice. PMID:11960505

  13. The ATLAS3D project - VIII. Modelling the formation and evolution of fast and slow rotator early-type galaxies within ΛCDM

    NASA Astrophysics Data System (ADS)

    Khochfar, Sadegh; Emsellem, Eric; Serra, Paolo; Bois, Maxime; Alatalo, Katherine; Bacon, R.; Blitz, Leo; Bournaud, Frédéric; Bureau, M.; Cappellari, Michele; Davies, Roger L.; Davis, Timothy A.; de Zeeuw, P. T.; Duc, Pierre-Alain; Krajnović, Davor; Kuntschner, Harald; Lablanche, Pierre-Yves; McDermid, Richard M.; Morganti, Raffaella; Naab, Thorsten; Oosterloo, Tom; Sarzi, Marc; Scott, Nicholas; Weijmans, Anne-Marie; Young, Lisa M.

    2011-10-01

    We propose a simple model for the origin of fast and slow rotator early-type galaxies (ETG) within the hierarchical Λcold dark matter (ΛCDM) scenario, that is based on the assumption that the mass fraction of stellar discs in ETGs is a proxy for the specific angular momentum expressed via λR. Within our model we reproduce the fraction of fast and slow rotators as a function of magnitude in the ATLAS3D survey, assuming that fast-rotating ETGs have at least 10 per cent of their total stellar mass in a disc component. In agreement with ATLAS3D observations we find that slow rotators are predominantly galaxies with M* > 1010.5 M⊙ contributing ˜20 per cent to the overall ETG population. We show in detail that the growth histories of fast and slow rotators are different, supporting the classification of ETGs into these two categories. Slow rotators accrete between ˜50 and 90 per cent of their stellar mass from satellites and their most massive progenitors have on average up to three major mergers during their evolution. Fast rotators in contrast accrete less than 50 per cent and have on average less than one major merger in their past. We find that the underlying physical reason for the different growth histories is the slowing down and ultimately complete shut-down of gas cooling in massive galaxies. Once cooling and associated star formation in disc stop, galaxies grow via infall from satellites. Frequent minor mergers thereby destroy existing stellar discs via violent relaxation and also tend to lower the specific angular momentum of the main stellar body, lowering λR into the slow rotator regime. On average, the last gas-rich major merger interaction in slow rotators happens at z > 1.5, followed by a series of minor mergers. These results support the idea that kinematically decoupled cores (KDC) form during gas-rich major mergers at high z followed by minor mergers, which build-up the outer layers of the remnant, and make remnants that are initially too flat

  14. Disease Modification of Breast Cancer–Induced Bone Remodeling by Cannabinoid 2 Receptor Agonists

    PubMed Central

    Symons-Liguori, Ashley M; Largent-Milnes, Tally M; Havelin, Josh J; Ferland, Henry L; Chandramouli, Anupama; Owusu-Ankomah, Mabel; Nikolich-Zugich, Tijana; Bloom, Aaron P; Jimenez-Andrade, Juan Miguel; King, Tamara; Porreca, Frank; Nelson, Mark A; Mantyh, Patrick W; Vanderah, Todd W

    2015-01-01

    Most commonly originating from breast malignancies, metastatic bone cancer causes bone destruction and severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain, and drug-induced side effects; furthermore, recent findings suggest that patients are severely undertreated for their cancer pain. Strong analgesics, namely opiates, are first-line therapy in alleviating cancer-related pain despite the severe side effects, including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which are associated with highly undesirable side effects, including nephrotoxicity and osteonecrosis of the jaw. In contrast, cannabinoid receptor 2 (CB2) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB2 agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB1/CB2 agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB2 agonists reduce breast cancer–induced bone pain, bone loss, and breast cancer proliferation via cytokine/chemokine suppression. Studies used the spontaneously-occurring murine mammary cell line (66.1) implanted into the femur intramedullary space; measurements of spontaneous pain, bone loss, and cancer proliferation were made. The systemic administration of a CB2 agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB2-mediated effects in vivo were reversed by concurrent treatment with a CB2 antagonist/inverse agonist but not with a CB1 antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB2 agonists as a

  15. Use of alpha-agonists for management of anaphylaxis occurring under anaesthesia: case studies and review.

    PubMed

    Heytman, M; Rainbird, A

    2004-12-01

    Anaphylaxis is an uncommon but serious complication of anaesthesia. Most current guidelines for the management of anaphylaxis list only epinephrine as a vasopressor to use in the event of cardiovascular collapse. We present two cases of anaphylaxis under anaesthesia where return of spontaneous circulation was refractory to epinephrine, but occurred following the administration of the alpha-agonist metaraminol. Potential advantages and disadvantages of using epinephrine in this setting, the role of alpha-agonists and some potential mechanisms accounting for their role in successful management are reviewed. PMID:15549981

  16. Chemical communication in scarab beetles: reciprocal behavioral agonist-antagonist activities of chiral pheromones.

    PubMed Central

    Leal, W S

    1996-01-01

    A novel mechanism of reciprocal behavioral agonist-antagonist activities of enantiomeric pheromones plays a pivotal role in overcoming the signal-to-noise problem derived from the use of a single-constituent pheromone system in scarab beetles. Female Anomala osakana produce (S, Z)-5-(+)-(1-decenyl)oxacyclopentan-2-one, which is highly attractive to males; the response is completely inhibited even by 5% of its antipode. These two enantiomers have reverse roles in the Popillia japonica sex pheromone system. Chiral GC-electroantennographic detector experiments suggest that A. osakana and P. japonica have both R and S receptors that are responsible for behavioral agonist and antagonist responses. PMID:8901541

  17. Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors.

    PubMed

    Jakubík, J; Bacáková, L; El-Fakahany, E E; Tucek, S

    1997-07-01

    It is well known that allosteric modulators of muscarinic acetylcholine receptors can both diminish and increase the affinity of receptors for their antagonists. We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Allosterically induced changes in the affinities for agonists were computed from changes in the ability of a fixed concentration of each agonist to compete with [3H]N-methylscopolamine for the binding to the receptors in the absence and the presence of varying concentrations of allosteric modulators. The effects of allosteric modulators varied greatly depending on the agonists and the subtypes of receptors. The affinity for acetylcholine was augmented by (-)-eburnamonine on the M2 and M4 receptors and by brucine on the M1 and M3 receptors. Brucine also enhanced the affinities for carbachol, bethanechol, furmethide, methylfurmethide, pilocarpine, 3-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1- methylpyridine (pentylthio-TZTP), oxotremorine-M, and McN-A-343 on the M1, M3, and M4 receptors, for pentylthio-TZTP on the M2 receptors, and for arecoline on the M3 receptors. (-)-Eburnamonine enhanced the affinities for carbachol, bethanechol, furmethide, methylfurmethide, pentylthio-TZTP, pilocarpine, oxotremorine and oxotremorine-M on the M2 receptors and for pilocarpine on the M4 receptors. Vincamine, strychnine, and alcuronium displayed fewer positive allosteric interactions with the agonists, but each allosteric modulator displayed positive cooperativity with at least one agonist on at least one muscarinic receptor subtype. The highest degrees of positive cooperativity were observed between (-)-eburnamonine and pilocarpine and (-)-eburnamonine and oxotremorine-M on the M2 receptors (25- and 7-fold increases in

  18. Discovery of biaryls as RORγ inverse agonists by using structure-based design.

    PubMed

    Enyedy, Istvan J; Powell, Noel A; Caravella, Justin; van Vloten, Kurt; Chao, Jianhua; Banerjee, Daliya; Marcotte, Douglas; Silvian, Laura; McKenzie, Andres; Hong, Victor Sukbong; Fontenot, Jason D

    2016-05-15

    RORγ plays a critical role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including T cells, γδ T cells, and innate lymphoid cells. RORγ-mediated inflammation has been linked to susceptibility to Crohn's disease, arthritis, and psoriasis. Thus inverse agonists of RORγ have the potential of modulating inflammation. Our goal was to optimize two RORγ inverse agonists: T0901317 from literature and 1 that we obtained from internal screening. We used information from internal X-ray structures to design two libraries that led to a new biaryl series. PMID:27080181

  19. The CRTH2 agonist Pyl A prevents lipopolysaccharide-induced fetal death but induces preterm labour

    PubMed Central

    Sykes, Lynne; Herbert, Bronwen R; MacIntyre, David A; Hunte, Emma; Ponnampalam, Sathana; Johnson, Mark R; Teoh, Tiong G; Bennett, Phillip R

    2013-01-01

    We have previously demonstrated that the anti-inflammatory prostaglandin 15-deoxy-Δ 12,14-prostaglandin J2 (15dPGJ2) delays inflammation-induced preterm labour in the mouse and improves pup survival through the inhibition of nuclear factor-κB (NF-κB) by a mechanism yet to be elucidated. 15dPGJ2 is an agonist of the second prostaglandin D2 receptor, chemoattractant receptor homologous to the T helper 2 cell (CRTH2). In human T helper cells CRTH2 agonists induce the production of the anti-inflammatory interleukins IL-10 and IL-4. We hypothesized that CRTH2 is involved in the protective effect of 15dPGJ2 in inflammation-induced preterm labour in the murine model. We therefore studied the effects of a specific small molecule CRTH2 agonist on preterm labour and pup survival. An intrauterine injection of lipopolysaccharide (LPS) was administered to CD1 mice at embryonic day 16, ± CRTH2 agonist/vehicle controls. Mice were killed at 4.5 hr to assess fetal wellbeing and to harvest myometrium and pup brain for analysis of NF-κB, and T helper type 1/2 interleukins. To examine the effects of the CRTH2 agonist on LPS-induced preterm labour, mice were allowed to labour spontaneously. Direct effects of the CRTH2 agonist on uterine contractility were examined ex vivo on contracting myometrial strips. The CRTH2 agonist increased fetal survival from 20 to 100% in LPS-treated mice, and inhibited circular muscle contractility ex vivo. However, it augmented LPS-induced labour and significantly increased myometrial NF-κB, IL-1β, KC-GRO, interferon-γ and tumour necrosis factor-α. This suggests that the action of 15dPGJ2 is not via CRTH2 and therefore small molecule CRTH2 agonists are not likely to be beneficial for the prevention of inflammation-induced preterm labour. PMID:23374103

  20. Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists.

    PubMed

    Yang, Bingwei V; Weinstein, David S; Doweyko, Lidia M; Gong, Hua; Vaccaro, Wayne; Huynh, Tram; Xiao, Hai-Yun; Doweyko, Arthur M; McKay, Lorraine; Holloway, Deborah A; Somerville, John E; Habte, Sium; Cunningham, Mark; McMahon, Michele; Townsend, Robert; Shuster, David; Dodd, John H; Nadler, Steven G; Barrish, Joel C

    2010-12-01

    A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed. PMID:21073190

  1. Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists.

    PubMed

    Urbanek, Rebecca A; Xiong, Hui; Wu, Ye; Blackwell, William; Steelman, Gary; Rosamond, Jim; Wesolowski, Steven S; Campbell, James B; Zhang, Minli; Brockel, Becky; Widzowski, Daniel V

    2013-01-15

    Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model. PMID:23237836

  2. Beta 2-adrenergic agonist as adjunct therapy to levodopa in Parkinson's disease.

    PubMed

    Alexander, G M; Schwartzman, R J; Nukes, T A; Grothusen, J R; Hooker, M D

    1994-08-01

    We studied the effect of the beta 2-adrenergic agonist albuterol on Parkinson's disease (PD) patients receiving chronic levodopa treatment. The albuterol-treated patients demonstrated reduced parkinsonian symptoms and an increased ability to tap their index finger between two points 20 cm apart, and were able to perform a "walk test" in 70% of their control time. Three patients currently on chronic albuterol therapy still show amelioration of their parkinsonian symptoms, and two have reduced their daily levodopa dose. This study suggests that beta 2-adrenergic agonists as adjunct therapy to levodopa may be beneficial in PD. PMID:8058159

  3. Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Rose, M. Franklin (Technical Monitor)

    2000-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

  4. Self-administration of agonists selective for dopamine D2, D3, and D4 receptors by rhesus monkeys.

    PubMed

    Koffarnus, Mikhail N; Collins, Gregory T; Rice, Kenner C; Chen, Jianyong; Woods, James H; Winger, Gail

    2012-08-01

    Dopamine receptor mechanisms are believed to play a role in the reinforcing effects of cocaine and other drugs of abuse. The lack of receptor-selective agonists has made it difficult to determine the role of the individual dopamine receptors in mediating these reinforcing effects. In this study, rhesus monkeys with a history of intravenous cocaine self-administration were tested for the reinforcing effects of several D(3)-preferring agonists, a D(2)-preferring agonist, and a D(4) agonist. The D(2)-preferring agonist did not maintain responding in any monkeys, and the D(4) agonist was self-administered at low rates, just above those maintained by saline, in one monkey. The D(3)-preferring agonists were self-administered by approximately half of the animals, although at lower rates than cocaine. These results indicate that the apparent limited reinforcing effectiveness of D(2)-like agonists requires activity at D(3) receptors. Previous data from this laboratory and others also suggest that these drugs may not serve as reinforcers directly; the behavior may be maintained by response-contingent delivery of stimuli previously paired with cocaine. The ability of drug-related stimuli to maintain responding apparently differs among monkeys and other organisms, and may be related to individual differences in drug-taking behavior in humans. PMID:22785383

  5. The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist

    SciTech Connect

    Madauss, Kevin P.; Bledsoe, Randy K.; Mclay, Iain; Stewart, Eugene L.; Uings, Iain J.; Weingarten, Gordon; Williams, Shawn P.

    2009-07-23

    The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).

  6. Chronic β2 adrenergic agonist, but not exercise, improves glucose handling in older type 2 diabetic mice.

    PubMed

    Elayan, Hamzeh; Milic, Milos; Sun, Ping; Gharaibeh, Munir; Ziegler, Michael G

    2012-07-01

    Insulin resistant type 2 diabetes mellitus in the obese elderly has become a worldwide epidemic. While exercise can prevent the onset of diabetes in young subjects its role in older diabetic people is less clear. Exercise stimulates the release of the β(2)-agonist epinephrine more in the young. Although epinephrine and β(2)-agonist drugs cause acute insulin resistance, their chronic effect on insulin sensitivity is unclear. We fed C57BL/6 mice a high fat diet to induce diabetes. These overweight animals became very insulin resistant. Exhaustive treadmill exercise 5 days a week for 8 weeks had no effect on their diabetes, nor did the β(2)-blocking drug ICI 118551. In contrast, exercise combined with the β(2)-agonist salbutamol (albuterol) had a beneficial effect on both glucose tolerance and insulin sensitivity after 4 and 8 weeks of exercise. The effect was durable and persisted 5 weeks after exercise and β(2)-agonist had stopped. To test whether β(2)-agonist alone was effective, the animals that had received β(2)-blockade were then given β(2)-agonist. Their response to a glucose challenge improved but their response to insulin was not significantly altered. The β(2)-agonists are commonly used to treat asthma and asthmatics have an increased incidence of obesity and type 2 diabetes. Although β(2)-agonists cause acute hyperglycemia, chronic treatment improves insulin sensitivity, probably by improving muscle glucose uptake. PMID:22422105

  7. MUC-1 Tumor Antigen Agonist Epitopes for Enhancing T-cell Responses to Human Tumors | NCI Technology Transfer Center | TTC

    Cancer.gov

    Scientists at NIH have identified 7 new agonist epitopes of the MUC-1 tumor associated antigen. Compared to their native epitope counterparts, peptides reflecting these agonist epitopes have been shown to enhance the generation of human tumor cells, which in turn have a greater ability to kill human tumor cells endogenously expressing the native MUC-1 epitope.

  8. Chronic treatment with estrogen receptor agonists restores acquisition of a spatial learning task in young ovariectomized rats

    PubMed Central

    Hammond, R.; Mauk, R.; Ninaci, D.; Nelson, D.; Gibbs, RB

    2009-01-01

    Previous work has shown that continuous estradiol replacement in young ovariectomized rats enhances acquisition of a delayed matching-to-position (DMP) T-maze task over that of ovariectomized controls. The mechanism by which estradiol confers this benefit has not been fully elucidated. This study examined the role of selective estrogen receptor agonists of ERα, ERβ, and GPR30 in the enhancement of spatial learning on a DMP task by comparing continuous estradiol replacement with continuous administration of PPT (an agonist of ERα), DPN (an agonist of ERβ), or G-1 (an agonist of GPR30) relative to gonadally intact and ovariectomized vehicle-treated controls. It was found that ovariectomy impaired acquisition on this task, whereas all ER selective agonists restored the rate of acquisition to that of gonadally intact controls. These data suggest that estradiol can work through any of several estrogen receptors to enhance the rate of acquisition on this task. PMID:19560466

  9. G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges.

    PubMed

    Ritter, Kurt; Buning, Christian; Halland, Nis; Pöverlein, Christoph; Schwink, Lothar

    2016-04-28

    In this Perspective, recent advances and challenges in the development of GPR119 agonists as new oral antidiabetic drugs will be discussed. Such agonists are expected to exhibit a low risk to induce hypoglycemia as well as to have a beneficial impact on body weight. Many pharmaceutical companies have been active in the search for GPR119 agonists, making it a highly competitive area in the industrial environment. Several GPR119 agonists have been entered into clinical studies, but many have failed either in phase I or II and none has progressed beyond phase II. Herein we describe the strategies chosen by the different medicinal chemistry teams in academia and the pharmaceutical industry to improve potency, physicochemical properties, pharmacokinetics, and the safety profile of GPR119 agonists in the discovery phase in order to improve the odds for successful development. PMID:26512410

  10. Inhibitory GTP binding protein G/sub i/ regulates US -adrenoceptor affinity towards US -agonists

    SciTech Connect

    Marbach, I.; Levitzki, A.

    1987-05-01

    Treatment of S-49 lymphoma cell membranes with pertussis toxin (PT) causes a three-fold reduction of US -adrenoceptor (US AR) affinity towards isoproterenol. A similar treatment with cholera toxin (CT) does not cause such a modulation. The effects were studied by the detailed analysis of SVI-cyanopindolol (CYP) binding curves in the absence and presence of increasing agonist concentrations. Thus, the authors were able to compare in detail the effects of G/sub s/ and G/sub i/ on the agonist-associated state of the US AR. In contrast to these findings, PT treatment does not have any effect on the displacement of SVI-CYP by (-)isoproterenol. These results demonstrate that the inhibitory GTP protein G/sub i/ modulates the US AR affinity towards US -agonists. This might be due to the association of G/sub i/ with the agonist-bound US AR x G/sub s/ x C complex within the membrane. This hypothesis, as well as others, is under investigation.

  11. Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation.

    PubMed

    Yunn, Na-Oh; Koh, Ara; Han, Seungmin; Lim, Jong Hun; Park, Sehoon; Lee, Jiyoun; Kim, Eui; Jang, Sung Key; Berggren, Per-Olof; Ryu, Sung Ho

    2015-09-18

    Due to their high affinity and specificity, aptamers have been widely used as effective inhibitors in clinical applications. However, the ability to activate protein function through aptamer-protein interaction has not been well-elucidated. To investigate their potential as target-specific agonists, we used SELEX to generate aptamers to the insulin receptor (IR) and identified an agonistic aptamer named IR-A48 that specifically binds to IR, but not to IGF-1 receptor. Despite its capacity to stimulate IR autophosphorylation, similar to insulin, we found that IR-A48 not only binds to an allosteric site distinct from the insulin binding site, but also preferentially induces Y1150 phosphorylation in the IR kinase domain. Moreover, Y1150-biased phosphorylation induced by IR-A48 selectively activates specific signaling pathways downstream of IR. In contrast to insulin-mediated activation of IR, IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells. Instead, AKT S473 phosphorylation is highly stimulated by IR-A48, resulting in increased glucose uptake both in vitro and in vivo. Here, we present IR-A48 as a biased agonist able to selectively induce the metabolic activity of IR through allosteric binding. Furthermore, our study also suggests that aptamers can be a promising tool for developing artificial biased agonists to targeted receptors. PMID:26245346

  12. Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of ...

  13. Binding characteristics of gamma-hydroxybutyric acid as a weak but selective GABAB receptor agonist.

    PubMed

    Mathivet, P; Bernasconi, R; De Barry, J; Marescaux, C; Bittiger, H

    1997-02-19

    The aim of this study was to reexamine the concept that gamma-hydroxybutyric acid (GHB) is a weak but selective agonist at gamma-aminobutyric acidB (GABAB) receptors, using binding experiments with several radioligands. Ki values of GHB were similar (approximately equal to 100 microM) in three agonist radioligand assays for GABAB receptors, [3H]baclofen (beta-para-chlorophenyl-gamma-aminobutyric acid), [3H]CGP 27492 (3-aminopropyl-phosphinic acid) and [3H]GABA, in the presence of the GABAA receptor agonist isoguvacine with rat cortical, cerebellar and hippocampal membranes. In competition experiments between GHB and the GABAB receptor antagonist, [3H]CGP 54626 (3-N [1-{(S)-3,4-dichlorophenyl}-ethylamino]-2-(S)-hydroxypropyl cyclo-hexylmethyl phosphinic acid), the IC50 values were significantly increased with 300 microM of 5'-guanyl-imidodiphosphate (Gpp(NH)p), which suggested that guanine nucleotide binding proteins (G-proteins) modulate GHB binding on GABAB receptors. The inhibition by GHB of [3H]CGP 27492 binding in cortical membranes was not altered in the presence of 0.3 or 3 mM of the two GHB dehydrogenase inhibitors, valproate and ethosuximide. Thus, GHB is not reconverted into GABA by GHB dehydrogenase. Taken together, the results of this study demonstrated that GHB is an endogenous weak but selective agonist at GABAB receptors. PMID:9083788

  14. Male receiver bias for red agonistic signalling in a yellow-signalling widowbird: a field experiment

    PubMed Central

    Ninnes, C. E.; Andersson, S.

    2014-01-01

    Receiver bias models of signal evolution are typically regarded as alternatives or complements to ornament evolution due to coevolving mate choice, whereas sexually or socially selected agonistic signals are rarely studied with respect to receiver psychology. Against the background of convergent evolution of red agonistic signals from yellow ancestors in the genus Euplectes (widowbirds and bishops), we experimentally test the function of a yellow signal in the montane marsh widowbird (E. psammocromius), as well as a hypothesized receiver bias for redder (longer wavelength) hues. In a field experiment in southern Tanzania, males that had their yellow wing patches blackened lost their territories or lost territorial contests more often than controls or reddened males, which together with a longer wavelength hue in territory holders, indicates an agonistic signal function. Males painted a novel red hue, matching that of red-signalling congeners, retained their territories and won contests more often than controls. To our knowledge, this is the first demonstration of a receiver bias driving agonistic signal evolution. Although the sensory or cognitive origin of this bias is yet unknown, it strengthens our view that genetically constrained signal production (i.e. carotenoid metabolism), rather than differential selection, explains the carotenoid colour diversification in Euplectes. PMID:25056624

  15. Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist.

    PubMed

    Młyniec, Katarzyna; Starowicz, Gabriela; Gaweł, Magdalena; Frąckiewicz, Ewelina; Nowak, Gabriel

    2016-09-01

    Some forms of depression appear to be more related to the glutamatergic system. G-coupled protein receptor 39 (GPR39) is the metabotropic zinc receptor, which may be involved in the pathophysiology of depression and in the antidepressant response. Its deficiency abolishes the antidepressant response, which means that GPR39 is required to obtain a therapeutic effect in depression. This raises the possibility that agonists of the zinc receptor may have a role in antidepressant treatment. To explore this possibility we investigated animal behaviour in the forced swim test, the tail suspension test (to assess antidepressant-like properties), the light/dark test and the elevated plus maze test (to assess anxiolytic-like properties), following acute administration of a GPR39 agonist (TC G-1008). We found an antidepressant response (as measured by the forced swim test but not by the tail suspension test) in mice following the GPR39 agonist treatment. Additionally, we observed the opposite results in the light/dark box (decreased overall distance; increased time spent in the lit compartment; decreased time spent in the dark compartment; increased freezing time) and elevated plus maze (no significant changes), which may be a consequence of the sedative effect of TC G-1008. We also found hippocampal GPR39 and brain-derived neurotrophic factor (BDNF) up-regulation following administration of the GPR39 agonist, which may be undiscovered so far as a possible novel agent in the treatment of mood disorders. PMID:27235821

  16. Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation

    PubMed Central

    Yunn, Na-Oh; Koh, Ara; Han, Seungmin; Lim, Jong Hun; Park, Sehoon; Lee, Jiyoun; Kim, Eui; Jang, Sung Key; Berggren, Per-Olof; Ryu, Sung Ho

    2015-01-01

    Due to their high affinity and specificity, aptamers have been widely used as effective inhibitors in clinical applications. However, the ability to activate protein function through aptamer-protein interaction has not been well-elucidated. To investigate their potential as target-specific agonists, we used SELEX to generate aptamers to the insulin receptor (IR) and identified an agonistic aptamer named IR-A48 that specifically binds to IR, but not to IGF-1 receptor. Despite its capacity to stimulate IR autophosphorylation, similar to insulin, we found that IR-A48 not only binds to an allosteric site distinct from the insulin binding site, but also preferentially induces Y1150 phosphorylation in the IR kinase domain. Moreover, Y1150-biased phosphorylation induced by IR-A48 selectively activates specific signaling pathways downstream of IR. In contrast to insulin-mediated activation of IR, IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells. Instead, AKT S473 phosphorylation is highly stimulated by IR-A48, resulting in increased glucose uptake both in vitro and in vivo. Here, we present IR-A48 as a biased agonist able to selectively induce the metabolic activity of IR through allosteric binding. Furthermore, our study also suggests that aptamers can be a promising tool for developing artificial biased agonists to targeted receptors. PMID:26245346

  17. Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus

    ERIC Educational Resources Information Center

    Segev, Amir; Akirav, Irit

    2011-01-01

    We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 [mu]g/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval.…

  18. Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid red...

  19. Toll-like receptor 7 agonists: chemical feature based pharmacophore identification and molecular docking studies.

    PubMed

    Yu, Hui; Jin, Hongwei; Sun, Lidan; Zhang, Liangren; Sun, Gang; Wang, Zhanli; Yu, Yongchun

    2013-01-01

    Chemical feature based pharmacophore models were generated for Toll-like receptors 7 (TLR7) agonists using HypoGen algorithm, which is implemented in the Discovery Studio software. Several methods tools used in validation of pharmacophore model were presented. The first hypothesis Hypo1 was considered to be the best pharmacophore model, which consists of four features: one hydrogen bond acceptor, one hydrogen bond donor, and two hydrophobic features. In addition, homology modeling and molecular docking studies were employed to probe the intermolecular interactions between TLR7 and its agonists. The results further confirmed the reliability of the pharmacophore model. The obtained pharmacophore model (Hypo1) was then employed as a query to screen the Traditional Chinese Medicine Database (TCMD) for other potential lead compounds. One hit was identified as a potent TLR7 agonist, which has antiviral activity against hepatitis virus in vitro. Therefore, our current work provides confidence for the utility of the selected chemical feature based pharmacophore model to design novel TLR7 agonists with desired biological activity. PMID:23526932

  20. Graft versus host disease: New insights into A2A receptor agonist therapy.

    PubMed

    Jones, Karlie R; Kang, Elizabeth M

    2015-01-01

    Allogeneic transplantation can cure many disorders, including sickle cell disease, chronic granulomatous disease (CGD), severe combined immunodeficiency (SCID) and many types of cancers. However, there are several associated risks that can result in severe immunological reactions and, in some cases, death. Much of this morbidity is related to graft versus host disease (GVHD) [1]. GVHD is an immune mediated reaction in which donor T cells recognize the host as antigenically foreign, causing donor T cells to expand and attack host tissues. The current method of treating recent transplant patients with immunosuppressants to prevent this reaction has met with only partial success, emphasizing a need for new methods of GVHD treatment and prevention. Recently, a novel strategy has emerged targeting adenosine A2A receptors (A2AR) through the use of adenosine agonists. These agonists have been shown in vitro to increase the TGFβ-induced generation of FoxP3(+) regulatory T cells (Tregs) and in vivo to improve weight gain and mortality as well as inhibit the release of pro-inflammatory cytokines in GVHD murine models [2,3]. Positive results involving A2AR agonists in vitro and in vivo are promising, suggesting that A2AR agonists should be a part of the management of clinical GvHD. PMID:25709759

  1. Identification of a novel partial agonist of liver X receptor α (LXRα) via screening.

    PubMed

    Li, Ni; Wang, Xiao; Zhang, Jing; Liu, Chang; Li, Yongzhen; Feng, Tingting; Xu, Yanni; Si, Shuyi

    2014-12-01

    Liver X receptor α (LXRα) plays an important role in the cholesterol metabolism process, and LXRα activation can reduce atherosclerosis. In the present study, using an LXRα-GAL4 luciferase reporter screening, we discovered IMB-170, a structural analog of quinazolinone, which showed potent LXRα agonistic activity. IMB-170 significantly activated LXRα, with an EC50 value of 0.27μM. Interestingly, IMB-170 not only increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1), which are related to the reverse cholesterol transport (RCT) process, but also influenced the expression levels of other genes involved in the cholesterol metabolism pathway in many cell lines. Moreover, IMB-170 significantly reduced cellular lipid accumulation and increased cholesterol efflux from RAW264.7 and THP-1 macrophages. Interestingly, compared with TO901317, IMB-170 only slightly increased protein expression levels of lipogenesis-related genes in HepG2 cells, indicating that IMB-170 may have a lower lipogenesis side effect in vivo. These results suggest that IMB-170 showed the selective agonistic activity for LXRα. Moreover, compared with full LXR-agonists, IMB-170 possesses a differential ability to recruit coregulators. This suggests that IMB-170 has distinct interactions with the active sites in the LXRα ligand-binding domain. In summary, IMB-170 is a novel partial LXRα agonist without the classical lipogenesis side effects, which could be used as a potential anti-atherosclerotic leading compound in the future. PMID:25450668

  2. Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo.

    PubMed

    Kataria, Hardeep; Lutz, David; Chaudhary, Harshita; Schachner, Melitta; Loers, Gabriele

    2016-09-01

    Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery after injury, leading to severe disabilities in motor functions and pain. Peripheral nerve injury impairs motor, sensory, and autonomic functions, particularly in cases where nerve gaps are large and chronic nerve injury ensues. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration after acute injury. We screened libraries of known drugs for small molecule agonists of L1 and evaluated the effect of hit compounds in cell-based assays in vitro and in mice after femoral nerve and spinal cord injuries in vivo. We identified eight small molecule L1 agonists and showed in cell-based assays that they stimulate neuronal survival, neuronal migration, and neurite outgrowth and enhance Schwann cell proliferation and migration and myelination of neurons in an L1-dependent manner. In a femoral nerve injury mouse model, enhanced functional regeneration and remyelination after application of the L1 agonists were observed. In a spinal cord injury mouse model, L1 agonists improved recovery of motor functions, being paralleled by enhanced remyelination, neuronal survival, and monoaminergic innervation, reduced astrogliosis, and activation of microglia. Together, these findings suggest that application of small organic compounds that bind to L1 and stimulate the beneficial homophilic L1 functions may prove to be a valuable addition to treatments of nervous system injuries. PMID:26253722

  3. Accessory Cell Mediated Activation of Porcine NK Cells by TLR7 and TLR8 Agonists

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The induction of innate immune responses by toll-like receptor (TLR) agonists is the subject of intense investigation in many different species. In large part, this reflects the potential of such compounds to be effective vaccine adjuvants. For that reason, we analyzed the activation of innate cells...

  4. Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease

    PubMed Central

    Lee, Hyun Jung; Yeon, Jong Eun; Ko, Eun Jung; Yoon, Eileen L; Suh, Sang Jun; Kang, Keunhee; Kim, Hae Rim; Kang, Seoung Hee; Yoo, Yang Jae; Je, Jihye; Lee, Beom Jae; Kim, Ji Hoon; Seo, Yeon Seok; Yim, Hyung Joon; Byun, Kwan Soo

    2015-01-01

    AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors (PPAR)-δ agonist treatment in nonalcoholic fatty liver disease (NAFLD) models. METHODS: Male C57BL/6J mice were classified according to control or high fat diet (HFD) with or without PPAR-δ agonist (GW) over period of 12 wk [control, HFD, HFD + lipopolysaccharide (LPS), HFD + LPS + GW group]. HepG2 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of GW. RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin (IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In HepG2 cells, PA and LPS treatment markedly increased mRNA of several nucleotide-binding and oligomerization domain-like receptor family members (NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α. CONCLUSION: PPAR-δ agonist reduces fatty acid-induced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD. PMID:26668503

  5. D-amino acid oxidase generates agonists of the aryl hydrocarbon receptor from D-tryptophan.

    PubMed

    Nguyen, Linh P; Hsu, Erin L; Chowdhury, Goutam; Dostalek, Miroslav; Guengerich, F Peter; Bradfield, Christopher A

    2009-12-01

    The aryl hydrocarbon receptor (AHR) is well-known for its role in mediating the toxic and adaptive responses to xenobiotic compounds. Recent studies also indicate that AHR ligands are endogenously produced and may be essential for normal development. Previously, we showed that the endogenous enzyme, aspartate aminotransferase (AST), generates the AHR proagonist, indole-3-pyruvic acid (I3P), by deamination of its substrate L-tryptophan. We hypothesized that other enzymatic pathways capable of producing I3P may generate AHR agonists in vivo. We now demonstrate that the enzyme d-amino acid oxidase (DAAO) catalyzes the production of AHR agonists through the enzymatic conversion of D-tryptophan to I3P. Moreover, we provide evidence that the nonenzymatic oxidation and condensation of I3P is a critical step in the generation of receptor agonists by DAAO and AST. Products of this process include two novel agonists, 1,3-di(1H-indol-3-yl)propan-2-one and 1-(1H-indol-3-yl)-3-(3H-indol-3-ylidene) propan-2-one [characterized in the accompanying paper, Chowdhury et al. ( 2009 ) Chem. Res. Toxicol. , DOI: 10.1021/tx9000418 ], both of which can potently activate the AHR at concentrations in the nanomolar range. These results show that endogenous AHR activity can be modulated by I3P production from amino acid precursors through multiple enzymatic pathways, including those catalyzed by DAAO and AST. PMID:19860415

  6. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.

    PubMed

    Wong, Gilbert Y; Gavva, Narender R

    2009-04-01

    The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions. PMID:19150372

  7. Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone

    PubMed Central

    Wang, Xue-Jiao; Zhang, Jun; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

    2014-01-01

    The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research. PMID:25422585

  8. Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor

    PubMed Central

    Taylor, Lewis; Christou, Ivy; Kapellos, Theodore S.; Buchan, Alice; Brodermann, Maximillian H.; Gianella-Borradori, Matteo; Russell, Angela; Iqbal, Asif J.; Greaves, David R.

    2015-01-01

    Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2-/- macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced β-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field. PMID:26033291

  9. Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor.

    PubMed

    Sahu, Ravi P; Ocana, Jesus A; Harrison, Kathleen A; Ferracini, Matheus; Touloukian, Christopher E; Al-Hassani, Mohammed; Sun, Louis; Loesch, Mathew; Murphy, Robert C; Althouse, Sandra K; Perkins, Susan M; Speicher, Paul J; Tyler, Douglas S; Konger, Raymond L; Travers, Jeffrey B

    2014-12-01

    Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation. PMID:25304264

  10. Divergent teratogenicity of agonists of retinoid X receptors in embryos of zebrafish (Danio rerio).

    PubMed

    Shi, Huahong; Zhu, Pan; Sun, Zhi; Yang, Bo; Zheng, Liang

    2012-07-01

    Zebrafish (Danio rerio) embryos were comparably exposed to seven known agonists of retinoid X receptors (RXRs) including two endogenous compounds (9-cis-retinoic acid and docosahexaenoic acid), four man-made selective ligands (LGD1069, SR11237, fluorobexarotene and CD3254), and a biocide (triphenyltin). The dominant phenotypes of malformation were sharp mouths and small caudal fins in 1 mg/L SR11237-treated group after 5 days exposure. 9-cis-retinoic acid and LGD1069 induced multiple malformations including small eyes, bent notochords, reduced brain, enlarged proctodaems, absence of fins, short tails and edema after 5 days exposure. Fluorobexarotene and CD3254 induced similar phenotypes of malformations after 5 days exposure at low concentration (20 μg/L) to those after the 1st d exposure at high concentrations (50 and 100 μg/L). Triphenlytin induced multiple malformations including deformed eyes, bent notochords, bent tails, and edema in hearts after 5 days exposure at concentrations of 1-10 μg Sn/L. In contrast, no discernible malformations were observed in triphenlytin-treated groups after each separate day exposure. These agonists not only showed different ability of teratogenicity but also induced different phenotypes of malformation in zebrafish embryos. In addition, the sensitive stages of zebrafish embryos were different in response to these agonists. Therefore, our results suggest that the agonists of RXRs had divergent teratogenicity in zebrafish embryos. PMID:22526925

  11. Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents

    PubMed Central

    Yasuda, Shin-ichiro; Tsuchida, Takuma; Oguma, Takahiro; Marley, Anna; Wennberg-Huldt, Charlotte; Hovdal, Daniel; Fukuda, Hajime; Yoneyama, Yukimi; Sasaki, Kazuyo; Johansson, Anders; Lundqvist, Sara; Brengdahl, Johan; Isaacs, Richard J.; Brown, Daniel; Geschwindner, Stefan; Benthem, Lambertus; Priest, Claire; Turnbull, Andrew

    2015-01-01

    Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents. PMID:26720709

  12. Agonistic Recognition in Education: On Arendt's Qualification of Political and Moral Meaning

    ERIC Educational Resources Information Center

    Ljunggren, Carsten

    2010-01-01

    Agonistic recognition in education has three interlinked modes of aesthetic experience and self-presentation where one is related to actions in the public realm; one is related to plurality in the way in which it comes into existence in confrontation with others; and one is related to the subject-self, disclosed by "thinking. Arendt"s conception…

  13. THE MORPHOLOGICAL BASIS FOR OLFACTORY PERCEPTION OF STEROIDS DUING AGONISTIC BEHAVIOR IN LOBSTER: PRELIMINARY EXPERIMENTS

    EPA Science Inventory

    The morphological basis for olfactory perception of steroids during agonistic behavior in lobsters: preliminary experiments. Borsay Horowitz, DJ1, Kass-Simon, G2, Coglianese, D2, Martin, L2, Boseman, M2, Cromarty, S3, Randall, K3, Fini, A.3 1US EPA, NHEERL, ORD, Atlantic Ecology...

  14. β2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease.

    PubMed

    Koeberl, Dwight D; Li, Songtao; Dai, Jian; Thurberg, Beth L; Bali, Deeksha; Kishnani, Priya S

    2012-02-01

    Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes. PMID:22154081

  15. β2 Agonists Enhance the Efficacy of Simultaneous Enzyme Replacement Therapy in Murine Pompe Disease

    PubMed Central

    Koeberl, Dwight D.; Li, Songtao; Dai, Jian; Thurberg, Beth L.; Bali, Deeksha; Kishnani, Priya S.

    2011-01-01

    Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes. PMID:22154081

  16. Characterizing novel metabolic pathways of melatonin receptor agonist agomelatine using metabolomic approaches

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Agomelatine (AGM), an analog of melatonin, is a potential agonist at melatonin receptors 1/2 and a selective antagonist at 5-hydroxytryptamine 2C receptors. AGM is widely used for the treatment of major depressive episodes in adults. However, multiple adverse effects associated with AGM have been re...

  17. Melanocortin 1 receptor agonist protects podocytes through catalase and RhoA activation.

    PubMed

    Elvin, Johannes; Buvall, Lisa; Lindskog Jonsson, Annika; Granqvist, Anna; Lassén, Emelie; Bergwall, Lovisa; Nyström, Jenny; Haraldsson, Börje

    2016-05-01

    Drugs containing adrenocorticotropic hormone have been used as therapy for patients with nephrotic syndrome. We have previously shown that adrenocorticotropic hormone and a selective agonist for the melanocortin 1 receptor (MC1R) exert beneficial actions in experimental membranous nephropathy with reduced proteinuria, reduced oxidative stress, and improved glomerular morphology and function. Our hypothesis is that MC1R activation in podocytes elicits beneficial effects by promoting stress fibers and maintaining podocyte viability. To test the hypothesis, we cultured podocytes and used highly specific agonists for MC1R. Podocytes were subjected to the nephrotic-inducing agent puromycin aminonucleoside, and downstream effects of MC1R activation on podocyte survival, antioxidant defense, and cytoskeleton dynamics were studied. To increase the response and enhance intracellular signals, podocytes were transduced to overexpress MC1R. We showed that puromycin promotes MC1R expression in podocytes and that activation of MC1R promotes an increase of catalase activity and reduces oxidative stress, which results in the dephosphorylation of p190RhoGAP and formation of stress fibers through RhoA. In addition, MC1R agonists protect against apoptosis. Together, these mechanisms protect the podocyte against puromycin. Our findings strongly support the hypothesis that selective MC1R-activating agonists protect podocytes and may therefore be useful to treat patients with nephrotic syndromes commonly considered as podocytopathies. PMID:26887829

  18. Identification of novel IP receptor agonists using historical ligand biased chemical arrays.

    PubMed

    McKeown, Stephen C; Charlton, Steven J; Cox, Brian; Fitch, Helen; Howson, Christopher D; Leblanc, Catherine; Meyer, Arndt; Rosethorne, Elizabeth M; Stanley, Emily

    2014-05-15

    By considering published structural information we have designed high throughput biaryl lipophilic acid arrays leveraging facile chemistry to expedite their synthesis. We rapidly identified multiple hits which were of suitable IP agonist potency. These relatively simple and strategically undecorated molecules present an ideal opportunity for optimization towards our target candidate profile. PMID:24736116

  19. New metabolically stabilized analogues of lysophosphatidic acid: agonists, antagonists and enzyme inhibitors.

    PubMed

    Prestwich, G D; Xu, Y; Qian, L; Gajewiak, J; Jiang, G

    2005-12-01

    Lysophosphatidic acid (LPA) is a metabolically labile natural phospholipid with a bewildering array of physiological effects. We describe herein a variety of long-lived receptor-specific agonists and antagonists for LPA receptors. Several LPA and PA (phosphatidic acid) analogues also inhibit LPP (lipid phosphate phosphatase). The sn-1 or sn-2 hydroxy groups have been replaced by fluorine, difluoromethyl, difluoroethyl, O-methyl or O-hydroxyethoxy groups to give non-migrating LPA analogues that resist acyltransferases. Alkyl ether replacement of acyl esters produced lipase and acyltransferase-resistant analogues. Replacement of the bridging oxygen in the monophosphate by an alpha-monofluoromethylene-, alpha-bromomethylene- or alpha,alpha-difluoromethylenephosphonate gave phosphatase-resistant analogues. Phosphorothioate analogues with O-acyl and O-alkyl chains are potent, long-lived agonists for LPA1 and LPA3 receptors. Most recently, we have (i) prepared stabilized O-alkyl analogues of lysobisphosphatidic acid, (ii) explored the structure-activity relationship of stabilized cyclic LPA analogues and (iii) synthesized neutral head group trifluoromethylsulphonamide analogues of LPA. Through collaborative studies, we have collected data for these stabilized analogues as selective LPA receptor (ant)agonists, LPP inhibitors, TREK (transmembrane calcium channel) K+ channel agonists, activators of the nuclear transcription factor PPAR-gamma (peroxisome-proliferator-activated receptor-gamma), promoters of cell motility and survival, and radioprotectants for human B-cells. PMID:16246118

  20. Incretin-like effects of small molecule trace amine-associated receptor 1 agonists

    PubMed Central

    Raab, Susanne; Wang, Haiyan; Uhles, Sabine; Cole, Nadine; Alvarez-Sanchez, Ruben; Künnecke, Basil; Ullmer, Christoph; Matile, Hugues; Bedoucha, Marc; Norcross, Roger D.; Ottaway-Parker, Nickki; Perez-Tilve, Diego; Conde Knape, Karin; Tschöp, Matthias H.; Hoener, Marius C.; Sewing, Sabine

    2015-01-01

    Objective Type 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight. Methods We investigated the peripheral human tissue distribution of TAAR1 by immunohistochemistry and tested the effect of a small molecule TAAR1 agonist on insulin secretion in vitro using INS1E cells and human islets and on glucose tolerance in C57Bl6, and db/db mice. Body weight effects were investigated in obese DIO mice. Results TAAR1 activation by a selective small molecule agonist increased glucose-dependent insulin secretion in INS1E cells and human islets and elevated plasma PYY and GLP-1 levels in mice. In diabetic db/db mice, the TAAR1 agonist normalized glucose excursion during an oral glucose tolerance test. Sub-chronic treatment of diet-induced obese (DIO) mice with the TAAR1 agonist resulted in reduced food intake and body weight. Furthermore insulin sensitivity was improved and plasma triglyceride levels and liver triglyceride content were lower than in controls. Conclusions We have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity. PMID:26844206

  1. MECHANISMS UNDERLYING ALC13 INHIBITION OF AGONIST-STIMULATED INOSITOL PHOSPHATE ACCUMULATION

    EPA Science Inventory

    Possible mechanisms of AlC13-induced inhibition of agonist-stimulated inositol phosphate (IP) accumulation were investigated using rat brain cortex slices, synaptosomes or homogenates. nder conditions in which AlC13 inhibits carbachol (CARB) stimulated IP accumulation (Gp-mediate...

  2. The Effects of Inhaled β-Adrenergic Agonists in Transient Tachypnea of the Newborn

    PubMed Central

    Keleş, Esengul; Gebeşçe, Arzu; Demirdöven, Mehmet; Yazgan, Hamza; Baştürk, Bülent; Tonbul, Alparslan

    2016-01-01

    Aim. To investigate the efficacy of an inhaled β-adrenergic agonists in transient tachypnea of the newborn (TTN). Method. We retrospectively analyzed a cohort of 51 term infants (Group 1) and 37 term infants (Group 2) monitored in the newborn intensive care unit diagnosed with TTN. Infants in Group 1 received humidified oxygen alone, and infants in Group 2 were administered the inhaled β-2 agonist plus humidified oxygen. Results. TTN clinical respiratory assessment, respiratory rate, oxygen saturation values, need for supplemental oxygen therapy, blood gas PH, PO2, and duration of hospitalization were significantly improved in infants in Group 2 as compared with infants in Group 1 (P < .05). No statistically significant difference was observed with regard to blood glucose, potassium, heart rate, and PCO2 (P > .05). Conclusion. Inhaled β-adrenergic agonist added to humidified oxygen was found to improve clinical and laboratory parameters. We believe that further studies should be conducted with larger groups to demonstrate the efficacy of β-2 agonists in TTN patients. PMID:27336017

  3. Male receiver bias for red agonistic signalling in a yellow-signalling widowbird: a field experiment.

    PubMed

    Ninnes, C E; Andersson, S

    2014-09-01

    Receiver bias models of signal evolution are typically regarded as alternatives or complements to ornament evolution due to coevolving mate choice, whereas sexually or socially selected agonistic signals are rarely studied with respect to receiver psychology. Against the background of convergent evolution of red agonistic signals from yellow ancestors in the genus Euplectes (widowbirds and bishops), we experimentally test the function of a yellow signal in the montane marsh widowbird (E. psammocromius), as well as a hypothesized receiver bias for redder (longer wavelength) hues. In a field experiment in southern Tanzania, males that had their yellow wing patches blackened lost their territories or lost territorial contests more often than controls or reddened males, which together with a longer wavelength hue in territory holders, indicates an agonistic signal function. Males painted a novel red hue, matching that of red-signalling congeners, retained their territories and won contests more often than controls. To our knowledge, this is the first demonstration of a receiver bias driving agonistic signal evolution. Although the sensory or cognitive origin of this bias is yet unknown, it strengthens our view that genetically constrained signal production (i.e. carotenoid metabolism), rather than differential selection, explains the carotenoid colour diversification in Euplectes. PMID:25056624

  4. Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone.

    PubMed

    Wang, Xue-Jiao; Zhang, Jun; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

    2014-01-01

    The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research. PMID:25422585

  5. Discovery and characterization of novel small-molecule CXCR4 receptor agonists and antagonists

    PubMed Central

    Mishra, Rama K.; Shum, Andrew K.; Platanias, Leonidas C.; Miller, Richard J.; Schiltz, Gary E.

    2016-01-01

    The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 are involved in a large number of physiological processes including HIV-1 infectivity, inflammation, tumorigenesis, stem cell migration, and autoimmune diseases. While previous efforts have identified a number of CXCR4 antagonists, there have been no small molecule agonists reported. Herein, we describe the identification of a novel series of CXCR4 modulators, including the first small molecules to display agonist behavior against this receptor, using a combination of structure- and ligand-based virtual screening. These agonists produce robust calcium mobilization in human melanoma cell lines which can be blocked by the CXCR4-selective antagonist AMD3100. We also demonstrate the ability of these new agonists to induce receptor internalization, ERK activation, and chemotaxis, all hallmarks of CXCR4 activation. Our results describe a new series of biologically relevant small molecules that will enable further study of the CXCR4 receptor and may contribute to the development of new therapeutics. PMID:27456816

  6. MULTIPLE STRESSORS IN THE ENVIRONMENT: INTERACTIONS BETWEEN ARYL HYDROCARBON RECEPTOR AGONISTS AND HYPOXIA

    EPA Science Inventory

    It is predicted that reciprocal crosstalk occurs between these two pathways, such that activation of each pathway will cause decreased activity in the other pathway. Accordingly, it is predicted that hypoxia and AhR agonists will exacerbate one another’s toxicity. Thi...

  7. Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist

    PubMed Central

    Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

    2015-01-01

    Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury. PMID:26196013

  8. Novel S1P1 receptor agonists - Part 4: Alkylaminomethyl substituted aryl head groups.

    PubMed

    Lescop, Cyrille; Müller, Claus; Mathys, Boris; Birker, Magdalena; de Kanter, Ruben; Kohl, Christopher; Hess, Patrick; Nayler, Oliver; Rey, Markus; Sieber, Patrick; Steiner, Beat; Weller, Thomas; Bolli, Martin H

    2016-06-30

    In a previous communication we reported on the discovery of alkylamino pyridine derivatives (e.g. 1) as a new class of potent, selective and efficacious S1P1 receptor (S1PR1) agonists. However, more detailed profiling revealed that this compound class is phototoxic in vitro. Here we describe a new class of potent S1PR1 agonists wherein the exocyclic nitrogen was moved away from the pyridine ring (e.g. 11c). Further structural modifications led to the identification of novel alkylaminomethyl substituted phenyl and thienyl derivatives as potent S1PR1 agonists. These new alkylaminomethyl aryl compounds showed no phototoxic potential. Based on their in vivo efficacy and ability to penetrate the brain, the 5-alkyl-aminomethyl thiophenes appeared to be the most interesting class. Potent and selective S1PR1 agonist 20e, for instance, maximally reduced the blood lymphocyte count (LC) for 24 h after oral administration of 10 mg/kg to rat and its brain concentrations reached >500 ng/g over 24 h. PMID:27061986

  9. A Robotic BG1Luc Reporter Assay to Detect Estrogen Receptor Agonists

    PubMed Central

    Stoner, Matthew A.; Yang, Chun Z.; Bittner, George D.

    2014-01-01

    Endocrine disrupting chemicals with estrogenic activity (EA) have been associated with various adverse health effects. US agencies (ICCVAM/NICEATM) tasked to assess in vitro transcription activation assays to detect estrogenic receptor (ER) agonists for EA have recently validated a BG1Luc assay in manual format, but prefer robotic formats. We have developed a robotic BG1Luc EA assay to detect EA that demonstrated 100% concordance with ICCVAM meta-analyses and ICCVAM BG1Luc results in manual format for 27 ICCVAM test substances, i.e. no false negatives or false positives. This robotic assay also consistently assessed other, more problematic ICCVAM test substances such as clomiphene citrate, L-thyroxin, and tamoxifen. Agonist responses using this robotic BG1Luc assay were consistently inhibited by the ER antagonist ICI 182,780, confirming that agonist responses were due to binding to ERs rather than to a non-specific agonist response. This robotic assay also detected EA in complex mixtures of substances such as extracts of personal care products, plastic resins or plastic consumer products. This robotic BG1Luc assay had at least as high accuracy and greater sensitivity and repeatability when compared to its manual version or to the other ICCVAM/OECD validated assays for EA (manual BG1Luc and CERI). PMID:24747293

  10. CoMSIA study on substituted aryl alkanoic acid analogs as GPR40 agonists.

    PubMed

    Bhatt, Aaditya; Patel, Pallav D; Patel, Maulik R; Singh, Satyakam; Lau-Cam, Cesar A; Talele, Tanaji T

    2011-05-01

    GPR40, a G-protein-coupled receptor has been well established to play a crucial role in regulating blood glucose levels. Hence, GPR40 is a potential target for future antidiabetic agents. The present 3D QSAR study is aimed at delineating structural parameters governing GPR40 agonistic activity. To meet this objective, a comparative molecular similarity indices analysis for 63 different GPR40 agonists was performed using two methods; a ligand-based 3D QSAR model employing the atom fit alignment method and a receptor-based 3D QSAR model that was derived from the predicted binding conformations obtained by docking all the GPR40 agonists at the active site of GPR40. The results of these studies showed the ligand-based model to be superior (r(cv)(2) value of 0.610) to the receptor-based model (r(cv)(2) value of 0.519) in terms of statistical data. The predictive ability of these models was evaluated using a test set of 15 compounds not included in the preliminary training set of 48 compounds. The predictive r(2) values for the ligand- and the receptor-based models were found to be 0.863 and 0.599, respectively. Further, interpretation of the comparative molecular similarity indices analysis contour maps with reference to the active site of GPR40 provided an insight into GPR40-agonist interactions. PMID:21352503

  11. New Insights into the PPAR γ Agonists for the Treatment of Diabetic Nephropathy.

    PubMed

    Jia, Zhanjun; Sun, Ying; Yang, Guangrui; Zhang, Aihua; Huang, Songming; Heiney, Kristina Marie; Zhang, Yue

    2014-01-01

    Diabetic nephropathy (DN) is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs), the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor- γ (PPAR γ ), had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPAR γ agonists involving the endogenous PPAR γ ligands and selective PPAR γ modulators (SPPARMs) are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPAR γ agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPAR γ agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPAR γ agonists were fully addressed. PMID:24624137

  12. NICOTINE EFFECTS ON THE ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.

    EPA Science Inventory

    Considerable research has shown long-lasting effects of early exposure in experimental animals to nicotine. Anatoxin-a is produced by cyanobacteria and has been shown to be a potent nicotinic agonist. This experiment evaluated the motor activity of adult mice, and their respons...

  13. Agonist-induced activation of rat mesenteric resistance vessels: comparison between noradrenaline and vasopressin

    SciTech Connect

    Cauvin, C.; Weir, S.W.; Wallnoefer, A.R.; Rueegg, U.P.

    1988-01-01

    The effects of noradrenaline (NA, 10(-5) M) and (arginine8)vasopressin (AVP, 10(-7) M) on tension in Ca2+-free medium and on membrane potential, and the inhibition of NA- and AVP-induced contractions by isradipine, have been compared in mesenteric resistance vessels (MRVs) from Wistar-Kyoto (WKY) rats. The release of intracellular Ca2+ by AVP contributed significantly less to its tension development than does that by NA. Nonetheless, the concentration-response curves for inhibition by isradipine of NA- and AVP-induced tonic tension were nearly identical. Similarly, these two agonists produced the same degree of membrane depolarization. In addition, both agonists were able to stimulate large contractions in vessels previously depolarized by 80 mM K+. AVP also stimulated /sup 45/Ca influx into rat cultured aortic smooth muscle cells. In contrast to the stimulation of /sup 45/Ca influx by KCl depolarization, the agonist-stimulated /sup 45/Ca influx was insensitive to inhibition by organic Ca2+ antagonists. It is concluded that Ca2+ entry through receptor-operated Ca2+-permeable channels (ROCs) may contribute to agonist-induced activation of rat aortic and MRV smooth muscle.

  14. Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors*

    PubMed Central

    Zhou, Lei; Lovell, Kimberly M.; Frankowski, Kevin J.; Slauson, Stephen R.; Phillips, Angela M.; Streicher, John M.; Stahl, Edward; Schmid, Cullen L.; Hodder, Peter; Madoux, Franck; Cameron, Michael D.; Prisinzano, Thomas E.; Aubé, Jeffrey; Bohn, Laura M.

    2013-01-01

    The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and βarrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects of KOR activation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through βarrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from βarrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activate G protein coupling but weakly recruit βarrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo. PMID:24187130

  15. Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors.

    PubMed

    Pullagurla, Manik R; Westkaemper, Richard B; Glennon, Richard A

    2004-09-01

    A graphics model of the human 5-HT6 receptor was constructed and automated docking studies were performed. The model suggests that 5-HT6 antagonist arylsulfonyltryptamines might bind differently than that of the agonist serotonin. Furthermore, the model explains many of the empirical results from our previous structure-affinity studies. PMID:15357994

  16. Continuous Inhalation of Ipratropium Bromide for Acute Asthma Refractory to β2-agonist Treatment

    PubMed Central

    Mastropietro, Christopher

    2015-01-01

    To present the case of a patient with persistent bronchospasm, refractory to treatment with β2-agonists, that resolved promptly with continuous inhalation of large dose (1000 mcg/hr) ipratropium bromide, and to discuss the possibility of tolerance to β2-agonists as the cause for his failure to respond to adrenergic medications. The patient had received multiple doses of albuterol, as well as subcutaneous terbutaline (0.3 mg), intravenous magnesium sulfate (1 g) and intravenous dexamethasone (10 mg) prior to his admission to the intensive care unit. He remained symptomatic despite systemic intravenous steroids, continuous intravenous terbutaline (up to 0.6 mcg/kg/min), and continuous nebulized albuterol (up to 20 mg/hr for 57 hr) followed by 49 hours of continuous levalbuterol (7 mg/hr). Due to the lack of response, all β2-agonists were discontinued at 106 hours post-admission, and he was started on large dose ipratropium bromide (1000 mcg/hr) by continuous nebulization. Clinical improvement was evident within 1 hour and complete resolution of his symptoms within 4 hours. Continuous inhalation of large dose ipratropium bromide may be an effective regimen for the treatment of patients hospitalized with acute asthma who are deemed to be nonresponsive and/or tolerant to β2-agonist therapy. PMID:25859173

  17. Continuous Inhalation of Ipratropium Bromide for Acute Asthma Refractory to β2-agonist Treatment.

    PubMed

    Koumbourlis, Anastassios C; Mastropietro, Christopher

    2015-01-01

    To present the case of a patient with persistent bronchospasm, refractory to treatment with β2-agonists, that resolved promptly with continuous inhalation of large dose (1000 mcg/hr) ipratropium bromide, and to discuss the possibility of tolerance to β2-agonists as the cause for his failure to respond to adrenergic medications. The patient had received multiple doses of albuterol, as well as subcutaneous terbutaline (0.3 mg), intravenous magnesium sulfate (1 g) and intravenous dexamethasone (10 mg) prior to his admission to the intensive care unit. He remained symptomatic despite systemic intravenous steroids, continuous intravenous terbutaline (up to 0.6 mcg/kg/min), and continuous nebulized albuterol (up to 20 mg/hr for 57 hr) followed by 49 hours of continuous levalbuterol (7 mg/hr). Due to the lack of response, all β2-agonists were discontinued at 106 hours post-admission, and he was started on large dose ipratropium bromide (1000 mcg/hr) by continuous nebulization. Clinical improvement was evident within 1 hour and complete resolution of his symptoms within 4 hours. Continuous inhalation of large dose ipratropium bromide may be an effective regimen for the treatment of patients hospitalized with acute asthma who are deemed to be nonresponsive and/or tolerant to β2-agonist therapy. PMID:25859173

  18. Discovery and characterization of novel small-molecule CXCR4 receptor agonists and antagonists.

    PubMed

    Mishra, Rama K; Shum, Andrew K; Platanias, Leonidas C; Miller, Richard J; Schiltz, Gary E

    2016-01-01

    The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 are involved in a large number of physiological processes including HIV-1 infectivity, inflammation, tumorigenesis, stem cell migration, and autoimmune diseases. While previous efforts have identified a number of CXCR4 antagonists, there have been no small molecule agonists reported. Herein, we describe the identification of a novel series of CXCR4 modulators, including the first small molecules to display agonist behavior against this receptor, using a combination of structure- and ligand-based virtual screening. These agonists produce robust calcium mobilization in human melanoma cell lines which can be blocked by the CXCR4-selective antagonist AMD3100. We also demonstrate the ability of these new agonists to induce receptor internalization, ERK activation, and chemotaxis, all hallmarks of CXCR4 activation. Our results describe a new series of biologically relevant small molecules that will enable further study of the CXCR4 receptor and may contribute to the development of new therapeutics. PMID:27456816

  19. Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

    SciTech Connect

    Bass, Jonathan Y.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Mills, Wendy Y.; Navas, III, Frank; Parks, Derek J.; Smalley, Jr., Terrence L.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2014-08-13

    To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

  20. Environmental enrichment improves novel object recognition and enhances agonistic behavior in male mice.

    PubMed

    Mesa-Gresa, Patricia; Pérez-Martinez, Asunción; Redolat, Rosa

    2013-01-01

    Environmental enrichment (EE) is an experimental paradigm in which rodents are housed in complex environments containing objects that provide stimulation, the effects of which are expected to improve the welfare of these subjects. EE has been shown to considerably improve learning and memory in rodents. However, knowledge about the effects of EE on social interaction is generally limited and rather controversial. Thus, our aim was to evaluate both novel object recognition and agonistic behavior in NMRI mice receiving EE, hypothesizing enhanced cognition and slightly enhanced agonistic interaction upon EE rearing. During a 4-week period half the mice (n = 16) were exposed to EE and the other half (n = 16) remained in a standard environment (SE). On PND 56-57, animals performed the object recognition test, in which recognition memory was measured using a discrimination index. The social interaction test consisted of an encounter between an experimental animal and a standard opponent. Results indicated that EE mice explored the new object for longer periods than SE animals (P < .05). During social encounters, EE mice devoted more time to sociability and agonistic behavior (P < .05) than their non-EE counterparts. In conclusion, EE has been shown to improve object recognition and increase agonistic behavior in adolescent/early adulthood mice. In the future we intend to extend this study on a longitudinal basis in order to assess in more depth the effect of EE and the consistency of the above-mentioned observations in NMRI mice. PMID:23588702