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Sample records for agonist bw 723c86

  1. Effects of the 5-HT2B receptor agonist, BW 723C86, on three rat models of anxiety.

    PubMed Central

    Kennett, G. A.; Bright, F.; Trail, B.; Baxter, G. S.; Blackburn, T. P.

    1996-01-01

    1. BW 723C86 (3 and 10 mg kg-1, s.c. 30 min pretest), a 5-HT2B receptor agonist, increased total interaction, but not locomotion in a rat social interaction test, a profile consistent with anxiolysis. 2. The effect of BW 723C86 in the social interaction test is likely to be 5-HT2B receptor-mediated as it was prevented by pretreatment with the 5-HT2C/2B receptor antagonist, SB 200646A, (1 and 2 mg kg-1, p.o., 1 h pretest) which did not affect basal levels of social interaction at the doses used. 3. An anxiolytic-like action was also observed in the rat Geller-Seifter conflict test, where BW 723C86 (0.5-50 mg kg-1, s.c. 30 min pretest) modestly, but significantly increased punished, but not unpublished responding. 4. In a rat 5 min elevated x-maze test, BW 723C86 (1-10 mg kg-1, s.c.) had no significant effect. 5. The maximal anxiolytic-like effect of BW 723C86 approached that of the benzodiazepine anxiolytic, chloradiazepoxide (5 mg kg-1, s.c. 30 min pretest) in the social interaction test, but was markedly less in the Geller-Siefter test. The effect of BW 723C86 was also clearly less than chlordiazepoxide in the elevated x-maze procedure where it had no significant effect. 6. In conclusion, BW 723C86 exerted an appreciable anxiolytic-like profile in a rat social interaction test, but had a weaker effect in the Geller-Siefter and was ineffective in the elevated x-maze test used. These effects are likely to be 5-HT2B receptor-mediated. PMID:8730737

  2. A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent

    PubMed Central

    Oh, Eun Ju; Park, Jong Il; Lee, Ji Eun; Myung, Cheol Hwan; Kim, Su Yeon; Chang, Sung Eun; Hwang, Jae Sung

    2016-01-01

    BW723C86, a serotonin receptor 2B agonist, has been investigated as a potential therapeutic for various conditions such as anxiety, hyperphagia and hypertension. However, the functional role of BW723C86 against melanogenesis remains unclear. In this study, we investigate the effect of serotonin receptor 2B (5-HTR2B) agonist on melanogenesis and elucidate the mechanism involved. BW723C86 reduced melanin synthesis and intracellular tyrosinase activity in melan-A cells and normal human melanocytes. The expression of melanogenesis-related proteins (tyrosinase, TRP-1 and TRP-2) and microphthalmia-associated transcription factor (MITF) in melan-A cells decreased after BW723C86 treatment. The promoter activity of MITF was also reduced by BW723C86 treatment. The reduced level of MITF was associated with inhibition of protein kinase A (PKA) and cAMP response element-binding protein (CREB) activation by BW723C86 treatment. These results suggest that the serotonin agonist BW723C86 could be a potential therapeutic agent for skin hyperpigmentation disorders. PMID:27077852

  3. Signal Transduction Mechanism for Serotonin 5-HT2B Receptor-Mediated DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes.

    PubMed

    Naito, Kota; Tanaka, Chizuru; Mitsuhashi, Manami; Moteki, Hajime; Kimura, Mitsutoshi; Natsume, Hideshi; Ogihara, Masahiko

    2016-01-01

    The involvement of serotonin (5-hydroxytryptamine; 5-HT) and the 5-HT2 receptor subtypes in the induction of DNA synthesis and proliferation was investigated in primary cultures of adult rat hepatocytes to elucidate the intracellular signal transduction mechanisms. Hepatocyte parenchymal cells maintained in a serum-free, defined medium, synthesized DNA and proliferated in the presence of 5-HT or a selective 5-HT2B receptor agonist, BW723C86, but not in the presence of 5-HT2A, or 5-HT2C receptor agonists (TCB-2 and CP809101, respectively), in a time- and dose-dependent manner. A selective 5-HT2B receptor antagonist, LY272015 (10(-7) M), and a specific phospholipase C (PLC) inhibitor, U-73122 (10(-6) M), as well as specific inhibitors of growth-related signal transducers-including AG1478, LY294002, PD98059, and rapamycin-completely inhibited 5-HT (10(-6) M)- or BW723C86 (10(-6) M)-induced hepatocyte DNA synthesis and proliferation. Both 5-HT and BW723C86 were shown to significantly stimulate the phosphorylation of epidermal growth factor (EGF)/transforming growth factor (TGF)-α receptor tyrosine kinase (p175 kDa) and extracellular signal-regulated kinase (ERK) 2 on Western blot analysis. These results suggest that the proliferative mechanism of activating 5-HT is mediated mainly through 5-HT2B receptor-stimulated Gq/PLC and EGF/TGF-α-receptor/phosphatidylinositol 3-kinase (PI3K)/ERK2/mammalian target of rapamycin (mTOR) signaling pathways in primary cultured hepatocytes.

  4. Establishing a CCD Light Curve For BW Vul (Abstract)

    NASA Astrophysics Data System (ADS)

    Cowall, D.

    2016-12-01

    (Abstract only) BW Vul is a pulsating variable star of the class BCEP. Review of the AID over the last 20 years reveals only scattered visual observations. Since 2011, a few CCD observations have been obtained with the BSMs, but not enough to obtain any knowledge of the light curve other than a mean color. Rapid cadence time series of BW Vul are currently underway using the AAVSOnet. The data generated should allow for modeling of the light curve and an updated ephemeris of Tmin values with O-C analysis.

  5. Design considerations of B&W internal circulation CFB boilers

    SciTech Connect

    Kavidass, S.; Belin, F.; James, D.E.

    1995-12-31

    Worldwide, the use of Circulating Fluidized-Bed (CFB) boiler technology is rapidly increasing due to the ability to burn low grade fuels while meeting the required NO{sub x}, SO{sub 2}, CO, VOC, and particulate emissions requirements. The CFB boiler can produce steam economically for process and electric power generation. This paper discusses various aspects of Babcock & Wilcox (B&W) internal recirculation circulating fluidized-bed (IR-CFB) boiler design including fuel, boiler process parameters, and emissions. The B&W CFB boiler is unique in design. It utilizes proven impact-type particle separators (U-beams) with in-furnace solids recirculation recirculation. The paper describes the methodology for setting up process parameters, heat duty, boiler design, including auxiliary equipment selection and advantages. The paper also updates the ongoing IR-CFB boiler contracts.

  6. Design considerations of B&W internal circulation CFB boilers

    SciTech Connect

    Kavidass, S.; Alexander, K.C.

    1995-12-31

    Worldwide, the use of Circulating Fluidized-Bed (CFB) boiler technology is rapidly increasing due to the ability to burn low grade fuels while meeting the required NO{sub x}, SO{sub 2}, CO, VOC, and particulate emissions requirements. The CFB boiler can produce steam economically for process and electric power generation. This paper discusses various aspects of Babcock & Wilcox (B&W) internal recirculation circulating fluidized-bed (IR-CFB) boiler design including fuel, boiler process parameters, and emissions. The B&W CFB boiler is unique in design. It utilizes proven impact-type particle separators (U-beams) with in-furnace solids recirculation. The paper describes the methodology for setting up process parameters, heat duty, boiler design, including auxiliary equipment selection and advantages.

  7. Agonistic sounds signal male quality in the Lusitanian toadfish.

    PubMed

    Amorim, M Clara P; Conti, Carlotta; Modesto, Teresa; Gonçalves, Amparo; Fonseca, Paulo J

    2015-10-01

    Acoustic communication during agonistic behaviour is widespread in fishes. Yet, compared to other taxa, little is known on the information content of fish agonistic calls and their effect on territorial defence. Lusitanian toadfish males (Halobatrachus didactylus) are highly territorial during the breeding season and use sounds (boatwhistles, BW) to defend nests from intruders. BW present most energy in either the fundamental frequency, set by the contraction rate of the sonic muscles attached to the swimbladder, or in the harmonics, which are multiples of the fundamental frequency. Here we investigated if temporal and spectral features of BW produced during territorial defence reflect aspects of male quality that may be important in resolving disputes. We found that higher mean pulse period (i.e. lower fundamental frequency) reflected higher levels of 11-ketotestosterone (11KT), the main teleost androgen which, in turn, was significantly related with male condition (relative body mass and glycogen content). BW dominant harmonic mean and variability decreased with sonic muscle lipid content. We found no association between BW duration and male quality. Taken together, these results suggest that the spectral content of fish agonistic sounds may signal male features that are key in fight outcome.

  8. Objectives and Tasks of Lunar Mission BW1

    NASA Astrophysics Data System (ADS)

    Laufer, R.; Roeser, H.-P.

    2007-08-01

    Lunar Mission BW1 is the forth project of the "Stuttgart Small Satellite Program" initiated in 2002 at the Institute of Space Systems (IRS), Universitaet Stuttgart, Germany. The small Moon orbiter is a 1 m cube spacecraft of approx. 200 kg launch mass currently under development with participation of diploma/masters and Ph.D. students as well as academic and industrial partners. Demonstrating the ability of an academic institution to participate and contribute to space exploration by designing, building and operating a complete space probe Lunar Mission BW1 will be a test bed to perform technology demonstration and other experiments beyond Earth orbit in cis-lunar space and at the Moon. The satellite is planned to be launched end of the decade as a piggyback payload from a geostationary transfer orbit (GTO) and will reach lunar orbit using its own electric propulsion systems (thermal arcjet and iMPD thrusters). The paper will present objectives and tasks of Lunar Mission BW1 and the elements of this mission, i.e. spacecraft, ground segment, operations. It will give also an overview about the experience and heritage gained from the three other missions of the Stuttgart Small Satellite Program (Flying Laptop - technology demonstration/Earth observation, Perseus - electric propulsion test/UV astronomy, Cermit - re-entry vehicle/GNC experiment).

  9. Dual-fuel engine developments at MAN B&W

    SciTech Connect

    Albrecht, A.

    1995-10-01

    MAN B&W in Augsburg, Germany has further developed its dual-fuel line of engines with the 32/40 DG engine family. These engines, with prechamber injection, augment the company`s spark-ignited gas and dual-fuel engines based on its four-stroke diesel engines. MAN B&W`s power range is between 400 and 16200 kW. Based on the well-proven 32/ 40 engine, the 32/40 DG dual-fuel engine was developed mainly for stationary applications in cogeneration plants and power stations, covering an output range from 2.4 to 7.2 MW. The engine line (bore 320 x stroke 400 mm) has a cylinder output of 400 kW at 750 r/min and a bmep of 19.9 bar with a maximum efficiency of 44.4%. The development focused on meeting TA Luft limits for NO{sub x} emissions of less than 500 mg/m{sup 3} NO{sub x}. This level was targeted without catalytic exhaust after treatment (SCR) and retaining high efficiency and high mean effective pressure similar to that of the diesel engine. To meet the development goals, a combustion system is used with two injection systems, one for the pilot injection into a prechamber and another for the main injection volume under diesel fuel operation.

  10. Polymorphic Sites Away From the Bw4 Epitope that Affect Interaction of Bw4+ HLA-B with KIR3DL1

    PubMed Central

    Sanjanwala, Bharati; Draghi, Monia; Norman, Paul J.

    2009-01-01

    KIR3DL1 is a polymorphic, inhibitory NK-cell receptor specific for the Bw4 epitope carried by subsets of HLA-A and -B allotypes. The Bw4 epitope is determined by the NIALR sequence motif at positions 77, 80, 81, 82 and 83 in the α1 helix. Mutation, of these positions to the residues present in the alternative and non-functional Bw6 motif, showed that the functional activity of the Bw4 epitopes of B*5101 and B*1513 is retained after substitution at positions 77, 80 and 81, but lost after substitution of position 83. Mutation of leucine to arginine at position 82, led to loss of function for B*5101 but not for B*1513. Further mutagenesis, in which B*1513 residues were replaced by their B*5101 counterparts, showed that polymorphisms in all three extracellular domains contribute to this functional difference. Prominent were positions 67 in the α1 domain, 116 in the α2 domain and 194 in the α3 domain. Lesser contributions were made by additional positions in the α2 domain. These positions are not part of the Bw4 epitope and include residues shaping the B and F pockets that determine the sequence and conformation of the peptides bound by HLA class I molecules. This analysis shows how polymorphism at sites throughout the HLA class I molecule can influence the interaction of the Bw4 epitope with KIR3DL1. This influence is likely mediated by changes in the peptides bound which alter the conformation of the Bw4 epitope. PMID:18941220

  11. Anti-inflammatory drug (BW755C) inhibits airway hyperresponsiveness induced by ozone in dogs

    SciTech Connect

    Fabbri, L.M.; Aizawa, H.; O'Byrne, P.M.; Bethel, R.A.; Walters, E.H.; Holtzman, M.J.; Nadel, J.A.

    1985-08-01

    To follow up a previous observation that airway hyperresponsiveness induced by ozone is linked to airway inflammation, the authors investigated the effect of BW755C, an anti-inflammatory drug, on ozone-induced hyperresponsiveness in dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance in two sets of experiments. In one set (placebo treatment), five dogs were given only saline solution treatment and were studied before treatment or ozone exposure and then after treatment both before and after ozone (3.0 ppm, 2 hours); in another set (BW755C treatment), the same dogs were studied before BW755C treatment or ozone and then after treatment (10 mg/kg intravenously) both before and after ozone. When the dogs were given no BW755C treatment, ozone induced a marked increase in airway responsiveness to acetylcholine. When the dogs were given BW755C, responsiveness was no different during treatment than before treatment but, more importantly, responsiveness did not increase significantly after ozone. The authors conclude that BW755C markedly inhibits ozone-induced airway hyperresponsiveness in dogs, probably by inhibiting the formation of oxygenation products of arachidonic acid.

  12. B&W IR-CFB: Operating Experience and New Developments

    NASA Astrophysics Data System (ADS)

    Maryamchik, M.; Wietzke, D. L.

    The paper provides an update on B&W Internal Recirculation (IR) CFB boiler operating experience, new commercial projects, and developments in boiler design and process. Availability data for two projects in the U.S. will be presented, as well as data collected from two additional projects by a B&W licensee in India. Two new commercial projects are currently going through commissioning. Yet another unit, Great River Energy (being erected), is described in detail. To achieve the required amount of in-furnace heat absorption in higher capacity CFB boilers, a new B&W development is its patented in-bed heat exchanger (IBHX). The IBHX allows control of the bed temperature in the furnace as well as steam temperature in the superheater and reheater surfaces, thus accommodating higher capacities.

  13. Antitheilerial activity of BW720C (buparvaquone): a comparison with parvaquone.

    PubMed

    McHardy, N; Wekesa, L S; Hudson, A T; Randall, A W

    1985-07-01

    A series of hydroxynaphthoquinones, all derivatives of the antitheilerial hydroxynaphthoquinone parvaquone (993C, Clexon; Wellcome) was tested for antitheilerial activity against Theileria parva (Muguga) in vitro. BW720C (buparvaquone) was 20 times more active than parvaquone. When tested in vivo BW720C cured all 13 cattle infected with T parva and all six infected with T annulata treated at a dose rate of 2.5 mg (kg bodyweight)-1 while parvaquone at 20 mg kg-1 cured nine of 10 cattle. All 16 untreated control cattle died of theileriosis.

  14. [Melatonin receptor agonist].

    PubMed

    Uchiyama, Makoto

    2015-06-01

    Melatonin is a hormone secreted by the pineal gland and is involved in the regulation of human sleep-wake cycle and circadian rhythms. The melatonin MT1 and MT2 receptors located in the suprachiasmatic nucleus in the hypothalamus play a pivotal role in the sleep-wake regulation. Based on the fact that MT1 receptors are involved in human sleep onset process, melatonin receptor agonists have been developed to treat insomnia. In this article, we first reviewed functions of melatonin receptors with special reference to MT1 and MT2, and properties and clinical application of melatonin receptor agonists as hypnotics.

  15. Phillips SA8016BW 2.5 GHz Synthesizer SEE Testing

    NASA Technical Reports Server (NTRS)

    Carts, Marty; Ladbury, Ray; Marshall, Paul W.; Mackey, Susan

    2008-01-01

    This viewgraph presentation reviews the Single Event Effects (SEE) testing of the Phillips SA8016BW 2.5 GHz Synthesizer that was chose by the GLAST Program for Frequency Generation. Included in this are diagrams of the phased-locked loop (PLL), the synthesizer, and heater.

  16. 4. East elevation, facing west (Note: B/W scale on east ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. East elevation, facing west (Note: B/W scale on east elevation in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  17. 7. West elevation, facing east (Note: B/W scale on west ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. West elevation, facing east (Note: B/W scale on west elevation in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  18. 5. South and west elevations, facing northwest (Note: B/W scale ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. South and west elevations, facing northwest (Note: B/W scale on south elevation in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  19. 3. East and north elevations, facing southwest (Note: B/W scale ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. East and north elevations, facing southwest (Note: B/W scale on east elevation in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  20. 8. West elevation with doors open, facing east (Note: B/W ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    8. West elevation with doors open, facing east (Note: B/W scale in doorway is in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  1. 11. View of interior, facing southwest (Note: B/W scale on ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    11. View of interior, facing southwest (Note: B/W scale on interior walls is in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  2. 2. North and west elevation, facing southeast (Note: B/W scale ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. North and west elevation, facing southeast (Note: B/W scale on north elevation in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  3. 10. View of interior, facing east (Note: B/W scale in ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. View of interior, facing east (Note: B/W scale in doorway is in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  4. 6. South elevation, facing north (Note: B/W scale on south ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. South elevation, facing north (Note: B/W scale on south elevation in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  5. 12. View of interior, facing northwest (Note: B/W scale on ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    12. View of interior, facing northwest (Note: B/W scale on interior walls is in 1/2 ft increments) - Nevada Test Site, Reactor Maintenance & Disassembly Complex, Junior Hot Cell, Jackass Flats, Area 25, South of intersection of Roads F & G, Mercury, Nye County, NV

  6. Aberrance Detection Powers of the BW and Person-Fit Indices

    ERIC Educational Resources Information Center

    Huang, Tsai-Wei

    2012-01-01

    The study compared the aberrance detection powers of the BW person-fit indices with other group-based indices (SCI, MCI, NCI, and Wc&Bs) and item response theory based (IRT-based) indices (OUTFITz, INFITz, ECI2z, ECI4z, and lz). Four kinds of comparative conditions, including content category (CC), types of aberrance (AT), severity of…

  7. ASASSN-17bw is a Type II Supernova in SBS 1657+505

    NASA Astrophysics Data System (ADS)

    Brimacombe, J.; Kiyota, S.; Post, R. S.; Klusmeyer, J.; Holoien, T. W.-S.; Prieto, J. L.; Stanek, K. Z.; Kochanek, C. S.; Brown, J. S.; Shields, J.; Thompson, T. A.; Shappee, B. J.; Bersier, D.; Dong, Subo; Bose, S.; Chen, Ping; Fernandez, J. M.; Krannich, G.; Masi, G.

    2017-02-01

    The transient source ASASSN-17bw (AT 2017zu) in the galaxy SBS 1657+505 was discovered by the All Sky Automated Survey for SuperNovae (ASAS-SN, Shappee et al. 2014), using data from the quadruple 14-cm "Brutus" telescope in Haleakala, Hawaii.

  8. The influence of BPC 157 on nitric oxide agonist and antagonist induced lesions in broiler chicks.

    PubMed

    Grabarevic, Z; Tisljar, M; Artukovic, B; Bratulic, M; Dzaja, P; Seiwerth, S; Sikiric, P; Peric, J; Geres, D; Kos, J

    1997-01-01

    We describe the effects of nitric oxide (NO) agonists and antagonists and the influence of a novel organoprotective pentadecapeptide BPC 157, on the development of pulmonary hypertension syndrome and tissue lesions in chicks. Acute toxicity, which includes single dose application of saline (1 mL intraperitoneally (i.p.)), BPC 157 (10 micrograms/kg bw), L-NAME (NO antagonist, doses 50, 100, 150 mg/kg bw) and L-arginine (NO agonist/100 mg/kg bw with their combination L-NAME + BPC 157; L-NAME + L-arginine) was investigated. In this experiment pathohistological examination of the spleen, heart, liver and lungs and hematological analysis was conducted. In the chronic toxicity experiment, the animals were treated daily for 5 weeks with L-NAME (10 mg/kg bw), L-arginine (100 mg/kg bw), BPC 157 (10 micrograms/kg bw) and their combinations (L-NAME + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine) i.p. Seven animals from each group, including controls (saline 1 mL i.p.) were killed every week. Application of L-NAME caused pulmonary hypertension syndrome (PHS) in the treated chicks, which was prevented by the simultaneous application of L-arginine and BPC 157. Pathohistological examination of both acute and chronic toxicity revealed that L-NAME caused severe tissue damage (myocardial and hepatic cell necrosis, necrosis of the lymphoid cells in the spleen) while L-arginine provoked predominantly congestion, edema and hemorrhages in all organs. The effect of L-NAME was successfully inhibited by the application of L-arginine and BPC 157 but the latter substance did not cause any tissue or organ damage. Hematological analysis shows significant hemoglobin and leukocyte number decrease in the L-NAME-treated groups of chicks.

  9. Melatonin agonists and insomnia.

    PubMed

    Ferguson, Sally A; Rajaratnam, Shantha M W; Dawson, Drew

    2010-02-01

    The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials.

  10. 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. PMID:27713285

  11. MAN B&W radial turbochargers after 32000 hours of HFO operation

    SciTech Connect

    1995-11-01

    In late 1990, the first three of 36 reengined 6L28/32H gen-sets built by MAN B&W Diesel A/S in Holeby, Denmark, were delivered for the Atlantic-class container vessel MV OOCL Inspiration (ex. Ile de France), owned by Sea-Land Service. One of the determining factors for the re-engining contract was the expected 2O000 hour interval between overhauls. The gen-sets are optimized for an output of 1260 kW at 720 r/min (bmep = 17.8 bar), and are supercharged by high-efficiency, water-free MAN B&W model NR20/R turbochargers. The supercharging principle is constant-pressure turbocharging. The service rating of these gen-sets normally is 80% (sea load), with part-load operation down to 30% load not uncommon. Unrestricted part-load operation in spite of the lower air excess ratio as compared to pulse-pressure turbocharging is one of the preconditions for real heavy-fuel oil capability, and the MAN B&W turbochargers play a significant part in achieving this. The result of the inspection was that both compressor and turbine were clean and without detectable deposits, as were the diffuser and the nozzle ring, where hardly any erosion marks and no blade shortening due to erosion could be found.

  12. 49 CFR 178.61 - Specification 4BW welded steel cylinders with electric-arc welded longitudinal seam.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Specification 4BW welded steel cylinders with... steel cylinders with electric-arc welded longitudinal seam. (a) Type, size and service pressure. A DOT 4BW cylinder is a welded type steel cylinder with a longitudinal electric-arc welded seam, a...

  13. 49 CFR 178.61 - Specification 4BW welded steel cylinders with electric-arc welded longitudinal seam.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Specification 4BW welded steel cylinders with... steel cylinders with electric-arc welded longitudinal seam. (a) Type, size and service pressure. A DOT 4BW cylinder is a welded type steel cylinder with a longitudinal electric-arc welded seam, a...

  14. 49 CFR 178.61 - Specification 4BW welded steel cylinders with electric-arc welded longitudinal seam.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Specification 4BW welded steel cylinders with... steel cylinders with electric-arc welded longitudinal seam. (a) Type, size and service pressure. A DOT 4BW cylinder is a welded type steel cylinder with a longitudinal electric-arc welded seam, a...

  15. 49 CFR 178.61 - Specification 4BW welded steel cylinders with electric-arc welded longitudinal seam.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Specification 4BW welded steel cylinders with... steel cylinders with electric-arc welded longitudinal seam. (a) Type, size and service pressure. A DOT 4BW cylinder is a welded type steel cylinder with a longitudinal electric-arc welded seam, a...

  16. Fasting heat production and metabolic BW in group-housed broilers.

    PubMed

    Noblet, J; Dubois, S; Lasnier, J; Warpechowski, M; Dimon, P; Carré, B; van Milgen, J; Labussière, E

    2015-07-01

    Fasting heat production (FHP) is used for characterizing the basal metabolic rate of animals and the corresponding maintenance energy requirements and in the calculation of net energy value of feeds. In broilers, the most recent FHP estimates were obtained in the 1980s in slow-growing and fatter birds than nowadays. The FHP values (n=73; six experiments) measured in 3 to 6-week-old modern lines of broilers weighing 0.6 to 2.8 kg and growing at 80 to 100 g/day were used to update these literature values. Each measurement was obtained in a group of fasting broilers (5 to 14 birds) kept in a respiration chamber for at least 24 h. The FHP estimate corresponds to the asymptotic heat production corrected for zero physical activity obtained by modeling the decrease in heat production during the fasting day. The compilation of these data indicates that FHP was linearly related to the BW(0.70) (in kg), which can be considered as the metabolic BW of modern broilers. The 0.70 exponent differs from the conventional value of 0.75 used for mature animals. The FHP per kg of BW(0.70) ranged between 410 and 460 kJ/day according to the experiment (P<0.01). An experiment conducted with a shorter duration of fasting (16 h) indicated that FHP values are higher than those obtained over at least 24 h of fasting. Our values are similar to those obtained previously on fatter and slow-growing birds, even though the comparison is difficult since measurement conditions and methodologies have changed during the last 30 years. The FHP values obtained in our trials represent a basis for energy nutrition of modern broilers.

  17. MAN B&W Diesel extends dual-fuel engine range up to 16 MW

    SciTech Connect

    Schaaf, H.

    1996-04-01

    In 1995, MAN B&W Diesel launched a dual-fuel version of the successful L + V (in-line and vee) configurations of the 32/40 diesel engine series, covering a power range between 2.4 and 7.2 MW. In 1996, the company is launching a dual-fuel version of the L + V 48/60 engine series, moving the power range of dual-fuel engines to 16.2 MW. With its new dual fuel type 32/40 DG and 48/60 DG engines, MAN B&W Diesel has designed prime movers offering a high efficiency at low operating costs, while simultaneously meeting the most stringent NO{sub x} emission limits without any exhaust gas after-treatment. These engines are based on the successful HFO-operated four-stroke diesel engines. They offer environment-friendly and, operating at high mean effective pressures, simultaneously cost effective propulsion alternatives, especially if natural gas is used as a fuel. Extension of the compatibility to permit further kinds of gas such as sewage gas to be used is being developed.

  18. SU-E-I-62: Reduction of Susceptibility Artifacts by Increasing the Bandwidth (BW) and Echo Train Length (ETL)

    SciTech Connect

    Mavroidis, P; Boci, N; Kostopoulos, S; Ninos, C; Glotsos, D; Oikonomou, G; Bakas, A; Roka, V; Cavouras, D; Lavdas, E; Sakkas, G; Tsagkalis, A; Chatzivasileiou, V; Batsikas, G; Papanikolaou, N; Stathakis, S

    2015-06-15

    Purpose: The aim of this present study is to increase bandwidth (BW) and echo train length (ETL) in Proton Density Turbo Spin Echo (PD TSE) sequences with and without fat saturation (FS) as well as in Turbo Inversion Recovery Magnitude sequences (TIRM) in order to assess whether these sequences are capable of reducing susceptibility artifacts. Methods: We compared 1) TIRM coronal (COR) with the same sequence with increased both BW and ETL 2) Conventional PD TSE sagittal (SAG) with FS with an increased BW 3) Conventional PD TSE SAG without FS with an increased BW 4) Conventional PD TSE SAG without FS with increased both BW and ETL. A quantitative analysis was performed to measure the extent of the susceptibility artifacts. Furthermore, a qualitative analysis was performed by two radiologists in order to evaluate the susceptibility artifacts, image distortion and fat suppression. The depiction of cartilage, menisci, muscles, tendons and bone marrow were also qualitatively analyzed. Results: The quantitative analysis found that the modified TIRM sequence is significantly superior to the conventional one regarding the extent of the susceptibility artifacts. In the qualitative analysis, the modified TIRM sequence was superior to the corresponding conventional one in eight characteristics out of ten that were analyzed. The modified PD TSE with FS was superior to the corresponding conventional one regarding the susceptibility artifacts, image distortion and depiction of bone marrow and cartilage while achieving effective fat saturation. The modified PD TSE sequence without FS with a high (H) BW was found to be superior corresponding to the conventional one in the case of cartilage. Conclusion: Consequently, TIRM sequence with an increased BW and ETL is proposed for producing images of high quality and modified PD TSE with H BW for smaller metals, especially when FS is used.

  19. The effect of colostrum period management on BW and immune system in lambs: from birth to weaning.

    PubMed

    Hernández-Castellano, L E; Suárez-Trujillo, A; Martell-Jaizme, D; Cugno, G; Argüello, A; Castro, N

    2015-10-01

    The aim of this study was to investigate the BW and immune status of lambs reared under natural conditions or under artificial conditions fed two different colostrum amounts. In this study, 60 lambs were randomly divided into groups according to treatment. Twenty lambs remained with their dams (natural rearing (NR) group). Forty lambs were removed from their dams at birth. Lambs were bottle-fed with a pool of sheep colostrum, receiving either 4 g of IgG/kg of BW at birth (C4 group) or 8 g of IgG/kg of BW at birth (C8 group). The total colostrum amount was equally divided into three meals at 2, 14 and 24 h after birth. After this period, lambs were bottle-fed a commercial milk replacer. Blood plasma sample analysis and BW recordings were carried out before feeding at birth and then at 1, 2, 3, 4, 5 and 20 days after birth. Another blood sample analysis and BW recording was carried out when animals reached 10 kg of BW. During weaning (30 days), sampling was carried out every 5 days. Blood plasma was used to determine the concentrations of IgG and IgM and the complement system activity - total and alternative pathways. The NR group showed greater BW than the C4 and C8 groups during milk feeding period, whereas the C4 and C8 groups had greater BW than the NR group at the end of weaning period. The C8 and NR groups had greater plasma IgG and IgM concentrations than the C4 group during milk feeding period. In addition, C4 and C8 groups showed similar IgG concentrations and greater IgM concentrations than the NR group at the end of the weaning period. Complement system activity was greater in the NR group than in the C4 and C8 groups during the first 3 days after birth. In conclusion, lambs fed amounts of colostrum equivalent to 8 g of IgG/kg of BW showed similar immune variables compared to lambs reared under natural conditions, obtaining a greater BW at the end of the weaning period. Nevertheless, this study shows that not only the colostrum amount but also the

  20. Biosimmer: A Virtual Reality Simulator for Training First Responders in a BW Scenario

    SciTech Connect

    Shawver, D.M.; Sobel, A.L.; Stansfield, S.A.

    1998-11-11

    BioSimMER (Bioterrorism Simulated Medical Emergency Response) is a Virtual Reality-based mission rehearsal and training environment. BioSimMER employs contingency-oriented, multiple-path algorithms and MOESINIOPS focused on real-world operations. BioSimMER is network-based and immerses multiple trainees in a high resolution synthetic environment, including virtual casualties and instruments that they may interact with and manipulate. Trainees are represented as individuals by virtual human Avatars. The simulation consists of several components: virtual casualties dynamically manifest the symptoms of their injuries and respond to the intervention of the trainees. Agent transport analysis is used to simulate casualty exposures and to drive the responses of simulated sensors/detectors. The selected prototype scenario is representative of combined injuries anticipated in BW operations.

  1. Agonist-activated ion channels

    PubMed Central

    Colquhoun, David

    2006-01-01

    This paper looks at ion channels as an example of the pharmacologist's stock in trade, the action of an agonist on a receptor to produce a response. Looked at in this way, ion channels have been helpful because they are still the only system which is simple enough for quantitative investigation of transduction mechanisms. A short history is given of attempts to elucidate what happens between the time when agonist first binds, and the time when the channel opens. PMID:16402101

  2. Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes

    PubMed Central

    Daniel, Joseph A.; Amelse, Lisa L.; Tanco, Valeria M.; Chameroy, Kelly A.; Schrick, F. Neal

    2015-01-01

    Kisspeptin receptor (KISS1R) agonists with increased half-life and similar efficacy to kisspeptin in vitro may provide beneficial applications in breeding management of many species. However, many of these agonists have not been tested in vivo. These studies were designed to test and compare the effects of a KISS1R agonist (FTM080) and kisspeptin on luteinizing hormone (LH) in vivo. In experiment 1 (pilot study), sheep were treated with FTM080 (500 pmol/kg BW) or sterile water (VEH) intravenosuly. Blood was collected every 15 min before (1 h) and after (1 h) treatment. In experiment 2, sheep were treated with KP-10 (human Metastin 45-54; 500 pmol/kg BW), one of three dosages of FTM080 (500 (FTM080:500), 2500 (FTM080:2500), or 5000 (FTM080:5000) pmol/kg BW), or VEH intravenously. Blood was collected every 15 min before (1 h) and after (4 h) treatment. In experiment 1, FTM080:500 increased (P < 0.05) plasma LH concentrations when compared to VEH. The area under the curve (AUC) of LH following FTM080:500 treatment was also increased (P < 0.05). In experiment 2, plasma LH concentrations increased (P < 0.05) following treatment with KP-10 and FTM080:5000 when compared to VEH and FTM080:500. The AUC of LH following KP-10 was greater than (P < 0.05) all other treatments and the AUC of LH following FTM080:5000 was greater than (P < 0.05) all treatments except KP-10. These data provide evidence to suggest that FTM080 stimulates the gonadotropic axis of ruminants in vivo. Any increased half-life and comparable efficacy of FTM080 to KP-10 in vitro does not appear to translate to in vivo in sheep. PMID:26587345

  3. 5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved

    PubMed Central

    2012-01-01

    Serotonin (5-hydroxytryptamine; 5-HT) delivered over 1 week results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. We hypothesized 5-HT lowers blood pressure through direct receptor-mediated vascular relaxation. In vivo, 5-HT reduced mean arterial pressure (MAP), increased heart rate, stroke volume, cardiac index, and reduced total peripheral resistance during a 1 week infusion of 5-HT (25 µg/kg/min) in the normotensive Sprague Dawley rat. The mesenteric vasculature was chosen as an ideal candidate for the site of 5-HT receptor mediated vascular relaxation given the high percentage of cardiac output the site receives. Real-time RT-PCR demonstrated that mRNA transcripts for the 5-HT2B, 5-HT1B, and 5-HT7 receptors are present in sham and DOCA-salt superior mesenteric arteries. Immunohistochemistry and Western blot validated the presence of the 5-HT2B, 5- HT1B and 5-HT7 receptor protein in sham and DOCA-salt superior mesenteric artery. Isometric contractile force was measured in endothelium-intact superior mesenteric artery and mesenteric resistance arteries in which the contractile 5- HT2A receptor was antagonized. Maximum concentrations of BW-723C86 (5- HT2B agonist), CP 93129 (5-HT1B agonist) or LP-44 (5-HT7 agonist) did not relax the superior mesenteric artery from DOCA-salt rats vs. vehicle. Additionally, 5-HT (10–9 M to 10–5 M) did not cause relaxation in either contracted mesenteric resistance arteries or superior mesenteric arteries from normotensive Sprague- Dawley rats. Thus, although 5-HT receptors known to mediate vascular relaxation are present in the superior mesenteric artery, they are not functional, and are therefore not likely involved in a 5-HT-induced fall in total peripheral resistance and MAP. PMID:22559843

  4. 5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved.

    PubMed

    Davis, Robert Patrick; Pattison, Jill; Thompson, Janice M; Tiniakov, Ruslan; Scrogin, Karie E; Watts, Stephanie W

    2012-05-06

    Serotonin (5-hydroxytryptamine; 5-HT) delivered over 1 week results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. We hypothesized 5-HT lowers blood pressure through direct receptor-mediated vascular relaxation. In vivo, 5-HT reduced mean arterial pressure (MAP), increased heart rate, stroke volume, cardiac index, and reduced total peripheral resistance during a 1 week infusion of 5-HT (25 µg/kg/min) in the normotensive Sprague Dawley rat. The mesenteric vasculature was chosen as an ideal candidate for the site of 5-HT receptor mediated vascular relaxation given the high percentage of cardiac output the site receives. Real-time RT-PCR demonstrated that mRNA transcripts for the 5-HT2B, 5-HT1B, and 5-HT7 receptors are present in sham and DOCA-salt superior mesenteric arteries. Immunohistochemistry and Western blot validated the presence of the 5-HT2B, 5- HT1B and 5-HT7 receptor protein in sham and DOCA-salt superior mesenteric artery. Isometric contractile force was measured in endothelium-intact superior mesenteric artery and mesenteric resistance arteries in which the contractile 5- HT2A receptor was antagonized. Maximum concentrations of BW-723C86 (5- HT2B agonist), CP 93129 (5-HT1B agonist) or LP-44 (5-HT7 agonist) did not relax the superior mesenteric artery from DOCA-salt rats vs. vehicle. Additionally, 5-HT (10-9 M to 10-5 M) did not cause relaxation in either contracted mesenteric resistance arteries or superior mesenteric arteries from normotensive Sprague- Dawley rats. Thus, although 5-HT receptors known to mediate vascular relaxation are present in the superior mesenteric artery, they are not functional, and are therefore not likely involved in a 5-HT-induced fall in total peripheral resistance and MAP.

  5. Data resources and sample applications for information analysis in CW and BW defense

    SciTech Connect

    Buescher, K.L.; Howse, J.W.; Liu, L.C.; Pedersen, P.S.

    1997-08-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The objective of this project was to identify representative problems in chemical warfare (CW) and biological warfare (BW) defense to which LANL`s information analysis capabilities can be applied. In particular, the focus was on methods for detecting the outbreak of diseases and predicting their evolution. The authors found that a number of disease models can be expressed in a common form, and that these models can be transformed in a way that allows their parameters to be estimated on-line in a computationally efficient manner. Using this technique, diseases could be tracked in an automated and cost-effective manner. However, the greatest needs in this area are epidemiological models that account for spatial and transport aspects of disease spread. Also, there is great potential for the mining of morbidity and disease data in order to identify similar cases that may indicate an emerging disease or an attack.

  6. Evidence for Magnetar Formation in Broad-lined Type Ic Supernovae 1998bw and 2002ap

    NASA Astrophysics Data System (ADS)

    Wang, L. J.; Yu, H.; Liu, L. D.; Wang, S. Q.; Han, Y. H.; Xu, D.; Dai, Z. G.; Qiu, Y. L.; Wei, J. Y.

    2017-03-01

    Broad-lined type Ic supernovae (SNe Ic-BL) are peculiar stellar explosions that are distinct from ordinary SNe. Some SNe Ic-BL are associated with long-duration (≳ 2 {{s}}) gamma-ray bursts (GRBs). Black holes and magnetars are two types of compact objects that are hypothesized to be central engines of GRBs. In spite of decades of investigations, no direct evidence for the formation of black holes or magnetars has yet been found for GRBs. Here we report the finding that the early peak (t≲ 50 {days}) and late-time (t≳ 300 {days}) slow decay displayed in the light curves of SNe 1998bw (associated with GRB 980425) and 2002ap (not GRB-associated) can be attributed to magnetar spin-down with an initial rotation period {P}0∼ 20 {ms}, while the intermediate-time (50≲ t≲ 300 {days}) exponential decline is caused by the radioactive decay of 56Ni. The connection between the early peak and late-time slow decline in the light curves is unexpected in alternative models. We thus suggest that GRB 980425 and SN 2002ap were powered by magnetars.

  7. Grazing incidence wide angle x-ray scattering at the wiggler beamline BW4 of HASYLAB

    SciTech Connect

    Perlich, J.; Rubeck, J.; Botta, S.; Gehrke, R.; Roth, S. V.; Ruderer, M. A.; Prams, S. M.; Rawolle, M.; Zhong, Q.; Koerstgens, V.; Mueller-Buschbaum, P.

    2010-10-15

    We present an upgrade of the available measurement techniques at the wiggler beamline BW4 of the Hamburger Synchrotronstrahlungslabor (HASYLAB) to grazing incidence wide angle x-ray scattering (GIWAXS). GIWAXS refers to an x-ray diffraction method, which, based on the measurement geometry, is perfectly suited for the investigation of the material crystallinity of surfaces and thin films. It is shown that the overall experimental GIWAXS setup employing a movable CCD-detector provides the capability of reliable and reproducible diffraction measurements in grazing incidence geometry. Furthermore, the potential usage of an additional detector enables the simultaneous or successive measurement of GIWAXS and grazing incidence small angle x-ray scattering (GISAXS). The new capability is illustrated by the microbeam GIWAXS measurement of a thin film of the conjugated polymer poly(3-octylthiophene) (P3OT). The investigation reveals the semicrystalline nature of the P3OT film by a clear identification of the wide angle scattering reflexes up to the third order in the [100]-direction as well as the first order in the [010]-direction. The corresponding microbeam GISAXS measurement on the present morphology complements the characterization yielding the complete sample informa-tion from subnanometer up to micrometer length scales.

  8. Man B&W introduces new big-bore, two-stroke diesel

    SciTech Connect

    1995-09-01

    The new K98MC-C model introduced by MAN B&W Diesel A/S marks a return to the 980 mm bore class engine. A new market for this class of engine comes from the higher power requirements of faster container ships. The new K98MC-C design is effectively a larger version of the K98MC/MC-C series. The key operating criteria for the K98MC-C engine are similar to those of the other MC engines, notably a mean effective pressure of 18.2 bar and a mean piston speed of 8.32 m/sec. A propeller speed measurement of 104 r/min was selected as the design basis, resulting in a stroke/bore ratio of 2.45 and a cylinder output of 5710 kW. The K98MC-C engine will be available on nine-, 10-, 11-, and 12-cylinder versions, yielding an output of up to 68 520 kW at 104 r/min. 1 fig., 1 tab.

  9. 49 CFR 178.61 - Specification 4BW welded steel cylinders with electric-arc welded longitudinal seam.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... DOT 4BW cylinder is a welded type steel cylinder with a longitudinal electric-arc welded seam, a water... a maximum wall stress of 24,000 p.s.i. in the formula described in paragraph (f)(4) of this section... weldable steel, the carbon content of which may not exceed 0.25 percent. (f) Wall thickness. For...

  10. Rapid, Potentially Automatable, Method Extract Biomarkers for HPLC/ESI/MS/MS to Detect and Identify BW Agents

    DTIC Science & Technology

    1997-11-01

    status can sometimes be reflected in the infectious potential or drug resistance of those pathogens. For example, in Mycobacterium tuberculosis ... Mycobacterium tuberculosis , its antibiotic resistance and prediction of pathogenicity amongst Mycobacterium spp. based on signature lipid biomarkers ...TITLE AND SUBTITLE Rapid, Potentially Automatable, Method Extract Biomarkers for HPLC/ESI/MS/MS to Detect and Identify BW Agents 5a. CONTRACT NUMBER 5b

  11. The involvement of 5-HT-like receptors in the regulation of food intake in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Pérez Maceira, Jorge J; Mancebo, María J; Aldegunde, Manuel

    2014-04-01

    It is known that in fish the serotonergic system is part of the neural network that controls feeding and that a pharmacologically induced increase in the brain 5-HT inhibits food intake. However, nothing is known about the 5-HT receptors involved in this inhibitory effect. In this study, we investigated the effects of several 5-HT1 and 5-HT2 receptor agonists on food intake in rainbow trout. In the first experiment, fish were injected i.p. or i.c.v. with two 5-HT1B receptor agonists, anpirtoline (2mg/kg, i.p.) and CP93129 (100 and 200μg/kg, i.c.v.). Neither of these treatments significantly altered food intake. In a second set of experiments, different groups of fish were injected i.p. (1mg/kg) or i.c.v. (30μg/kg) with the 5-HT1A receptor agonist 8-OH-DPAT. In both cases, administration of the 5-HT1A receptor agonist inhibited food intake. In a third set of experiments, we explored the effects of different 5-HT2 receptor agonists. Different groups of fish were injected i.p. or i.c.v. with the mixed 5-HT2B/2C agonist m-CPP (5mg/kg, i.p.), 5-HT2C agonist MK212 (60μg/kg, i.c.v.) and 5-HT2B agonist BW723C86 (50 and 100μg/kg, i.c.v.). Administration of the 5-HT2B/2C and 5HT2C receptor agonists significantly inhibited food intake. Administration of the lowest dose of the 5-HT2B receptor agonist did not have any significant effect, while administration of the highest dose induced a significant increase in food intake. Activation of the 5-HT1A-like (food intake inhibition) and 5-HT1B-like (no effect on food intake) receptors in the rainbow trout induced different effects on food intake from those observed in mammals. We conclude that in rainbow trout the anorexigenic actions of 5-HT are probably mediated by activation of 5-HT1A and 5-H2C-like receptors.

  12. Studying at the Universities of the Armed Forces: Comparative Results from the 1999 Student Questionnaire (Studieren an den UniBw: Vergleichende Ergebnisse aus der Studentenbefragung 1999)

    DTIC Science & Technology

    2002-12-01

    distanziert kollegial UniBw Miinchen: Auf den ersten Blick scheint das allgemeine Kommunikationsgeschehen in M • nchen im Prinzip dem an der Hamburger UniBw...Hochschulforschung m )chten wir an dieser Stelle danken fMr das Oberlassen des Frageinstrumen- tariums, das dem ZHQ zur Nutzung fu-r die eigene...gerweise war schon im Grandungskonzept der UniBw diesem Moment einer m ~glichst nahen, en- gen und transparenten Kommunikation besondere Beachtung

  13. Dopamine agonist therapy in hyperprolactinemia.

    PubMed

    Webster, J

    1999-12-01

    Introduction of the dopamine agonist bromocriptine heralded a major advance in the management of hyperprolactinemic disorders. Although its side effects of nausea, dizziness and headache and its short elimination half-life are limiting factors, its efficacy established it as a reference compound against the activity of which several dopamine agonists, like pergolide, lysuride, metergoline, terguride and dihydroergocristine, fell by the wayside. More recently, two new agents, cabergoline and quinagolide, have been introduced and appear to offer considerable advantages over bromocriptine. Cabergoline, an ergoline D2 agonist, has a long plasma half-life that enables once- or twice-weekly administration. Quinagolide, in contrast, is a nonergot D2 agonist with an elimination half-life intermediate between those of bromocriptine and cabergoline, allowing the drug to be administered once daily. Comparative studies indicate that cabergoline is clearly superior to bromocriptine in efficacy (prolactin suppression, restoration of gonadal function) and in tolerability. In similar studies, quinagolide appeared to have similar efficacy and superior tolerability to that of bromocriptine. Results of a small crossover study indicate that cabergoline is better tolerated, with a trend toward activity superior to that of quinagolide. In hyperprolactinemic men and in women not seeking to become pregnant, cabergoline may be regarded as the treatment of choice.

  14. Photographer: JPL P-21741 BW Range: 2.6 million kilometers (1.6 million miles) This picture of Io,

    NASA Technical Reports Server (NTRS)

    1979-01-01

    Photographer: JPL P-21741 BW Range: 2.6 million kilometers (1.6 million miles) This picture of Io, taken by Voyager 1, shows the region of the Jovian moon which will be monitored for volcanic eruptions by Voyager 2 during the 'Io movie' sequence. The white and orange patches probably are deposits of sulphur compounds and other volcanic materials. The Voyager 2 pictures of this region will be much more detailed.

  15. Spatial pattern analysis in Persian oak (Quercus brantii var. persica) forests on B&W aerial photographs.

    PubMed

    Erfanifard, Yousef; Feghhi, Jahangir; Zobeiri, Mahmoud; Namiranian, Manouchehr

    2009-03-01

    The purpose of this investigation was to develop a method to determine the spatial pattern of trees as a robust indicator to monitor changes from B&W aerial photographs in Persian oak forests of Zagros, Iran. A 500 x 600 m study area was selected in Servak forests next to Yasuj city in Kohgiluyeh-Va-BuyerAhmad Province. All the trees were tagged in the study area and the point map of stems were prepared. The spatial distribution of trees was determined as "dispersed" using nearest neighbour technique. Then the index of "C" calculated by T-square sampling method was applied to the point map of the study area in 30 systematic sample points in a 100 x 100 m network. Comparing the results of this method with the true spatial pattern of the study area showed that "C" can detect the spatial arrangement of trees. Thereafter the index was used on the air photo of the study area that was made of B&W aerial photographs. The method suggested in this study provides a suitable approach for detecting the spatial pattern of trees in Zagros forests on B&W air photos.

  16. Prolonged Activation of the Htr2b Serotonin Receptor Impairs Glucose Stimulated Insulin Secretion and Mitochondrial Function in MIN6 Cells

    PubMed Central

    Cataldo, Luis Rodrigo; Mizgier, María L.; Bravo Sagua, Roberto; Jaña, Fabián; Cárdenas, César; Llanos, Paola; Busso, Dolores; Olmos, Pablo; Galgani, José E.; Santos, José L.; Cortés, Víctor A.

    2017-01-01

    Aims Pancreatic β-cells synthesize and release serotonin (5 hydroxytryptamine, 5HT); however, the role of 5HT receptors on glucose stimulated insulin secretion (GSIS) and the mechanisms mediating this function is not fully understood. The aims of this study were to determine the expression profile of 5HT receptors in murine MIN6 β-cells and to examine the effects of pharmacological activation of 5HT receptor Htr2b on GSIS and mitochondrial function. Materials and Methods mRNA levels of 5HT receptors in MIN6 cells were quantified by RT qPCR. GSIS was assessed in MIN6 cells in response to global serotonergic activation with 5HT and pharmacological Htr2b activation or inhibition with BW723C86 or SB204741, respectively. In response to Htr2b activation also was evaluated the mRNA and protein levels of PGC1α and PPARy by RT-qPCR and western blotting and mitochondrial function by oxygen consumption rate (OCR) and ATP cellular content. Results We found that mRNA levels of most 5HT receptors were either very low or undetectable in MIN6 cells. By contrast, Htr2b mRNA was present at moderate levels in these cells. Preincubation (6 h) of MIN6 cells with 5HT or BW723C86 reduced GSIS and the effect of 5HT was prevented by SB204741. Preincubation with BW723C86 increased PGC1α and PPARy mRNA and protein levels and decreased mitochondrial respiration and ATP content in MIN6 cells. Conclusions Our results indicate that prolonged Htr2b activation in murine β-cells decreases glucose-stimulated insulin secretion and mitochondrial activity by mechanisms likely dependent on enhanced PGC1α/PPARy expression. PMID:28129327

  17. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  18. Estrogen agonist/antagonist properties of dibenzyl phthalate (DBzP) based on in vitro and in vivo assays.

    PubMed

    Zhang, Zhaobin; Hu, Ying; Zhao, Liang; Li, Jun; Bai, Huicheng; Zhu, Desheng; Hu, Jianying

    2011-11-10

    The most commonly used phthalates have been banned or restricted for use as plasticizers in toys in some countries because of their endocrine-disrupting properties. Dibenzyl phthalate (DBzP) has been proposed as a possible alternative for the banned/restricted phthalates. In this study, the estrogen agonist/antagonist properties of DBzP were predicted by molecular docking and confirmed by yeast estrogen screen (YES) and immature mouse uterotrophic assays. The YES assay results showed a dose-dependent increase in DBzP estrogen agonist activity from 10⁻⁶ to 10⁻⁴ M, and at concentrations from 1.95×10⁻⁶ M to higher, DBzP significantly inhibited the agonist activity of 10⁻⁹ M 17β-estradiol (E₂), inhibiting 10⁻⁹ M E₂ by 74.5% at its maximum effectiveness. The in vivo estrogen agonist/antagonist activities of DBzP were demonstrated in immature mouse uterotrophic assays. The antagonist activity of DBzP inhibited E₂-induced uterine growth promoted at 40 and 400 μg/kg bw (body weight) (P<0.05). In addition, we also analyzed the estrogen agonist/antagonist potentials of benzyl butyl phthalate (BBP) by YES, and found both were weaker than those of DBzP, suggesting DBzP would be more toxic than BBP and should not be used as an alternative plasticizer.

  19. Regulation of membrane cholecystokinin-2 receptor by agonists enables classification of partial agonists as biased agonists.

    PubMed

    Magnan, Rémi; Masri, Bernard; Escrieut, Chantal; Foucaud, Magali; Cordelier, Pierre; Fourmy, Daniel

    2011-02-25

    Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of β-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or β-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and β-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser(437)-Xaa(438)-Thr(439)-Thr(440)-Xaa(441)-Ser(442)-Thr(443)) were critical for β-arrestin recruitment. However, this region and β-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R·β-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.

  20. Effects of genistein and estrogen receptor subtype-specific agonists in ArKO mice following different administration routes.

    PubMed

    Bliedtner, Anja; Zierau, Oliver; Albrecht, Steffen; Liebhaber, Steffi; Vollmer, Günter

    2010-01-15

    We have scrutinized the effects of the phytoestrogen genistein and three synthetic estrogen receptor agonists, 17 alpha-ethynylestradiol (EE), propylpyrazole-triol (PPT) and diarylpropionitrile (DPN) in the completely estrogen-free background of aromatase knockout (ArKO) mice by means of two routes of substance administration: oral via diet (per os; po) or subcutaneous injection (sc) with the intention to evaluate the ArKO mice as sensitive model organism for uterotrophic assays. Additionally, we were aiming to qualitatively analyze effects resulting from oral administration path, in particular for PPT and DPN. Therefore, we analyzed the resulting uterine wet weights (UWW) and epithelial heights as physiological endpoints of function as well as the gonadotropin levels. Moreover, the gene expression profiles of estrogen receptors as well as important uterine and ovarian estrogen-response genes were investigated by real-time PCR. The uterus of ArKO mice responded very sensitive upon the substitution with EE (sc 5 microg/kg BW; po 50 microg/kg BW) in a proliferative manner. This was evaluated inter alia by increased UWW and by up-regulation of the expression of proliferation-associated and estrogen-response genes. It is important to note, that ER alpha and ER beta-agonist, PPT and DPN respectively (po 5mg/kg BW and sc 0.5mg/kg BW), have only been used for sc applications so far. Here, effects resulting from oral application were qualitatively described and evaluated for their applicability. The UWW and expression of proliferation-associated genes were increased following both po and sc treatment with PPT. In contrast, DPN did not exert an increase of the UWW, but a significant decrease of proliferation-associated gene and protein expression. Additionally, a substantial hypoplasia was detectable in the uterine cross-sections of DPN-treated mice. On the other hand, the phytoestrogen genistein (sc 10mg/kg BW; po 70 mg/kg BW) did not cause detectable uterotrophic

  1. 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

  2. REFINED ORBITAL SOLUTION AND QUIESCENT VARIABILITY IN THE BLACK HOLE TRANSIENT GS 1354-64 (= BW Cir)

    SciTech Connect

    Casares, J.; Zurita, C.; Shahbaz, T.; Corral-Santana, J. M.; Martinez-Pais, I. G. E-mail: czurita@iac.es E-mail: jcorral@iac.es

    2009-03-15

    In Casares et al. we presented the first radial velocity curve of the companion star to BW Cir which demonstrates the presence of a black hole in this historical X-ray transient. But these data were affected by aliasing and two possible periods at 2.5445 days and 2.5635 days were equally possible. Here we present new spectroscopic data that enable us to break the 1-year aliasing and confirm 2.5445 days as the correct orbital period. We also present R-band photometry over 14 years, which reveals the presence of important flaring activity dominating the light curves00.

  3. Photographer: JPL P-21740 BW Range: 2,318,000 kilometers (1,438,000 miles) This picture of Callisto

    NASA Technical Reports Server (NTRS)

    1979-01-01

    Photographer: JPL P-21740 BW Range: 2,318,000 kilometers (1,438,000 miles) This picture of Callisto taken by Voyager 2 shows the moon covered with bright spots which are metoerite impact craters--a fact originally discovered from the high resolution pictures taken by Voyager 1. Scientists believe that heavily cratered terrains like these on Callisto are indicative of ancient planetary surfaces. Voyager 2 mapped the side of Callisto not seen by Voyager 1. The obsure dark streaks in this area may be fault zones, but higher resolution pictures are needed for identification.

  4. Activating KIR and HLA Bw4 Ligands Are Associated to Decreased Susceptibility to Pemphigus Foliaceus, an Autoimmune Blistering Skin Disease

    PubMed Central

    Augusto, Danillo G.; Lobo-Alves, Sara C.; Melo, Marcia F.; Pereira, Noemi F.; Petzl-Erler, Maria Luiza

    2012-01-01

    The KIR genes and their HLA class I ligands have thus far not been investigated in pemphigus foliaceus (PF) and related autoimmune diseases, such as pemphigus vulgaris. We genotyped 233 patients and 204 controls for KIR by PCR-SSP. HLA typing was performed by LABType SSO reagent kits. We estimated the odds ratio, 95% confidence interval and performed logistic regression analyses to test the hypothesis that KIR genes and their known ligands influence susceptibility to PF. We found significant negative association between activating genes and PF. The activating KIR genes may have an overlapping effect in the PF susceptibility and the presence of more than three activating genes was protective (OR = 0.49, p = 0.003). A strong protective association was found for higher ratios activating/inhibitory KIR (OR = 0.44, p = 0.001). KIR3DS1 and HLA-Bw4 were negatively associated to PF either isolated or combined, but higher significance was found for the presence of both together (OR = 0.34, p<10−3) suggesting that the activating function is the major factor to interfere in the PF pathogenesis. HLA-Bw4 (80I and 80T) was decreased in patients. There is evidence that HLA-Bw4(80T) may also be important as KIR3DS1 ligand, being the association of this pair (OR = 0.07, p = 0.001) stronger than KIR3DS1-Bw4(80I) (OR = 0.31, p = 0.002). Higher levels of activating KIR signals appeared protective to PF. The activating KIR genes have been commonly reported to increase the risk for autoimmunity, but particularities of endemic PF, like the well documented influence the environmental exposure in the pathogenesis of this disease, may be the reason why activated NK cells probably protect against pemphigus foliaceus. PMID:22768326

  5. Nonpeptidic delta (delta) opioid agonists and antagonists of the diarylmethylpiperazine class: what have we learned?

    PubMed

    Calderon, Silvia N

    2011-01-01

    The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of delta-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the delta opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective delta opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the delta opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic delta opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.

  6. Nonpeptidic Delta (δ) Opioid Agonists and Antagonists of the Diarylmethylpiperazine Class: What Have We Learned?

    NASA Astrophysics Data System (ADS)

    Calderon, Silvia N.

    The discovery of the selective delta (δ) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of δ-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the δ opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective δ opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the δ opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic δ opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.

  7. Facilitation of serotonin-induced contraction of rat mesenteric artery by ketamine

    PubMed Central

    Park, Sang Woong; Noh, Hyun Ju; Kim, Jung Min; Kim, Bokyung; Cho, Sung-Il; Kim, Yoon Soo; Woo, Nam Sik

    2016-01-01

    Ketamine is an anesthetic with hypertensive effects, which make it useful for patients at risk of shock. However, previous ex vivo studies reported vasodilatory actions of ketamine in isolated arteries. In this study, we reexamined the effects of ketamine on arterial tones in the presence and absence of physiological concentrations of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) by measuring the isometric tension of endothelium-denuded rat mesenteric arterial rings. Ketamine little affected the resting tone of control mesenteric arterial rings, but, in the presence of 5-HT (100~200 nM), ketamine (10~100 µM) markedly contracted the arterial rings. Ketamine did not contract arterial rings in the presence of NE (10 nM), indicating that the vasoconstrictive action of ketamine is 5-HT-dependent. The concentration-response curves (CRCs) of 5-HT were clearly shifted to the left in the presence of ketamine (30 µM), whereas the CRCs of NE were little affected by ketamine. The left shift of the 5-HT CRCs caused by ketamine was reversed with ketanserin, a competitive 5-HT2A receptor inhibitor, indicating that ketamine facilitated the activation of 5-HT2A receptors. Anpirtoline and BW723C86, selective agonists of 5-HT1B and 5-HT2B receptors, respectively, did not contract arterial rings in the absence or presence of ketamine. These results indicate that ketamine specifically enhances 5-HT2A receptor-mediated vasoconstriction and that it is vasoconstrictive in a clinical setting. The facilitative action of ketamine on 5-HT2A receptors should be considered in ketamine-induced hypertension as well as in the pathogenesis of diseases such as schizophrenia, wherein experimental animal models are frequently generated using ketamine. PMID:27847437

  8. The contractile effect of the ghrelin receptor antagonist, D-Lys3-GHRP-6, in rat fundic strips is mediated through 5-HT receptors.

    PubMed

    Depoortere, Inge; Thijs, Theo; Peeters, Theo

    2006-05-10

    Ghrelin is an orexigenic peptide present in the stomach with gastroprokinetic properties. Previous in vivo studies have shown that the ghrelin receptor antagonist, D-Lys(3)-GHRP-6, reduced food intake and delayed gastric emptying in rodents but these effects are at variance with the normal phenotype of the ghrelin knockout mice. To verify the specificity of the effects observed with D-Lys(3)-GHRP-6 this study aimed to investigate the pharmacology of D-Lys(3)-GHRP-6 in vitro. Rat fundic strips were suspended in a tissue bath and the contraction of strips to 10(-5) M of ghrelin, GHRP-6 or D-Lys(3)-GHRP-6 was measured isometrically in the absence and presence of blockers. Neither ghrelin, nor GHRP-6, induced significant contractions in the absence of electrical field stimulation thereby excluding the presence of ghrelin receptors on smooth muscle cells. In contrast D-Lys(3)-GHRP-6, induced a pronounced biphasic contraction of 13.9+/-1.8% and 40.5+/-3.2% relative to the response to 60 mM KCl. The contraction was blocked by the 5-HT(1,2) receptor antagonist methysergide and was markedly reduced by the 5-HT(2B) receptor antagonist, yohimbine, which also profoundly affected 5-HT induced contractions in fundic strips. The existence of 5-HT(2B) receptors in the fundus was confirmed by use of the 5-HT(2B) receptor agonist, BW 723C86. In contrast to ghrelin and GHRP-6, the ghrelin receptor antagonist, D-Lys(3)-GHRP-6, induced pronounced smooth muscle contractions in the rat fundus by interacting with 5-HT(2B) receptors. This may question the role of endogenous ghrelin in the effects observed with D-Lys(3)-GHRP-6 on food intake and gastric emptying in vivo.

  9. Dopamine receptor agonists, partial agonists and psychostimulant addiction.

    PubMed

    Pulvirenti, L; Koob, G F

    1994-10-01

    Despite the epidemic growth of psychostimulant addiction over the past years, few pharmacological means of intervention are available to date for clinical treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines is characterized, among other symptoms, by intense craving for the abused drug, and this is considered a critical factor leading into relapse of drug use. In this article, Luigi Pulvirenti and George Koob focus on the modulatory role shown by drugs acting at the dopamine receptor on the various phases of psychostimulant dependence in preclinical models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have therapeutic potential.

  10. BW A256C, a chemically novel class 1 antiarrhythmic agent. A comparison of in vitro and in vivo activity with other class 1 antiarrhythmic agents.

    PubMed Central

    Allan, G.; Donoghue, S.; Follenfant, M. J.; Sawyer, D. A.

    1986-01-01

    BW A256C (5(3)-amino-6-(2,3-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2 -isopropyl-1,2,4-triazine) is a novel class 1 antiarrhythmic agent designed to combine the features of potency with reduced central nervous system penetration. BW A256C reduced the maximum rate of depolarization of guinea-pig ventricle and dog Purkinje fibres in vitro (EC50, 2.2 X 10(-6) M and 1.8 X 10(-6) M, respectively), being significantly more potent than quinidine, lidocaine, disopyramide and flecainide. BW A256C was also more potent than these agents at inhibiting aconitine-induced arrhythmias in anaesthetized rats; however, unlike these agents, BW A256C was devoid of hypotensive activity at antiarrhythmic doses. In anaesthetized dogs, intravenous administration of BW A256C (0.25-1 mg kg-1) caused a dose-dependent suppression of ventricular arrhythmias that occurred on reperfusion of an occluded coronary artery. In conscious dogs, intravenous infusion (total dose, 1.5 mg kg-1) or oral administration of BW A256C (1.25-5 mg kg-1) caused dose-dependent suppression of the ventricular ectopic activity that occurred following 20-24 h of permanent coronary artery ligation. In the conscious dog, BW A256C was approximately 7 times more potent and was also longer acting than flecainide. Administration of BW A256C was not associated with any evidence of peripheral or CNS toxicity. However, plasma levels 3-4 times greater than the antiarrhythmic levels were associated with a proarrhythmic activity. PMID:3730698

  11. 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...

  12. Small molecule fluoride toxicity agonists.

    PubMed

    Nelson, James W; Plummer, Mark S; Blount, Kenneth F; Ames, Tyler D; Breaker, Ronald R

    2015-04-23

    Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here, we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride.

  13. Small Molecule Fluoride Toxicity Agonists

    PubMed Central

    Nelson1, James W.; Plummer, Mark S.; Blount, Kenneth F.; Ames, Tyler D.; Breaker, Ronald R.

    2015-01-01

    SUMMARY Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch-reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID:25910244

  14. Comparison of the new antihistamine acrivastine (BW 825C) versus cyproheptadine in the treatment of idiopathic cold urticaria.

    PubMed

    Neittaanmäki, H; Fräki, J E; Gibson, J R

    1988-01-01

    A double-blind, crossover trial with a new triprolidine derivative, acrivastine (BW 825C; 8 mg 3 times daily), cyproheptadine (4 mg 3 times daily) and placebo was carried out in 18 patients suffering from idiopathic cold urticaria. Acrivastine and cyproheptadine significantly (p less than 0.01) reduced weal areas following ice cube challenge when compared to placebo. Acrivastine was found to be significantly more effective (p less than 0.01) than cyproheptadine in reducing weal areas. Furthermore, cyproheptadine caused significantly more drowsiness than acrivastine (p = 0.021) or placebo (p = 0.013), which did not differ from each other. This study shows that acrivastine is an effective agent in the treatment of cold urticaria and suggests that acrivastine in the dose used lacks adverse effects, such as drowsiness, traditionally associated with antihistamine therapy.

  15. Inhibition of cyst growth in PCK and Wpk rat models of polycystic kidney disease with low doses of peroxisome proliferator-activated receptor γ agonists

    PubMed Central

    Flaig, Stephanie M.; Gattone, Vincent H.

    2016-01-01

    Abstract Background and Objectives The studies were designed to test the efficacy of two peroxisome proliferator-activated receptor γ (PPARγ) agonists in two rodent models of polycystic kidney disease (PKD). Materials and Methods The PCK rat is a slowly progressing cystic model while the Wpk-/- rat is a rapidly progressing model. PCK rats were fed with a pharmacological (0.4 mg/kg body weight [BW]) and a sub-pharmacological (0.04 mg/kg BW) dose of rosiglitazone (week 4–28). Wpk-/- rats were fed with pharmacological (2.0 mg/kg BW) and sub-pharmacologic (0.2 mg/kg BW) doses of pioglitazone from day 5 to 18. At termination, kidney weights of treated versus untreated cystic animals were used to determine efficacy. The current studies were also compared with previous studies containing higher doses of PPARγ agonists. The concentrations used in the animals were calculated with reference to equivalent human doses for both drugs. Results The current studies demonstrate: 1) that low, pharmacologically relevant, doses of the PPARγ agonists effectively inhibit cyst growth; 2) there is a class action of the drugs with both commercially available PPARγ agonists, rosiglitazone, and pioglitazone, inhibiting cyst growth; 3) the drugs showed efficacy in two different preclinical cystic models. In the PCK rat, animals fed with a sub-pharmacological dose of rosiglitazone for 24 weeks had significantly lower kidney weights than untreated animals (3.68 ± 0.13 g vs. 4.17 ± 0. 11 g, respectively, P < 0.01) while treatment with a pharmacologic dose had no significant effect on kidney weight. The rapidly progressing Wpk-/- rats were fed with pharmacological and sub-pharmacologic doses of pioglitazone from day 5 to 18 and the kidneys were compared with non-treated, cystic animals. Kidney weights on the pharmacologic dose were not statistically lower than the untreated animals while rats fed a sub-pharmacologic dose showed a significant decrease compared with untreated animals (3

  16. Phase II study of the oxygen saturation curve left shifting agent BW12C in combination with the hypoxia activated drug mitomycin C in advanced colorectal cancer

    PubMed Central

    Propper, D J; Levitt, N C; O'Byrne, K; Braybrooke, J P; Talbot, D C; Ganesan, T S; Thompson, C H; Rajagopalan, B; Littlewood, T J; Dixon, R M; Harris, A L

    2000-01-01

    BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) stabilizes oxyhaemoglobin, causing a reversible left-shift of the oxygen saturation curve (OSC) and tissue hypoxia. The activity of mitomycin C (MMC) is enhanced by hypoxia. In this phase II study, 17 patients with metastatic colorectal cancer resistant to 5-fluorouracil (5-FU) received BW12C and MMC. BW12C was given as a bolus loading dose of 45 mg kg−1over 1 h, followed by a maintenance infusion of 4 mg kg−1h−1for 5 h. MMC 6 mg m−2was administered over 15 min immediately after the BW12C bolus. The 15 evaluable patients had progressive disease after a median of 2 (range 1–4) cycles of chemotherapy. Haemoglobin electrophoresis 3 and 5 h after the BW12C bolus dose showed a fast moving band consistent with the BW12C-oxyhaemoglobin complex, accounting for approximately 50% of total haemoglobin. The predominant toxicities – nausea/vomiting and vein pain – were mild and did not exceed CTC grade 2. Liver31P magnetic resonance spectroscopy of patients with hepatic metastases showed no changes consistent with tissue hypoxia. The principle of combining a hypoxically activated drug with an agent that increases tissue hypoxia is clinically feasible, producing an effect equivalent to reducing tumour oxygen delivery by at least 50%. However, BW12C in combination with MMC for 5-FU-resistant colorectal cancer is not an effective regimen. This could be related to drug resistance rather than a failure to enhance cytotoxicity. © 2000 Cancer Research Campaign PMID:10839290

  17. Regional Fluctuation in the Functional Consequence of LINE-1 Insertion in the Mitf Gene: The Black Spotting Phenotype Arisen from the Mitfmi-bw Mouse Lacking Melanocytes.

    PubMed

    Takeda, Kazuhisa; Hozumi, Hiroki; Ohba, Koji; Yamamoto, Hiroaki; Shibahara, Shigeki

    2016-01-01

    Microphthalmia-associated transcription factor (Mitf) is a key regulator for differentiation of melanoblasts, precursors to melanocytes. The mouse homozygous for the black-eyed white (Mitfmi-bw) allele is characterized by the white-coat color and deafness with black eyes due to the lack of melanocytes. The Mitfmi-bw allele carries LINE-1, a retrotransposable element, which results in the Mitf deficiency. Here, we have established the black spotting mouse that was spontaneously arisen from the homozygous Mitfmi-bw mouse lacking melanocytes. The black spotting mouse shows multiple black patches on the white coat, with age-related graying. Importantly, each black patch also contains hair follicles lacking melanocytes, whereas the white-coat area completely lacks melanocytes. RT-PCR analyses of the pigmented patches confirmed that the LINE-1 insertion is retained in the Mitf gene of the black spotting mouse, thereby excluding the possibility of the somatic reversion of the Mitfmi-bw allele. The immunohistochemical analysis revealed that the staining intensity for beta-catenin was noticeably lower in hair follicles lacking melanocytes of the homozygous Mitfmi-bw mouse and the black spotting mouse, compared to the control mouse. In contrast, the staining intensity for beta-catenin and cyclin D1 was higher in keratinocytes of the black spotting mouse, compared to keratinocytes of the control mouse and the Mitfmi-bw mouse. Moreover, the keratinocyte layer appears thicker in the Mitfmi-bw mouse, with the overexpression of Ki-67, a marker for cell proliferation. We also show that the presumptive black spots are formed by embryonic day 15.5. Thus, the black spotting mouse provides the unique model to explore the molecular basis for the survival and death of developing melanoblasts and melanocyte stem cells in the epidermis. These results indicate that follicular melanocytes are responsible for maintaining the epidermal homeostasis; namely, the present study has provided

  18. Investigation of the mechanism of agonist and inverse agonist action at D2 dopamine receptors.

    PubMed

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

    2004-05-01

    This study investigated, for the D2 dopamine receptor, the relation between the ability of agonists and inverse agonists to stabilise different states of the receptor and their relative efficacies. Ki values for agonists were determined in competition versus the binding of the antagonist [3H]spiperone. Competition data were fitted best by a two-binding site model (with the exception of bromocriptine, for which a one-binding site model provided the best fit) and agonist affinities for the higher (Kh) (G protein-coupled) and lower affinity (Kl) (G protein-uncoupled) sites determined. Ki values for agonists were also determined in competition versus the binding of the agonist [3H]N-propylnorapomorphine (NPA) to provide a second estimate of Kh. Maximal agonist effects (Emax) and their potencies (EC50) were determined from concentration-response curves for agonist stimulation of guanosine-5'-O-(3-[32S]thiotriphosphate) ([35S]GTPgammaS) binding. The ability of agonists to stabilise the G protein-coupled state of the receptor (Kl/Kh determined from ligand-binding assays) did not correlate with either of two measures of relative efficacy (relative Emax, Kl/EC50) of agonists determined in [35S]GTPgammaS-binding assays, when the data for all of the compounds tested were analysed. For a subset of compounds, however, there was a relation between Kl/Kh and Emax. Competition-binding data versus [3H]spiperone and [3H]NPA for a range of inverse agonists were fitted best by a one-binding site model. Ki values for the inverse agonists tested were slightly lower in competition versus [3H]NPA compared to [3H]spiperone. These data do not provide support for the idea that inverse agonists act by binding preferentially to the ground state of the receptor.

  19. Long-term beneficial effects of BW619C89 on neurological deficit, cognitive deficit and brain damage after middle cerebral artery occlusion in the rat.

    PubMed

    Smith, S E; Hodges, H; Sowinski, P; Man, C M; Leach, M J; Sinden, J D; Gray, J A; Meldrum, B S

    1997-04-01

    4-Amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine (BW619C89) is a sodium channel antagonist which when administered parenterally reduces neurological deficit and infarct volume after middle cerebral artery occlusion in rats. We have investigated whether BW619C89 administered orally before middle cerebral artery occlusion is cerebroprotective when rats are assessed at one day after stroke, and whether cerebroprotection is long lasting and related to functional recovery. A cerebroprotective oral dose of BW619C89 (20 mg/kg) was used to determine whether reduction in infarct volume is long lasting and can be enhanced with continued therapy, and whether behavioural deficits occurring after middle cerebral artery occlusion such as disturbances in cognition and motor coordination are ameliorated by treatment with BW619C89. Rats received sham surgery or middle cerebral artery occlusion with a single treatment of BW619C89 (20 mg/kg) 1 h before middle cerebral artery occlusion, a double treatment group receiving 20 mg/kg BW619C89 1 h before and 10 mg/kg 5 h after middle cerebral artery occlusion, or continued treatment with BW619C89 for up to five days. Neurological deficit, assessed from days 1 to 21, and at 70 days after middle cerebral artery occlusion, was reduced to a similar extent in all three groups of rats treated with BW619C89, compared with vehicle-treated controls. At 70 days after middle cerebral artery occlusion, all groups performed at control level. Vehicle-treated rats were impaired in the Morris water maze and step-through passive avoidance paradigm five to eight weeks after middle cerebral artery occlusion, when neurological deficit was minimal. These deficits were partially alleviated, to a similar extent, by all of the three treatments with BW619C89. Total volumes of brain damage, assessed at 70 days after middle cerebral artery occlusion in Luxol Fast Blue- and Cresyl Violet-stained coronal sections, were reduced in all three groups

  20. Significantly enhanced creep resistance of low volume fraction in-situ TiBw/Ti6Al4V composites by architectured network reinforcements

    NASA Astrophysics Data System (ADS)

    Wang, S.; Huang, L. J.; Geng, L.; Scarpa, F.; Jiao, Y.; Peng, H. X.

    2017-01-01

    We present a new class of TiBw/Ti6Al4V composites with a network reinforcement architecture that exhibits a significant creep resistance compared to monolithic Ti6Al4V alloys. Creep tests performed at temperatures between 773 K and 923 K and stress range of 100 MPa-300 MPa indicate both a significant improvement of the composites creep resistance due to the network architecture made by the TiB whiskers (TiBw), and a decrease of the steady-state creep rates by augmenting the local volume fractions of TiBw in the network region. The deformation behavior is driven by a diffusion-controlled dislocation climb process. Moreover, the activation energies of these composites are significantly higher than that of Ti6Al4V alloys, indicating a higher creep resistance. The increase of the activation energy can be attributed to the TiBw architecture that severely impedes the movements of dislocation and grain boundary sliding and provides a tailoring of the stress transfer. These micromechanical mechanisms lead to a remarkable improvement of the creep resistance of these networked TiBw/Ti6Al4V composites featuring the special networked architecture.

  1. Significantly enhanced creep resistance of low volume fraction in-situ TiBw/Ti6Al4V composites by architectured network reinforcements

    PubMed Central

    Wang, S.; Huang, L. J.; Geng, L.; Scarpa, F.; Jiao, Y.; Peng, H. X.

    2017-01-01

    We present a new class of TiBw/Ti6Al4V composites with a network reinforcement architecture that exhibits a significant creep resistance compared to monolithic Ti6Al4V alloys. Creep tests performed at temperatures between 773 K and 923 K and stress range of 100 MPa-300 MPa indicate both a significant improvement of the composites creep resistance due to the network architecture made by the TiB whiskers (TiBw), and a decrease of the steady-state creep rates by augmenting the local volume fractions of TiBw in the network region. The deformation behavior is driven by a diffusion-controlled dislocation climb process. Moreover, the activation energies of these composites are significantly higher than that of Ti6Al4V alloys, indicating a higher creep resistance. The increase of the activation energy can be attributed to the TiBw architecture that severely impedes the movements of dislocation and grain boundary sliding and provides a tailoring of the stress transfer. These micromechanical mechanisms lead to a remarkable improvement of the creep resistance of these networked TiBw/Ti6Al4V composites featuring the special networked architecture. PMID:28094350

  2. [Safety of beta-agonists in asthma].

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

    Beta 2 agonist bronchodilators (β2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The β2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting β2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting β2 agonists (LABAs) The long-acting bronchodilators β2A (Long acting β2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

  3. Dipeptidyl peptidase IV inhibitor lowers PPARγ agonist-induced body weight gain by affecting food intake, fat mass, and beige/brown fat but not fluid retention

    PubMed Central

    Masuda, Takahiro; Fu, Yiling; Eguchi, Akiko; Czogalla, Jan; Rose, Michael A.; Kuczkowski, Alexander; Gerasimova, Maria; Feldstein, Ariel E.; Scadeng, Miriam

    2013-01-01

    Peroxisome proliferator-activated receptor-γ (PPARγ) agonists like pioglitazone (PGZ) are effective antidiabetic drugs, but they induce fluid retention and body weight (BW) gain. Dipeptidyl peptidase IV (DPP IV) inhibitors are antidiabetic drugs that enhance renal Na+ and fluid excretion. Therefore, we examined whether the DPP IV inhibitor alogliptin (ALG) ameliorates PGZ-induced BW gain. Male Sv129 mice were treated with vehicle (repelleted diet), PGZ (220 mg/kg diet), ALG (300 mg/kg diet), or a combination of PGZ and ALG (PGZ + ALG) for 14 days. PGZ + ALG prevented the increase in BW observed with PGZ but did not attenuate the increase in body fluid content determined by bioimpedance spectroscopy (BIS). BIS revealed that ALG alone had no effect on fat mass (FM) but enhanced the FM-lowering effect of PGZ; MRI analysis confirmed the latter and showed reductions in visceral and inguinal subcutaneous (sc) white adipose tissue (WAT). ALG but not PGZ decreased food intake and plasma free fatty acid concentrations. Conversely, PGZ but not ALG increased mRNA expression of thermogenesis mediator uncoupling protein 1 in epididymal WAT. Adding ALG to PGZ treatment increased the abundance of multilocular cell islets in sc WAT, and PGZ + ALG increased the expression of brown-fat-like “beige” cell marker TMEM26 in sc WAT and interscapular brown adipose tissue and increased rectal temperature vs. vehicle. In summary, DPP IV inhibition did not attenuate PPARγ agonist-induced fluid retention but prevented BW gain by reducing FM. This involved ALG inhibition of food intake and was associated with food intake-independent synergistic effects of PPARγ agonism and DPP-IV inhibition on beige/brown fat cells and thermogenesis. PMID:24347054

  4. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  5. Long-term studies of dopamine agonists.

    PubMed

    Hubble, Jean P

    2002-02-26

    Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

  6. Rapid, potentially automatable, method extract biomarkers for HPLC/ESI/MS/MS to detect and identify BW agents

    SciTech Connect

    White, D.C. |; Burkhalter, R.S.; Smith, C.; Whitaker, K.W.

    1997-12-31

    The program proposes to concentrate on the rapid recovery of signature biomarkers based on automated high-pressure, high-temperature solvent extraction (ASE) and/or supercritical fluid extraction (SFE) to produce lipids, nucleic acids and proteins sequentially concentrated and purified in minutes with yields especially from microeukaryotes, Gram-positive bacteria and spores. Lipids are extracted in higher proportions greater than classical one-phase, room temperature solvent extraction without major changes in lipid composition. High performance liquid chromatography (HPLC) with or without derivatization, electrospray ionization (ESI) and highly specific detection by mass spectrometry (MS) particularly with (MS){sup n} provides the detection, identification and because the signature lipid biomarkers are both phenotypic as well as genotypic biomarkers, insights into potential infectivity of BW agents. Feasibility has been demonstrated with detection, identification, and determination of infectious potential of Cryptosporidium parvum at the sensitivity of a single oocyst (which is unculturable in vitro) and accurate identification and prediction, pathogenicity, and drug-resistance of Mycobacteria spp.

  7. Multidimensional Simulations for Early-Phase Spectra of Aspherical Hypernovae: SN 1998bw and Off-Axis Hypernovae

    NASA Astrophysics Data System (ADS)

    Tanaka, Masaomi; Maeda, Keiichi; Mazzali, Paolo A.; Nomoto, Ken'ichi

    2007-10-01

    Early-phase optical spectra of aspherical jet-like supernovae (SNe) are presented. We focus on energetic core-collapse SNe, or hypernovae. Based on hydrodynamic and nucleosynthetic models, radiative transfer in the SN atmosphere is solved with a multidimensional Monte Carlo radiative transfer code, SAMURAI. Since the luminosity is boosted in the jet direction, the temperature there is higher than in the equatorial plane by ~2000 K. This causes anisotropic ionization in the ejecta. Emergent spectra are different depending on viewing angle, reflecting both aspherical abundance distribution and anisotropic ionization. Spectra computed with an aspherical explosion model with kinetic energy 20×1051 ergs are compatible with those of the Type Ic SN 1998bw if ~10%-20% of the synthesized metals are mixed out to higher velocities. The simulations enable us to predict the properties of off-axis hypernovae. Even if an aspherical hypernova explosion is observed from the side, it should show hypernova-like spectra but with some differences in the line velocity, the width of the Fe absorptions, and the strength of the Na I line.

  8. The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats.

    PubMed

    Rasmussen, Dennis D; Alexander, Laura; Malone, Julia; Federoff, David; Froehlich, Janice C

    2014-09-01

    Evidence suggests that noradrenergic signaling may play a role in mediating alcohol-drinking behavior in both rodents and humans. We have investigated this possibility by administering clonidine to alcohol-drinking rats selectively bred for alcohol preference (P line). Clonidine is an α2-adrenergic receptor agonist which, at low doses, inhibits noradrenergic signaling by decreasing norepinephrine release from presynaptic noradrenergic neurons. Adult male P rats were given 24 h access to food and water and scheduled access to a 15% (v/v) alcohol solution for 2 h daily. Rats received intra-peritoneal (IP) injections with clonidine (0, 10, 20, 40, or 80 μg/kg body weight [BW], 10-11 rats/treatment group) once/day at 30 min prior to onset of the daily 2 h alcohol access period for 2 consecutive days. Clonidine, in doses of 40 or 80 μg/kg BW, significantly reduced alcohol intake on both days of treatment (p<0.001). Two weeks later, rats were treated with clonidine for 5 consecutive days and clonidine, in doses of 40 or 80 μg/kg BW, reduced alcohol intake on all 5 treatment days (p < 0.001). Clonidine did not alter water consumption during the daily 2 h free-choice between alcohol and water. In a separate group of male P rats, clonidine (40 μg/kg BW) suppressed intake of a saccharin solution (0.04 g/L). These results are consistent with and complement our previous findings that the α1-adrenergic receptor antagonist, prazosin, decreases voluntary alcohol drinking in alcohol-preferring rats, but suggests that effects of clonidine may not be specific for alcohol. The results suggest that although activation of the noradrenergic system plays an important role in mediating voluntary alcohol drinking, care is needed in selecting which drugs to use to suppress central noradrenergic signaling in order to maximize the selectivity of the drugs for treating alcohol-use disorders.

  9. PPARγ agonist-induced fluid retention depends on αENaC expression in connecting tubules

    PubMed Central

    Fu, Yiling; Gerasimova, Maria; Batz, Falk; Kuczkowski, Alexander; Alam, Yasaman; Sanders, Paul W.; Ronzaud, Caroline; Hummler, Edith; Vallon, Volker

    2014-01-01

    Background/Aims Thiazolidinediones (TZDs, e.g. rosiglitazone (RGZ)) are peroxisome proliferator–activated receptor γ (PPARγ) agonists used to treat type 2 diabetes. Clinical limitations include TZD-induced fluid retention and body weight (BW) increase, which are inhibited by amiloride, an epithelial-sodium channel (ENaC) blocker. RGZ-induced fluid retention is maintained in mice with αENaC knockdown in the collecting duct (CD). Since ENaC in the connecting tubule (CNT) rather than in CD appears to be critical for normal NaCl retention, we aimed to further explore the role of ENaC in CNT in RGZ-induced fluid retention. Methods Mice with conditional inactivation of αENaC in both CNT and CD were used (αENaC lox/lox AQP2-Cre; “αENaC-CNT/CD-KO”) and compared with littermate controls (αENaC lox/lox mice; “WT”). BW was monitored, and total body water (TBW) and extracellular fluid volume (ECF) determined by bioelectrical impedance spectroscopy (BIS) before and after RGZ (320 mg/kg diet for 10 days). Results On regular NaCl diet, αENaC-CNT/CD-KO had normal BW, TBW, ECF, hematocrit, and plasma Na+, K+, and creatinine, associated with an increase in plasma aldosterone compared with WT. Challenging αENaC-CNT/CD-KO with a low NaCl diet unmasked impaired NaCl and K homeostasis, consistent with effective knockdown of αENaC. In WT, RGZ increased BW (+6.1%), TBW (+8.4%) and ECF (+10%), consistent with fluid retention. These changes were significantly attenuated in αENaC-CNT/CD-KO (+3.4, 1.3, and 4.3%). Conclusion Together with previous studies, the current results are consistent with a role of αENaC in CNT in RGZ-induced fluid retention, which dovetails with the physiological relevance of ENaC in this segment. PMID:25531136

  10. The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.

    PubMed

    Warne, Tony; Moukhametzianov, Rouslan; Baker, Jillian G; Nehmé, Rony; Edwards, Patricia C; Leslie, Andrew G W; Schertler, Gebhard F X; Tate, Christopher G

    2011-01-13

    β-adrenergic receptors (βARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit βARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) β(1)-adrenergic receptor (β(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.

  11. Insertion of long interspersed element-1 in the Mitf gene is associated with altered neurobehavior of the black-eyed white Mitf(mi-bw) mouse.

    PubMed

    Takeda, Kazuhisa; Hozumi, Hiroki; Nakai, Kunihiko; Yoshizawa, Miki; Satoh, Hiroshi; Yamamoto, Hiroaki; Shibahara, Shigeki

    2014-02-01

    Microphthalmia-associated transcription factor (Mitf) is required for the differentiation of melanoblasts of the neural crest origin. The mouse homozygous for the black-eyed white (Mitf(mi-bw) ) allele is characterized by white-coat color and deafness with black eye, due to the loss of melanoblasts during embryonic development. The Mitf(mi-bw) allele carries an insertion of long interspersed element-1 (L1) in intron 3 of the Mitf gene, which may cause the deficiency of melanocyte-specific Mitf-M. Here, we show that the L1 insertion results in the generation of alternatively spliced Mitf-M mRNA species, such as Mitf-M mRNA lacking exon 3, exon 4 or both exons 3 and 4, each of which encodes Mitf-M protein with an internal deletion. Transient expression assays showed the loss of or reduction in function of each aberrant Mitf-M protein and the dominant negative effect of Mitf-M lacking exon 4 that encodes an activation domain. Thus, the L1 insertion may decrease the expression level of functional Mitf-M. Importantly, Mitf-M mRNA is expressed in the wild-type mouse brain, with the highest expression level in the hypothalamus. Likewise, aberrant Mitf-M mRNAs are expressed in the bw mouse brain. The bw mice show the altered neurobehavior under a stressful environment, suggesting the role of Mitf-M in sensory perception.

  12. Muscimol as an ionotropic GABA receptor agonist.

    PubMed

    Johnston, Graham A R

    2014-10-01

    Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol(®)) and 4-PIOL.

  13. Corepressors of agonist-bound nuclear receptors

    SciTech Connect

    Gurevich, Igor; Aneskievich, Brian J.

    2007-09-15

    Nuclear receptors (NRs) rely on coregulator proteins to modulate transcription of target genes. NR coregulators can be broadly subdivided into coactivators which potentiate transcription and corepressors which silence gene expression. The prevailing view of coregulator action holds that in the absence of agonist the receptor interacts with a corepressor via the corepressor nuclear receptor (CoRNR, 'corner') box motifs within the corepressor. Upon agonist binding, a conformational change in the receptor causes the shedding of corepressor and the binding of a coactivator which interacts with the receptor via NR boxes within the coregulator. This view was challenged with the discovery of RIP140 which acts as a NR corepressor in the presence of agonist and utilizes NR boxes. Since then a number of other corepressors of agonist-bound NRs have been discovered. Among them are LCoR, PRAME, REA, MTA1, NSD1, and COPR1 Although they exhibit a great diversity of structure, mechanism of repression and pathophysiological function, these corepressors frequently have one or more NR boxes and often recruit histone deacetylases to exert their repressive effects. This review highlights these more recently discovered corepressors and addresses their potential functions in transcription regulation, disease pharmacologic responses and xenobiotic metabolism.

  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. Serotonergic agonists behave as partial agonists at the dopamine D2 receptor.

    PubMed

    Rinken, A; Ferré, S; Terasmaa, A; Owman, C; Fuxe, K

    1999-02-25

    RAT dopamine D2short receptors expressed in CHO cells were characterized by activation of [35S]GTPgammaS binding. There were no significant differences between the maximal effects seen in activation of [35S]GTPgammaS binding caused by dopaminergic agonists, but the effects of 5-HT, 8OH-DPAT and 5-methoxytryptamine amounted to 47 +/- 7%, 43 +/- 5% and 70 +/- 7% of the dopamine effect, respectively. The dopaminergic antagonist (+)butaclamol inhibited activations of both types of ligands with equal potency (pA2 = 8.9 +/- 0.1), indicating that only one type of receptor is involved. In competition with [3H]raclopride binding, dopaminergic agonists showed 53 +/- 2% of the binding sites in the GTP-dependent high-affinity state, whereas 5-HT showed only 20 +/- 3%. Taken together, the results indicate that serotonergic agonists behave as typical partial agonists for D2 receptors with potential antiparkinsonian activity.

  16. Note: Comparison of grazing incidence small angle x-ray scattering of a titania sponge structure at the beamlines BW4 (DORIS III) and P03 (PETRA III)

    SciTech Connect

    Rawolle, M.; Koerstgens, V.; Ruderer, M. A.; Metwalli, E.; Guo, S.; Mueller-Buschbaum, P.; Herzog, G.; Benecke, G.; Schwartzkopf, M.; Buffet, A.; Perlich, J.; Roth, S. V.

    2012-10-15

    Grazing incidence small angle x-ray scattering (GISAXS) is a powerful technique for morphology investigation of nanostructured thin films. GISAXS measurements at the newly installed P03 beamline at the storage ring PETRA III in Hamburg, Germany, are compared to the GISAXS data from the beamline BW4 at the storage ring DORIS III, which had been used extensively for GISAXS investigations in the past. As an example, a titania thin film sponge structure is investigated. Compared to BW4, at beamline P03 the resolution of larger structures is slightly improved and a higher incident flux leads to a factor of 750 in scattered intensity. Therefore, the acquisition time in GISAXS geometry is reduced significantly at beamline P03.

  17. The effects of the adenosine A3 receptor agonist IB-MECA on sodium taurocholate-induced experimental acute pancreatitis.

    PubMed

    Prozorow-Krol, Beata; Korolczuk, Agnieszka; Czechowska, Grazyna; Slomka, Maria; Madro, Agnieszka; Celinski, Krzysztof

    2013-09-01

    The role of adenosine A3 receptors and their distribution in the gastrointestinal tract have been widely investigated. Most of the reports discuss their role in intestinal inflammations. However, the role of adenosine A3 receptor agonist in pancreatitis has not been well established. The aim of this study is [corrected] to evaluate the effects of the adenosine A3 receptor agonist on the course of sodium taurocholate-induced experimental acute pancreatitis (EAP). The experiments were performed on 80 male Wistar rats, 58 of which survived, subdivided into 3 groups: C--control rats, I--EAP group, and II--EAP group treated with the adenosine A3 receptor agonist IB-MECA (1-deoxy-1-6[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide at a dose of 0.75 mg/kg b.w. i.p. at 48, 24, 12 and 1 h before and 1 h after the injection of 5% sodium taurocholate solution into the biliary-pancreatic duct. Serum for α-amylase and lipase determinations and tissue samples for morphological examinations were collected at 2, 6, and 24 h of the experiment. In the IB-MECA group, α-amylase activity was decreased with statistically high significance compared to group I. The activity of lipase was not significantly different among the experimental groups but higher than in the control group. The administration of IB-MECA attenuated the histological parameters of inflammation as compared to untreated animals. The use of A3 receptor agonist IB-MECA attenuates EAP. Our findings suggest that stimulation of adenosine A3 receptors plays a positive role in the sodium taurocholate-induced EAP in rats.

  18. Polychlorinated biphenyls (PCBs) contamination and aryl hydrocarbon receptor (AhR) agonist activity of Omega-3 polyunsaturated fatty acid supplements: implications for daily intake of dioxins and PCBs.

    PubMed

    Bourdon, J A; Bazinet, T M; Arnason, T T; Kimpe, L E; Blais, J M; White, P A

    2010-11-01

    Omega-3 polyunsaturated fatty acid (n-3 PUFA) rich oils derived primarily from fish are frequently consumed as supplements. Due to the tendency of persistent organic pollutants (POPs) to accumulate in exposed organisms, n-3 PUFA supplements can contain sufficient POPs to present a risk to consumers. Here we investigated PCB concentrations and aryl hydrocarbon receptor (AhR) agonist activity in 17 n-3 PUFA supplements available in Canada. PCBs ranged from <0.8 to 793 ng g(-1) oil, with salmon- and seal-derived products yielding the highest values. AhR agonist activity from a reporter gene assay ranged from 1.3 to 72.2 pg TEQ g(-1) oil, with salmon and tuna yielding the highest values. When consumed at the recommended doses and as a supplement to the average Canadian diet, seal-derived oil can contribute to exceedance of the tolerable daily intake of 20 ng PCBs kg-BW(-1)day(-1), and salmon-, tuna-, and sea herring-derived oils can contribute to exceedance of the tolerable daily intake limit of 2.3 pg TEQ kg-BW(-1)day(-1). The beneficial properties of fish and n-3 PUFA supplements, and the results of this study suggest that it is prudent to consume supplements derived from small, cold-water fatty fish. Further research will be necessary to draw firm conclusions.

  19. Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea-pig.

    PubMed Central

    Adcock, J. J.; Schneider, C.; Smith, T. W.

    1988-01-01

    1. Antitussive, antinociceptive and respiratory depressant effects of codeine, morphine and H.Tyr.D-Arg.Gly.Phe(4-NO2) Pro.NH2 (compound BW443C) were investigated in unanaesthetized guinea-pigs. Antagonism of the antitussive and antinociceptive effects was investigated by the use of nalorphine and N-methylnalorphine. Naloxone was used to antagonize respiratory depression. 2. Antitussive ED50s (with 95% confidence limits) for inhibition of cough induced by citric acid vapour were for codeine, morphine and BW443C respectively, 9.1(5.8-15), 1.3(0.7-2.4) and 1.2(0.6-2.6) mg kg-1 s.c. and 8.7(4.2-12), 1.6(1.2-1.9) and 0.67(0.002-3.3) mg kg-1, i.v. The antitussive effects of subcutaneous codeine (25 mg kg-1) morphine (8.1 mg kg-1) and BW443C (2.5 mg kg-1) were significantly antagonized by subcutaneous nalorphine (3.0 mg kg-1) and N-methylnalorphine (3.0 mg kg-1). 3. In the multiple toe-pinch test, the antinociceptive ED50s (with 95% confidence limits) of codeine and morphine were 18(16-22) and 2.3(0.4-4.3) mg kg-1, s.c., respectively. Compound BW443C was ineffective in doses of 2.5 and 10 mg kg-1 s.c., a result consistent with its lacking penetration into the CNS. Subcutaneous nalorphine (3.0 mg kg-1) antagonized the antinociceptive action of codeine (25 mg kg-1) and morphine (8.1 mg kg-1). In contrast, N-methylnalorphine (3.0 mg kg-1) had no significant effect on the antinociceptive action of codeine and morphine, suggesting lack of penetration of the CNS by N-methylnalorphine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3349236

  20. Controllable two-scale network architecture and enhanced mechanical properties of (Ti5Si3+TiBw)/Ti6Al4V composites

    PubMed Central

    Jiao, Y.; Huang, L. J.; Duan, T. B.; Wei, S. L.; Kaveendran, B.; Geng, L.

    2016-01-01

    Novel Ti6Al4V alloy matrix composites with a controllable two-scale network architecture were successfully fabricated by reaction hot pressing (RHP). TiB whiskers (TiBw) were in-situ synthesized around the Ti6Al4V matrix particles, and formed the first-scale network structure (FSNS). Ti5Si3 needles (Ti5Si3) precipitated in the β phase around the equiaxed α phase, and formed the secondary-scale network structure (SSNS). This resulted in increased deformation compatibility accompanied with enhanced mechanical properties. Apart from the reinforcement distribution and the volume fraction, the ratio between Ti5Si3 and TiBw fraction were controlled. The prepared (Ti5Si3 + TiBw)/Ti6Al4V composites showed higher tensile strength and ductility than the composites with a one-scale microstructure, and superior wear resistance over the Ti6Al4V alloy under dry sliding wear conditions at room temperature. PMID:27622992

  1. Application of UPTF data for modeling liquid draindown in the downcomer region of a PWR using RELAP5/MOD2-B&W

    SciTech Connect

    Wissinger, G.; Klingenfus, J.

    1995-09-01

    B&W Nuclear Technologies (BWNT) currently uses an evaluation model that analyzes large break loss-of-coolant accidents in pressurized water reactors using several computer codes. These codes separately calculate the system performance during the blowdown, refill, and reflooding phases of the transient. Multiple codes are used, in part, because a single code has been unable to effectively model the transition from blowdown to reflood, particularly in the downcomer region where high steam velocities do not allow the injected emergency core cooling (ECC) liquid to penetrate and begin to refill the vessel lower plenum until after the end of blowdown. BWNT is developing a method using the RELAP5/MOD2-B&W computer code that can correctly predict the liquid draindown behavior in the downcomer during the late blowdown and refill phases. Benchmarks of this method have been performed against Upper Plenum Test Facility (UPTF) data for ECC liquid penetration and valves using both cold leg and downcomer ECC injection. The use of this new method in plant applications should result in the calculation of a shorter refill period, leading to lower peak clad temperature predictions and increased core peaking. This paper identifies changes made to the RELAP/MOD2-B&W code to improve its predictive capabilities with respect to the data obtained in the UPTF tests.

  2. Behçet’s disease in HLA-B*51 negative Germans and Turks shows association with HLA-Bw4-80I

    PubMed Central

    2014-01-01

    Introduction Behçet’s disease (BD) as systemic vasculitis of unknown etiology is associated with HLA-B*51 in European and Asian populations. HLA-A*26 was claimed as an additional BD susceptibility marker in Japanese and Greek patients. This study was performed to test for HLA associations in HLA-B*51 negative German and Turkish BD populations. Methods In total, 65 German and 46 Turkish patients lacking HLA-B*51 were analyzed in comparison to healthy HLA-B*51 negative Germans (n = 1500) and Turks (n = 130). HLA-A/B genotypes were determined by SSOP. P-values with correction for multiple testing (pc), χ2-test and odds ratio (OR) were used for statistical evaluation. Results HLA-A*26 was significantly more frequent in HLA-B*51− German patients [pc = 0.0076, OR = 3.23, 95% CI 1.63 to 6.39] than in respective controls. HLA-A*26 was also elevated in a smaller group of Turkish patients versus the controls. Significant association of HLA-Bw4 with isoleucine at amino-acid position 80 (HLA-Bw4-80I) was found in the HLA-B*51− German cohort of BD patients [pc = 0.0042, OR = 2.35, 95% CI 1.41 to 3.93) and in the Turkish patients in comparison to the respective controls [p = 0.025, OR = 2.17, 95% CI 1.09 to 4.31]. On the contrary, HLA-Bw4-80 T was reduced in both HLA-B*51− BD patient cohorts. Conclusions The study shows a significant association of HLA-Bw4-80I present on HLA-B*51 as well as on other B-locus molecules with BD. This indicates that distinctive Bw4 epitopes on HLA-B locus molecules could play a role in BD pathogenesis. The study also indicates an association with HLA-A*26 in German and Turkish BD patients as a genetic risk factor independent of HLA-B*51. PMID:24887019

  3. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

    Reproductive and agonistic behaviors in Siamese fighting fish were investigated in eight experiments, and some consequences and determinants of these sequences were isolated. First, fights and the formation of dominance-subordinancy relations were studied. Second, it was determined that large body size as well as males' prior residency in a tank produced an agonistic advantage; the magnitude of this advantage was positively related to the duration of residency. Third, the prior-residency effect in Bettas was determined by males' familiarity with visual and/or tactile cues in their home tanks. Fourth, dominant males had greater access to living space and were more likely to display at a mirror, build nests, and approach females than were subordinates. Finally, it was discovered that chemical cues associated with presumedly inert plastic tank dividers influence Bettas' social behavior.

  4. Agonists block currents through acetylcholine receptor channels.

    PubMed Central

    Sine, S M; Steinbach, J H

    1984-01-01

    We have examined the effects of high concentrations of cholinergic agonists on currents through single acetylcholine receptor (AChR) channels on clonal BC3H1 cells. We find that raised concentrations of acetylcholine (ACh; above 300 microM) or carbamylcholine (Carb; above 1,000 microM) produce a voltage- and concentration-dependent reduction in the mean single-channel current. Raised concentrations of suberyldicholine (Sub; above 3 microM) produce a voltage- and concentration-dependent increase in the number of brief duration low-conductance interruptions of open-channel currents. These observations can be quantitatively described by a model in which agonist molecules enter and transiently occlude the ion-channel of the AChR. PMID:6478036

  5. Ropinirole, a non-ergoline dopamine agonist.

    PubMed

    Jost, Wolfgang H; Angersbach, Dieter

    2005-01-01

    Dopamine agonists have become indispensable in the treatment of Parkinson's disease. In every-day practice, however, the decision to select the best compound for an individual patient is rendered difficult because of the large number of substances available on the market. This review article provides a closer look at the experimental and clinical studies with ropinirole published so far. Ropinirole is a non-ergoline dopamine agonist which has been proven to be effective in both, monotherapy and combination therapy of idiopathic Parkinson's disease. In addition to ameliorating bradykinesia, rigor, and tremor, ropinirole facilitates the daily life and improves depressive moods of patients with Parkinson's disease. The long-term complications of levodopa are avoided, and problems commonly associated with levodopa treatment are reduced. Ropinirole appears to have a neuroprotective effect. In addition to Parkinson's disease, ropinirole has also been used successfully in the treatment of restless legs syndrome.

  6. The identification of orally bioavailable thrombopoietin agonists.

    PubMed

    Munchhof, Michael J; Antipas, Amy S; Blumberg, Laura C; Brissette, William H; Brown, Matthew F; Casavant, Jeffrey M; Doty, Jonathan L; Driscoll, James; Harris, Thomas M; Wolf-Gouveia, Lilli A; Jones, Christopher S; Li, Qifang; Linde, Robert G; Lira, Paul D; Marfat, Anthony; McElroy, Eric; Mitton-Fry, Mark; McCurdy, Sandra P; Reiter, Lawrence A; Ripp, Sharon L; Shavnya, Andrei; Thomasco, Lisa M; Trevena, Kristen A

    2009-03-01

    Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.

  7. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

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

    2016-02-08

    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.

  8. Ankaflavin: a natural novel PPARγ agonist upregulates Nrf2 to attenuate methylglyoxal-induced diabetes in vivo.

    PubMed

    Lee, Bao-Hong; Hsu, Wei-Hsuan; Chang, Yu-Ying; Kuo, Hsuan-Fu; Hsu, Ya-Wen; Pan, Tzu-Ming

    2012-12-01

    Ankaflavin (AK) is an active compound having anti-inflammatory, anti-cancer, antiatherosclerotic, and hypolipidemic effects. We have previously reported that AK acts as an antioxidant and antidiabetic drug; however, the mechanism by which AK prevents diabetes remains unknown. Hyperglycemia is associated with protein glycation, which produces advanced glycation end-products (AGEs). Methylglyoxal (MG)-a metabolite of carbohydrates-is believed to cause insulin resistance by inducing inflammation and pancreas damage. In this work, diabetes was induced in Wistar rats (4 weeks of age) by treating them with MG (600 mg/kg bw) for 4 weeks. We observed that AK (10mg/kg bw) exerted peroxisome proliferator-activated receptor-γ (PPARγ) agonist activity, thereby enhancing insulin sensitivity (as indicated by hepatic GLUT2 translocation, PTP1B suppression, and glucose uptake) by downregulating blood glucose and upregulating pancreatic and duodenal homeobox-1 and Maf-A expression and increasing insulin production in MG-induced rats. However, these effects were abolished by the administration of GW9662 (PPARγ antagonist), but the expression of hepatic heme oxygenase-1 (HO-1) and glutamate-cysteine ligase (GCL) was not suppressed in MG-induced rats. Therefore, the nuclear factor erythroid-related factor-2 (Nrf2) activation was investigated. AK did not affect hepatic Nrf2 mRNA or protein expression but significantly increased Nrf2 phosphorylation (serine 40), which was accompanied by increased transcriptional activation of hepatic HO-1 and GCL. These data indicated that AK protected rats from oxidative stress resulting from MG-induced insulin resistance. In contrast, these effects were not detected when the rats were treated with the antidiabetic drug rosiglitazone (10mg/kg bw). Moreover, we found that AK did not inhibit the generation of AGEs in vitro; however, the glutathione (GSH) levels in liver and pancreas of MG-induced rats were elevated in rats administered AK. Therefore

  9. 5-HT is a potent relaxant in rat superior mesenteric veins.

    PubMed

    Watts, Stephanie W; Darios, Emma S; Seitz, Bridget M; Thompson, Janice M

    2015-02-01

    Serotonin (5-HT, 5-hydroxytryptamine) reduces blood pressure of the conscious rat when administered chronically (1 week). 5-HT does not directly relax isolated arteries, and microsphere experiments in 5-HT-infused rats suggested that 5-HT increased flow to the splanchnic bed. We hypothesized that 5-HT increased splanchnic flow because of direct venous relaxation; our focus was thus on the superior mesenteric vein (SMV) as an important vein in splanchnic circulation. Real-time RT-PCR, immunohistochemistry and Western analyses supported the predominant expression of the 5-HT2B and 5-HT7 receptor in the SMV. The SMV was mounted in tissue baths for measurement of isometric contraction. 5-HT caused a concentration-dependent relaxation of the endothelin-1 (ET-1)-contracted vein. The threshold of 5-HT-induced venous relaxation was significantly lower than for 5-HT-induced venous contraction (∼2 vs. 700 nmol/L, respectively). A series of serotonergic agonists established in their use of receptor characterization was tested, and the following rank order of potency found for agonist-induced relaxation (receptor selectivity): 5-CT (5-HT1/5-HT7)>5-HT = LP-44 (5-HT7)>PNU109291 (5-HT1D) = BW723C86 (5-HT2B). 8-OH-DPAT (5-HT1A/7), CP93129 (5-HT1B), mCPBG (5-HT3/4), AS19 (5-HT7) and TCB-2 (5-HT2A) did not relax the isolated vein. Consistent with these findings, two different 5-HT7 receptor antagonists SB 269970 and LY215840 but not the 5-HT2B receptor antagonist LY272015 nor the nitric oxide synthase inhibitor LNNA abolished 5-CT-induced relaxation of the isolated SMV. 5-CT (1 μg kg(-1) min(-1), sc) also reduced blood pressure over 7 days. These findings suggest that 5-HT directly relaxes the SMV primarily through activation of the 5-HT7 receptor.

  10. 5-HT is a potent relaxant in rat superior mesenteric veins

    PubMed Central

    Watts, Stephanie W; Darios, Emma S; Seitz, Bridget M; Thompson, Janice M

    2015-01-01

    Serotonin (5-HT, 5-hydroxytryptamine) reduces blood pressure of the conscious rat when administered chronically (1 week). 5-HT does not directly relax isolated arteries, and microsphere experiments in 5-HT-infused rats suggested that 5-HT increased flow to the splanchnic bed. We hypothesized that 5-HT increased splanchnic flow because of direct venous relaxation; our focus was thus on the superior mesenteric vein (SMV) as an important vein in splanchnic circulation. Real-time RT-PCR, immunohistochemistry and Western analyses supported the predominant expression of the 5-HT2B and 5-HT7 receptor in the SMV. The SMV was mounted in tissue baths for measurement of isometric contraction. 5-HT caused a concentration-dependent relaxation of the endothelin-1 (ET-1)-contracted vein. The threshold of 5-HT-induced venous relaxation was significantly lower than for 5-HT-induced venous contraction (∼2 vs. 700 nmol/L, respectively). A series of serotonergic agonists established in their use of receptor characterization was tested, and the following rank order of potency found for agonist-induced relaxation (receptor selectivity): 5-CT (5-HT1/5-HT7)>5-HT = LP-44 (5-HT7)>PNU109291 (5-HT1D) = BW723C86 (5-HT2B). 8-OH-DPAT (5-HT1A/7), CP93129 (5-HT1B), mCPBG (5-HT3/4), AS19 (5-HT7) and TCB-2 (5-HT2A) did not relax the isolated vein. Consistent with these findings, two different 5-HT7 receptor antagonists SB 269970 and LY215840 but not the 5-HT2B receptor antagonist LY272015 nor the nitric oxide synthase inhibitor LNNA abolished 5-CT-induced relaxation of the isolated SMV. 5-CT (1 μg kg−1 min−1, sc) also reduced blood pressure over 7 days. These findings suggest that 5-HT directly relaxes the SMV primarily through activation of the 5-HT7 receptor. PMID:25692021

  11. KIR-HLA-A and B alleles of the Bw4 epitope against HIV infection in discordant heterosexual couples in Chaco Argentina

    PubMed Central

    Habegger de Sorrentino, Alicia; Sinchi, Jessica L; Marinic, Karina; López, Rosana; Iliovich, Ernesto

    2013-01-01

    Activating and inhibitory killer immunoglobulin-like receptors (KIR) and their ligands HLA-Bw4 (loci A and B) were studied by way of establishing whether they can contribute to protection against HIV-1 infection in highly exposed and persistently seronegative (HESN) patients. Twenty-three HIV-1 serodiscordant heterosexual couples, 100 HIV-1+ patients and 200 healthy individuals were included in this retrospective case–control study. HLA typing was performed by means of PCR followed by sequence-specific oligonucleotide probe reverse hybridization. KIR3DL1 and KIR3DS1 were studied by PCR sequence-specific primers. The frequency of KIR3DS1(3DS1/3DL1)-Bw4 combination was significantly higher in HESN patients versus the discordant couples (P = 0·0003) and HIV-1+ patients (P = 0·0001). Conversely, the KIR3DL1/KIR3DL1 homozygosity was significantly decreased in HESN patients versus the discordant couples (P = 0·00003), and HIV-1+ patients (P = 0·00066). The frequency of HLA-A*32 and HLA-B*44 was higher in HESN versus their discordant couples (P = 0·009; P = 0·049), and HIV-1+ patients (P = 0·00002; P = 0·0001). This had greater significance in combination with KIR3DS1 (3DS1/3DL1). KIR3DS1(3DS1/3DL1) could have a greater effect on protection against HIV-1 infection in HESN patients when bound to a specific HLA allele, in this case HLA-A*32 and HLA-B*44, both Bw4 alleles. The differences probably arise both in the HLA alleles and in the subtypes of KIR receptors depending on the ethnic group studied. PMID:23789883

  12. A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] pyridine analogue, BW A746C.

    PubMed Central

    Allan, G.; Cambridge, D.; Follenfant, M. J.; Stone, D.; Whiting, M. V.

    1988-01-01

    1. BW A746C is a chemical analogue of the imidazo [4,5b] pyridine, sulmazole (AR-L115 BS). Like sulmazole, BW A746C possesses positive inotropic and vasodilator activity in vivo. 2. In anaesthetized guinea-pigs, dogs and primates, a bolus i.v. injection of BW A746C, (0.001-1.0 mg kg-1) caused a significant, dose-related increase in ventricular dP/dt, and reduction in diastolic blood pressure, with small increases in heart rate. In these species, a significantly higher dose of BW A746C was required to lower blood pressure by 30% from basal, than was needed to raise ventricular dP/dt by 50% over basal. 3. In anaesthetized guinea-pigs and dogs, bolus i.v. injections of sulmazole (0.1-10.0 mg kg-1) caused similar effects to those observed with BW A746C. In these species, however, there was no significant difference between the dose of sulmazole required to lower blood pressure by 30% from basal and that required to raise ventricular dP/dt by 50%. 4. In conscious dogs, i.v. infusion of BW A746C (to a total dose of 0.3 mg kg-1) caused a significant increase in ventricular dP/dt, but no significant change in either diastolic blood pressure or heart rate. 5. In cell-free biochemical assays, there were no clear differences between the observed activities of BW A746C and sulmazole. Both compounds are cyclic nucleotide phosphodiesterase inhibitors with similar potencies and selectivities for the Type III enzyme (IC50 BW A746C = 3.0 +/- 0.5 X 10(-5) M, sulmazole 5.0 +/- 1.9 X 10(-5) M). The compounds had little or no effects on sarcolemmal Na+/K+-ATPase, Ca2+ ATPase or Na+/Ca2+ exchange, and sulmazole, but not BW A746C, had a small, stimulatory effect on myofibrillar ATPase. 6. In anaesthetized guinea-pigs and dogs, BW A746C was significantly more potent as a positive inotrope than sulmazole. In contrast with sulmazole, BW A746C produced its inotropic effects at significantly lower doses than those required to reduce diastolic blood pressure. This was also apparent from the

  13. Effects of melanocortin-4 receptor agonists and antagonists on expression of genes related to reproduction in spotted scat, Scatophagus argus.

    PubMed

    Jiang, Dong-Neng; Li, Jian-Tao; Tao, Ya-Xiong; Chen, Hua-Pu; Deng, Si-Ping; Zhu, Chun-Hua; Li, Guang-Li

    2017-02-14

    Melanocortin-4 receptor (Mc4r) function related to reproduction in fish has not been extensively investigated. Here, we report on gene expression changes by real-time PCR following treatment with Mc4r agonists and antagonists in the spotted scat (Scatophagus argus). Using in vitro incubated hypothalamus, the Mc4r nonselective agonist NDP-MSH ([Nle(4), D-Phe(7)]-α-melanocyte stimulating hormone; 10(-6) M) and selective agonist THIQ (N-[(3R)-1, 2, 3, 4-Tetrahydroisoquinolinium-3-ylcarbonyl]- (1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl) piperidin-1-yl]-2-oxoethylamine; 10(-7) M) significantly increased the expression of gnrh (Gonadotropin releasing hormone), while the Mc4r nonselective antagonist SHU9119 (Ac-Nle-[Asp-His-DPhe/DNal(2')-Arg-Trp-Lys]-NH2; 10(-6) M) and selective antagonist Ipsen 5i (compound 5i synthesized in Ipsen Research Laboratories; 10(-6) M) significantly inhibited gnrh expression after 3 h of incubation. In incubated pituitary tissue, NDP-MSH and THIQ significantly increased the expression of fshb (Follicle-stimulating hormone beta subunit) and lhb (Luteinizing hormone beta subunit), while SHU9119 and Ipsen 5i significantly decreased fshb and lhb expression after 3 h of incubation. During the in vivo experiment, THIQ (1 mg/kg bw) significantly increased gnrh expression in hypothalamic tissue, as well as the fshb and lhb expression in pituitary tissue 12 h after abdominal injection. Furthermore, Ipsen 5i (1 mg/kg bw) significantly inhibited gnrh expression in hypothalamic tissue, as well as fshb and lhb gene expression in pituitary tissue 12 h after abdominal injection. In summary, Mc4r singling appears to stimulate gnrh expression in the hypothalamus, thereby modulating the synthesis of Fsh and Lh in the pituitary. In addition, Mc4r also appears to directly regulate fshb and lhb levels in the pituitary in spotted scat. Our study suggests that Mc4r, through the hypothalamus and pituitary, participates in

  14. Discovery of G Protein-Biased EP2 Receptor Agonists

    PubMed Central

    2016-01-01

    To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors. PMID:26985320

  15. Sports doping: emerging designer and therapeutic β2-agonists.

    PubMed

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

  16. Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity.

    PubMed

    Gurevich, V V; Pals-Rylaarsdam, R; Benovic, J L; Hosey, M M; Onorato, J J

    1997-11-14

    The rapid decrease of a response to a persistent stimulus, often termed desensitization, is a widespread biological phenomenon. Signal transduction by numerous G protein-coupled receptors appears to be terminated by a strikingly uniform two-step mechanism, most extensively characterized for the beta2-adrenergic receptor (beta2AR), m2 muscarinic cholinergic receptor (m2 mAChR), and rhodopsin. The model predicts that activated receptor is initially phosphorylated and then tightly binds an arrestin protein that effectively blocks further G protein interaction. Here we report that complexes of beta2AR-arrestin and m2 mAChR-arrestin have a higher affinity for agonists (but not antagonists) than do receptors not complexed with arrestin. The percentage of phosphorylated beta2AR in this high affinity state in the presence of full agonists varied with different arrestins and was enhanced by selective mutations in arrestins. The percentage of high affinity sites also was proportional to the intrinsic activity of an agonist, and the coefficient of proportionality varies for different arrestin proteins. Certain mutant arrestins can form these high affinity complexes with unphosphorylated receptors. Mutations that enhance formation of the agonist-receptor-arrestin complexes should provide useful tools for manipulating both the efficiency of signaling and rate and specificity of receptor internalization.

  17. Agonistic behavior in food animals: review of research and techniques.

    PubMed

    McGlone, J J

    1986-04-01

    One type of social behavior--agonistic behavior--is commonly observed among food animals. Agonistic behaviors are those behaviors which cause, threaten to cause or seek to reduce physical damage. Agonistic behavior is comprised of threats, aggression and submission. While any one of these divisions of agonistic behavior may be observed alone, they usually are found, in sequence, from the start to the end of an interaction. Food animals may show interspecific or intraspecific agonistic behaviors. Interspecific agonistic behavior has not been extensively studied but it is agriculturally important because farm workers may become injured or killed by aggressive food animals. Types of intraspecific agonistic behavior are: when animals are brought together, intermale fighting, resource defense, inter-gender fighting and aberrant aggression. Common pitfalls in research on agonistic behavior among food animals include too few replicates to detect a biological difference, the assumptions of the analysis are not met, only aggression and not submission or other agonistic behavior components are measured, incomplete description of the behaviors are reported and a complete, quantitive ethogram did not form the basis for selecting behavioral measures.

  18. 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.

  19. D-Cycloserine: Agonist turned antagonist.

    PubMed

    Lanthorn, T H

    1994-10-01

    D-Cycloserine can enhance activation of the NMDA receptor complex and could enhance the induction of long-term potentiation (LTP). In animals and humans, D-cycloserine can enhance performance in learning and memory tasks. This enhancing effect can disappear during repeated administration. The enhancing effects are also lost when higher doses are used, and replaced by behavioral and biochemical effects like those produced by NMDA antagonists. It has been reported that NMDA agonists, applied before or after tetanic stimulation, can block the induction of LTP. This may be the result of feedback inhibition of second messenger pathways stimulated by receptor activation. This may explain the antagonist-like effects of glycine partial agonists like D-cycloserine. In clinical trials of D-cycloserine in age-associated memory impairment (AAMI) and Alzheimer's disease, chronic treatment provided few positive effects on learning and memory. This may be due to inhibition of second messenger pathways following chronic stimulation of the receptor complex.

  20. Inverse agonist properties of atypical antipsychotic drugs.

    PubMed

    Akam, Elizabeth; Strange, Philip G

    2004-06-01

    Mechanisms of action of several atypical antipsychotic drugs have been examined at the D(2) dopamine receptor expressed in CHO cells. The drugs tested were found to exhibit inverse agonist activity at the D(2) dopamine receptor based on their effects to potentiate forskolin-stimulated cyclic AMP (cAMP) accumulation. Each of the antipsychotic drugs tested (clozapine, olanzapine, quetiapine and risperidone) increased cAMP accumulation to the same extent. The increase in cAMP was also similar to that seen with typical antipsychotic drugs. Inverse agonism at the D(2) dopamine receptor seems, therefore, to be a property common to all classes of antipsychotic drugs. The effect of sodium ions on the binding of the drugs to the receptor was also assessed. Each of the atypical antipsychotic drugs tested here bound with higher affinity in the absence of sodium ions. Previous studies have shown that some antipsychotic drugs are insensitive to sodium ions and some bind with higher affinity in the presence of sodium ions. Given that all of these antipsychotic drugs are inverse agonists, it may be concluded that this sodium ion sensitivity is unrelated to mechanisms of inverse agonism.

  1. Fates of endocytosed somatostatin sst2 receptors and associated agonists.

    PubMed Central

    Koenig, J A; Kaur, R; Dodgeon, I; Edwardson, J M; Humphrey, P P

    1998-01-01

    Somatostatin agonists are rapidly and efficiently internalized with the somatostatin sst2 receptor. The fate of internalized agonists and receptors is of critical importance because the rate of ligand recycling back to the cell surface can limit the amount of radioligand accumulated inside the cells, whereas receptor recycling might be of vital importance in providing the cell surface with dephosphorylated, resensitized receptors. Furthermore the accumulation of radioisotope-conjugated somatostatin agonists inside cancer cells resulting from receptor-mediated internalization has been used as a treatment for cancers that overexpress somatostatin receptors. In the present study, radio-iodinated agonists at the sst2 somatostatin receptor were employed to allow quantitative analysis of the fate of endocytosed agonist. After endocytosis, recycling back to the cell surface was the main pathway for both 125I-labelled somatostatin-14 (SRIF-14) and the more stable agonist 125I-labelled cyclo(N-Me-Ala-Tyr-d-Trp-Lys-Abu-Phe) (BIM-23027; Abu stands for aminobutyric acid), accounting for 75-85% of internalized ligand when re-endocytosis of radioligand was prevented. We have shown that there is a dynamic cycling of both somatostatin agonist ligands and receptors between the cell surface and internal compartments both during agonist treatment and after surface-bound agonist has been removed, unless steps are taken to prevent the re-activation of receptors by recycled agonist. Internalization leads to increased degradation of 125I-labelled SRIF-14 but not 125I-labelled BIM-23027. The concentration of recycled agonist accumulating in the extracellular medium was sufficient to re-activate the receptor, as measured both by the inhibition of forskolin-stimulated adenylate cyclase and the recovery of surface receptor number after internalization. PMID:9820803

  2. Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration

    PubMed Central

    Chakrabarti, Mrinmay; Haque, Azizul; Banik, Naren L.; Nagarkatti, Prakash; Nagarkatti, Mitzi; Ray, Swapan K.

    2014-01-01

    Recent results from laboratory investigations and clinical trials indicate important roles for estrogen receptor (ER) agonists in protecting the central nervous system (CNS) from noxious consequences of neuroinflammation and neurodegeneration. Neurodegenerative processes in several CNS disorders including spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) are associated with activation of microglia and astrocytes, which drive the resident neuroinflammatory response. During neurodegenerative processes, activated microglia and astrocytes cause deleterious effects on surrounding neurons. The inhibitory activity of ER agonists on microglia activation might be a beneficial therapeutic option for delaying the onset or progression of neurodegenerative injuries and diseases. Recent studies suggest that ER agonists can provide neuroprotection by modulation of cell survival mechanisms, synaptic reorganization, regenerative responses to axonal injury, and neurogenesis process. The anti-inflammatory and neuroprotective actions of ER agonists are mediated mainly via two ERs known as ERα and ERβ. Although some studies have suggested that ER agonists may be deleterious to some neuronal populations, the potential clinical benefits of ER agonists for augmenting cognitive function may triumph over the associated side effects. Also, understanding the modulatory activities of ER agonists on inflammatory pathways will possibly lead to the development of selective anti-inflammatory molecules with neuroprotective roles in different CNS disorders such as SCI, MS, PD, and AD in humans. Future studies should be concentrated on finding the most plausible molecular pathways for enhancing protective functions of ER agonists in treating neuroinflammatory and neurodegenerative injuries and diseases in the CNS. PMID:25245209

  3. 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...

  4. 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…

  5. A quasi-classical trajectory study of the Cl + H2 (D2) reaction on a new BW3 potential energy surface

    NASA Astrophysics Data System (ADS)

    Shu-Bao, Dong; Er-Yin, Feng; Wu-Ying, Huang; Zhi-Feng, Cui

    2005-01-01

    Molecular reaction dynamics of Cl + H2 (D2) has been studied on the latest analytical potential energy surface called BW3 using the Monte Carlo quasi-classical trajectory method. Excitation functions, differential cross sections and angular distributions of HCl and DCl products have been calculated. The excitation functions of the Cl (2P3/2) + n-H2 and Cl(2P3/2) + n-D2 reactions are also studied. The results are compared with those of quasi-classical trajectory [M. Alagia et al.: Phys. Chem. Chem. Phys. 2 (2000); F. J. Aoiz et al.: J. Phys. Chem. 100 (1996)], quantum mechanical (QM) calculations [F. J. Aoiz et al.:J. Chem. Phys. 115 (2001)] and experimental data [S. H. Lee et al.: J. Chem. Phys. 110 (1999); F. Dong et al.: J. Chem. Phys. 115 (2001)]. Discussions are given to some new results.

  6. Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia

    PubMed Central

    Zhang, Yonghua; Kimelberg, Harold K.

    2005-01-01

    Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top killers worldwide, and intensive studies have been performed to reduce neural cell death after cerebral ischemia. Alpha 2-adrenergic agonists have been shown to improve the histomorphological and neurological outcome after cerebral ischemic injury when administered during ischemia, and recent studies have provided considerable evidence that alpha 2-adrenergic agonists can protect the brain from ischemia/reperfusion injury. Thus, alpha 2-adrenergic agonists are promising potential drugs in preventing cerebral ischemic injury, but the mechanisms by which alpha 2-adrenergic agonists exert their neuroprotective effect are unclear. Activation of both the alpha 2-adrenergic receptor and imidazoline receptor may be involved. This mini review examines the recent progress in alpha 2-adrenergic agonists - induced neuroprotection and its proposed mechanisms in cerebral ischemic injury. PMID:18369397

  7. Effects of energy intake on type 1 plasminogen activator inhibitor levels in glomeruli of lupus-prone B/W mice.

    PubMed Central

    Troyer, D. A.; Chandrasekar, B.; Thinnes, T.; Stone, A.; Loskutoff, D. J.; Fernandes, G.

    1995-01-01

    Calorie restriction (CR) and/or reduced energy intake ameliorates the progression of autoimmune renal disease in (NZB x NZW)F1 (B/W) female mice and increases life span. Like other forms of glomerulonephritis, the lupus-like kidney disease observed in these animals is frequently accompanied by glomerular deposition of fibrin and increased accumulation of mesangial matrix. Because alterations in plasminogen activator inhibitor type 1 (PAI-1) expression or function may be involved in both fibrin deposition and accumulation of extracellular matrix, we have studied the effects of CR on the expression of PAI-1 in kidneys from female B/W mice fed either ad libitum or on a 40% CR diet. By immunohistochemistry and immunoblotting, we found that the glomerular levels of PAI-1 antigen were highest in older ad lib fed animals with more advanced glomerular disease. Increased levels of PAI-1 protein were paralleled by increased levels of PAI-1 mRNA in total RNA extracted from renal cortex and in diseased glomeruli as detected by in situ hybridization. CR diminished the accumulation of PAI-1 protein and reduced the expression of PAI-1 mRNA. Thus, glomeruli from animals fed ad lib showed much greater deposition of PAI-1 protein, increased expression of PAI-1 mRNA, and more severe histological abnormalities than animals on a CR diet. The differences between CR and ad lib animals were more pronounced in animals studied at 9 to 10 months versus those at 3 to 4 months of age. These observations indicate that the ameliorating effects of CR include diminished PAI-1 gene expression and decreased localization of PAI-1 in glomeruli. Images Figure 2 Figure 3 Figure 4 PMID:7856720

  8. KIR2DL3 and the KIR ligand groups HLA-A-Bw4 and HLA-C2 predict the outcome of hepatitis B virus infection.

    PubMed

    Di Bona, Danilo; Aiello, Anna; Colomba, Claudia; Bilancia, Massimo; Accardi, Giulia; Rubino, Raffaella; Giannitrapani, Lidia; Tuttolomondo, Antonino; Cascio, Antonio; Caiaffa, Maria Filomena; Rizzo, Sergio; Di Lorenzo, Gabriele; Candore, Giuseppina; Macchia, Luigi; Montalto, Giuseppe; Caruso, Calogero

    2017-02-17

    Killer immunoglobulin-like receptors (KIRs) regulate the activation of Natural Killer cells through their interaction with human leukocyte antigens (HLA). KIR and HLA loci are highly polymorphic and certain HLA-KIR combinations have been found to protect against viral infections. In this study we analyzed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty-seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection, and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA-A-Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P< 0.001), and HC (10%) (crude OR,12.38; P< 0.001). Similar results were obtained for the HLA-C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P< 0.10), and HC (60%) (crude OR, 3.56; P< 0.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR,0.10; P< 0.05). These results suggest a detrimental role of HLA-A-Bw4 and HLA-C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%), and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection. This article is protected by copyright. All rights reserved.

  9. Association of KIR3DL1/S1 and HLA-Bw4 with CD4 T cell counts in HIV-infected Mexican mestizos.

    PubMed

    Hernández-Ramírez, Daniel; Esparza-Pérez, Mario A; Ramirez-Garcialuna, José L; Arguello, J Rafael; Mandeville, Peter B; Noyola, Daniel E; García-Sepúlveda, Christian A

    2015-08-01

    Certain genotypic combinations of killer-cell immunoglobulin-like receptors (KIR) and human leukocyte antigens (HLA) have been associated with favourable outcomes after exposure to human immunodeficiency virus in Caucasoid and African populations. Human immunodeficiency virus (HIV) infection is characterized by a rapid exhaustion of CD4 cells, which results in impaired cellular immunity. During this early phase of infection, it is thought that the natural killer (NK) cells represent the main effector arm of the host immune response to HIV. This study investigates whether KIR and HLA factors are associated to CD4 T cell numbers after HIV infection in Mexican mestizos as assessed at the time of initial medical evaluation and subsequent clinical follow-up. KIR and HLA-B gene carrier frequency differences were compared between groups of patients stratified by CD4 T cell numbers as assessed during their first medical evaluation (a point in time at which all patients were anti-retroviral therapy naïve). In addition, the influence that these genetic factors have on averaged historical CD4 cell counts in patients subjected to follow-up (mostly therapy-experienced) was also evaluated. Our results suggest a protective role for the HLA-Bw4 and KIR3D + Bw4 combination in both therapy-naïve and therapy-experienced patients. This report furthers our understanding on the way that immune genes modulate HIV disease progression in less-studied human populations such as the Mexican mestizos with a special focus on CD4 T cell number and behaviour.

  10. Quantifying agonist activity at G protein-coupled receptors.

    PubMed

    Ehlert, Frederick J; Suga, Hinako; Griffin, Michael T

    2011-12-26

    When an agonist activates a population of G protein-coupled receptors (GPCRs), it elicits a signaling pathway that culminates in the response of the cell or tissue. This process can be analyzed at the level of a single receptor, a population of receptors, or a downstream response. Here we describe how to analyze the downstream response to obtain an estimate of the agonist affinity constant for the active state of single receptors. Receptors behave as quantal switches that alternate between active and inactive states (Figure 1). The active state interacts with specific G proteins or other signaling partners. In the absence of ligands, the inactive state predominates. The binding of agonist increases the probability that the receptor will switch into the active state because its affinity constant for the active state (K(b)) is much greater than that for the inactive state (K(a)). The summation of the random outputs of all of the receptors in the population yields a constant level of receptor activation in time. The reciprocal of the concentration of agonist eliciting half-maximal receptor activation is equivalent to the observed affinity constant (K(obs)), and the fraction of agonist-receptor complexes in the active state is defined as efficacy (ε) (Figure 2). Methods for analyzing the downstream responses of GPCRs have been developed that enable the estimation of the K(obs) and relative efficacy of an agonist. In this report, we show how to modify this analysis to estimate the agonist K(b) value relative to that of another agonist. For assays that exhibit constitutive activity, we show how to estimate K(b) in absolute units of M(-1). Our method of analyzing agonist concentration-response curves consists of global nonlinear regression using the operational model. We describe a procedure using the software application, Prism (GraphPad Software, Inc., San Diego, CA). The analysis yields an estimate of the product of K(obs) and a parameter proportional to efficacy (

  11. Agonistic behavior in males and females: effects of an estrogen receptor beta agonist in gonadectomized and gonadally intact mice

    PubMed Central

    Allen, Amy E. Clipperton; Cragg, Cheryl L.; Wood, Alexis J.; Pfaff, Donald W.; Choleris, Elena

    2010-01-01

    Summary Affiliative and agonistic social interactions are mediated by gonadal hormones. Research with estrogen receptor alpha (ERα) or beta (ERβ) knockout (KO) mice show that long-term inactivation of ERα decreases, while inactivation of ERβ increases, male aggression. Opposite effects were found in female αERKO and βERKO mice. The role of acute activation of ERα or ERβ in the agonistic responses of adult non-KO mice is unknown. We report here the effects of the ERβ selective agonist WAY-200070 on agonistic and social behavior in gonadally intact and gonadectomized (gonadex) male and female CD-1 mice towards a gonadex, same-sex intruder. All 15 min resident-intruder tests were videotaped for comprehensive behavioral analysis. Separate analyses assessed: 1) effects of WAY-200070 on each sex and gonadal condition; 2) differences between sexes, and between gonadally intact and gonadex mice, in untreated animals. Results show that in gonadally intact male and female mice WAY-200070 increased agonistic behaviors such as pushing down and aggressive grooming, while leaving attacks unaffected. In untreated mice, males attacked more than females, and gonadex animals showed less agonistic behavior than same-sex, gonadally intact mice. Overall, our detailed behavioral analysis suggested that in gonadally intact male and female mice, ERβ mediates patterns of agonistic behavior that are not directly involved in attacks. This suggests that specific aspects of aggressive behavior are acutely mediated by ERβ in adult mice. Our results also showed that, in resident-intruder tests, female mice spend as much time in intrasexual agonistic interactions as males, but use agonistic behaviors that involve extremely low levels of direct attacks. This non-attack aggression in females is increased by acute activation of ERβ. Thus, acute activation of ERβ similarly mediates agonistic behavior in adult male and female CD-1 mice. PMID:20129736

  12. BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis

    PubMed Central

    Carino, Adriana; Cipriani, Sabrina; Marchianò, Silvia; Biagioli, Michele; Santorelli, Chiara; Donini, Annibale; Zampella, Angela; Monti, Maria Chiara; Fiorucci, Stefano

    2017-01-01

    Non-alcoholic steatohepatitis (NASH) is a highly prevalent chronic liver disease. Here, we have investigated whether BAR502, a non-bile acid, steroidal dual ligand for FXR and GPBAR1, reverses steato-hepatitis in mice fed a high fat diet (HFD) and fructose. After 9 week, mice on HFD gained ≈30% of b.w (P < 0.01 versus naïve) and were insulin resistant. These overweighting and insulin resistant mice were randomized to receive HFD or HFD in combination with BAR502. After 18 weeks, HFD mice developed NASH like features with severe steato-hepatitis and fibrosis, increased hepatic content of triacylglycerol and cholesterol and expression of SREPB1c, FAS, ApoC2, PPARα and γ, α-SMA, α1 collagen and MCP1 mRNAs. Treatment with BAR502 caused a ≈10% reduction of b.w., increased insulin sensitivity and circulating levels of HDL, while reduced steatosis, inflammatory and fibrosis scores and liver expression of SREPB1c, FAS, PPARγ, CD36 and CYP7A1 mRNA. BAR502 increased the expression of SHP and ABCG5 in the liver and SHP, FGF15 and GLP1 in intestine. BAR502 promoted the browning of epWAT and reduced liver fibrosis induced by CCl4. In summary, BAR502, a dual FXR and GPBAR1 agonist, protects against liver damage caused by HFD by promoting the browning of adipose tissue. PMID:28202906

  13. 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.

  14. Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity

    PubMed Central

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don; Hurd, Alexander; Aicher, Thomas D.; Toogood, Peter L.; Glick, Gary D.; Paulos, Chrystal M.; Zou, Weiping; Carter, Laura L.

    2016-01-01

    ABSTRACT RORγt is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ−/− T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer. PMID:28123897

  15. Twin Peaks (B/W)

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The Twin Peaks are modest-size hills to the southwest of the Mars Pathfinder landing site. They were discovered on the first panoramas taken by the IMP camera on the 4th of July, 1997, and subsequently identified in Viking Orbiter images taken over 20 years ago. The peaks are approximately 30-35 meters (-100 feet) tall. North Twin is approximately 860 meters (2800 feet) from the lander, and South Twin is about a kilometer away (3300 feet). The scene includes bouldery ridges and swales or 'hummocks' of flood debris that range from a few tens of meters away from the lander to the distance of the South Twin Peak. The large rock at the right edge of the scene is nicknamed 'Hippo'. This rock is about a meter (3 feet) across and 25 meters (80 feet) distant.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The IMP was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  16. [Histrelin acetate--the first once yearly LHRH agonist].

    PubMed

    Altarac, Silvio

    2011-01-01

    Long-acting synthetic luteinising hormone-releasing hormone agonists have become the mainstay for androgen-deprivation therapy, because they avoid the physical and psychological discomfort associated with orchidectomy and lack the potential cardiotoxicity associated with estrogens such as diethylstilbestrol. Currently available luteinising hormone-releasing hormone agonist analogues include leuprolide, goserelin, triptorelin, degarelix and buserelin were administered as either intramuscular or subcutaneous depot injections on a 1, 2, 3 or 6 months basis. Histrelin acetate is the first long-acting luteinising hormone-releasing hormone agonist available as a once-yearly subcutaneous implant.

  17. Toll-like receptor agonists in cancer therapy

    PubMed Central

    Adams, Sylvia

    2010-01-01

    Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recent advances in the field and highlights potential opportunities for the clinical development of TLR agonists as single agent immunomodulators, vaccine adjuvants and in combination with conventional cancer therapies. PMID:20563267

  18. Characterization of a novel bivalent morphinan possessing kappa agonist and micro agonist/antagonist properties.

    PubMed

    Mathews, Jennifer L; Peng, Xuemei; Xiong, Wennan; Zhang, Ao; Negus, S Stevens; Neumeyer, John L; Bidlack, Jean M

    2005-11-01

    Previous research has shown that compounds with mixed kappa and mu activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent morphinan that was shown to be a kappa opioid receptor agonist and a mu opioid receptor agonist/antagonist. MCL-145 [bis(N-cyclobutylmethylmorphinan) fumarate] is related to the morphinan cyclorphan and its N-cyclobutylmethyl derivative MCL-101 [3-hydroxy-N-cyclobutylmethyl morphinan S-(+)-mandelate]. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had K(i) values of 0.078 and 0.20 nM for the kappa and mu opioid receptors, respectively, using radioligand binding assays as shown by Neumeyer et al. in 2003. In the guanosine 5'-O -(3-[(35) S]thiotriphosphate) binding assay, MCL-145 produced an E(max) value of 80% for the kappa opioid receptor and 42% for the mu opioid receptor. The EC(50) values obtained for this compound were 4.3 and 3.1 nM for the kappa and mu opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55 degrees C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the mu-selective antagonist beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. MCL-145 also acted as a mu antagonist, as measured by the inhibition of morphine-induced antinociception.

  19. Octopaminergic agonists for the cockroach neuronal octopamine receptor.

    PubMed

    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.

  20. (R)-(-)-10-methyl-11-hydroxyaporphine: a highly selective serotonergic agonist.

    PubMed

    Cannon, J G; Mohan, P; Bojarski, J; Long, J P; Bhatnagar, R K; Leonard, P A; Flynn, J R; Chatterjee, T K

    1988-02-01

    Prior work in these laboratories identified (+/-)-5-hydroxy-6-methyl-2- (di-n-propylamino)tetralin as a dopaminergic agonist prodrug. The ortho methyl hydroxy aromatic substitution pattern in this molecule has now been incorporated into the aporphine ring system to give a congener of the dopaminergic agonist apomorphine in which the position 10 OH group has been replaced by methyl. Preparation of the target compound involved acid-catalyzed rearrangement of the 3-(1-phenyltetrazolyl) ether of morphine and subsequent molecular modification of the product, the 10-(1-phenyltetrazolyl) ether of (R)-(-)-apomorphine. Surprisingly, the target compound elicited no responses in any assays for effects at dopamine receptors, but rather it displayed pharmacological properties consistent with its being a serotonergic agonist with a high degree of selectivity for 5-HT1A receptors similar to the serotonergic agonist 8-hydroxy-2-(di-n-propylamino)tetralin.

  1. 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.

  2. Agonist Replacement for Stimulant Dependence: A Review of Clinical Research

    PubMed Central

    Stoops, William W.; Rush, Craig R.

    2013-01-01

    Stimulant use disorders are an unrelenting public health concern worldwide. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. The present paper reviewed clinical data from human laboratory self-administration studies and clinical trials to determine whether agonist replacement therapy is a viable strategy for managing cocaine and/or amphetamine use disorders. The extant literature suggests that agonist replacement therapy may be effective for managing stimulant use disorders, however, the clinical selection of an agonist replacement medication likely needs to be based on the pharmacological mechanism of the medication and the stimulant abused by patients. Specifically, dopamine releasers appear most effective for reducing cocaine use whereas dopamine reuptake inhibitors appear most effective for reducing amphetamine use. PMID:23574440

  3. 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.

  4. 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

  5. Beta2-agonists and exercise-induced asthma.

    PubMed

    Anderson, Sandra D; Caillaud, Corinne; Brannan, John D

    2006-01-01

    Beta2-agonists taken immediately before exercise provide significant protection against exercise- induced asthma (EIA) in most patients. However, when they are taken daily, there are some negative aspects regarding severity, control, and recovery from EIA. First, there is a significant minority (15-20%) of asthmatics whose EIA is not prevented by beta2-agonists, even when inhaled corticosteroids are used concomitantly. Second, with daily use, there is a decline in duration of the protective effect of long-acting beta2-agonists. Third, if breakthrough EIA occurs, recovery of lung function is slower in response to a beta2-agonist, and additional doses are often required to achieve pre-exercise values. If a person who takes a beta2-agonist daily experiences problems with exercise, then the physician should consider changing the treatment regimen to achieve better control of EIA. These problems likely result from desensitization of the beta2-receptor on the mast cell, which enhances mediator release, and on the bronchial smooth muscle, which enhances the bronchoconstrictor response and delays recovery from EIA. These effects are reversed within 72 h after cessation of a beta2-agonists. The important clinical question is: Are we actually compromising the beneficial effects of beta2-agonists on the prevention and recovery from EIA by prescribing them daily? Patients with EIA need to ensure that their doses of inhaled corticosteroid or other anti-inflammatory therapy are optimized so that, if necessary, a beta2-agonist can be used intermittently as prophylactic medication with greater confidence in the outcome.

  6. [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.

  7. [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.

  8. 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.

  9. Opioid receptor agonists reduce brain edema in stroke.

    PubMed

    Yang, Li; Wang, Hezhen; Shah, Kaushik; Karamyan, Vardan T; Abbruscato, Thomas J

    2011-04-06

    Cerebral edema is a leading cause of mortality in stroke patients. The purpose of this study was to assess a non-selective opioid receptor agonist, biphalin, in decreasing reducing brain edema formation using both in vitro and in vivo models of stroke. For the in situ model of ischemia, hippocampal slices were exposed to oxygen glucose deprivation (OGD) conditions and we observed that hippocampal water content was increased, compared to normoxia. Treatment with the mu agonist, Tyr-D-Ala', N-CH, -Phe4, Glyol-Enkephalin (DAMGO), delta opioid agonists, D-pen(2), D-phe(5) enkephalin (DPDPE), and kappa agonist, U50 488, all significantly decreased brain slice water gain. Interestingly, the non-selective agonist, biphalin, exhibited a statistically significant (P<0.01) greater effect in decreasing water content in OGD-exposed hippocampal slices, compared with mu, delta, and kappa selective opioid agonists. Moreover, biphalin exhibited anti-edematous effects in a dose responsive manner. The non-selective opioid antagonist, naloxone, returned the water content nearly back to original OGD values for all opioid agonist treatments, supporting that these effects were mediated by an opioid receptor pathway. Furthermore, biphalin significantly decreased edema (53%) and infarct (48%) ratios, and neuronal recovery from stroke, compared with the vehicle-treated groups in a 12h permanent middle cerebral artery occlusion (MCAO) model of focal ischemia. Biphalin also significantly decreased the cell volume increase in primary neuronal cells exposed to OGD condition. These data suggest that opioid receptor activation may provide neuroprotection during stroke and further investigations are needed in the development of novel opioid agonist as efficacious treatments for brain ischemia.

  10. Dual Roles of Capsular Extracellular Polymeric Substances in Photocatalytic Inactivation of Escherichia coli: Comparison of E. coli BW25113 and Isogenic Mutants

    PubMed Central

    Huang, Guocheng; Xia, Dehua; Ng, Tsz Wai; Yip, Ho Yin; Li, Guiying; Zhao, Huijun

    2015-01-01

    The dual roles of capsular extracellular polymeric substances (EPS) in the photocatalytic inactivation of bacteria were demonstrated in a TiO2-UVA system, by comparing wild-type Escherichia coli strain BW25113 and isogenic mutants with upregulated and downregulated production of capsular EPS. In a partition system in which direct contact between bacterial cells and TiO2 particles was inhibited, an increase in the amount of EPS was associated with increased bacterial resistance to photocatalytic inactivation. In contrast, when bacterial cells were in direct contact with TiO2 particles, an increase in the amount of capsular EPS decreased cell viability during photocatalytic treatment. Taken together, these results suggest that although capsular EPS can protect bacterial cells by consuming photogenerated reactive species, it also facilitates photocatalytic inactivation of bacteria by promoting the adhesion of TiO2 particles to the cell surface. Fluorescence microscopy and scanning electron microscopy analyses further confirmed that high capsular EPS density led to more TiO2 particles attaching to cells and forming bacterium-TiO2 aggregates. Calculations of interaction energy, represented by extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) potential, suggested that the presence of capsular EPS enhances the attachment of TiO2 particles to bacterial cells via acid-base interactions. Consideration of these mechanisms is critical for understanding bacterium-nanoparticle interactions and the photocatalytic inactivation of bacteria. PMID:26002903

  11. Performance of the extreme ultraviolet high resolution undulator beamline BW3 at Hasylab: First results and time-of-flight spectroscopy

    NASA Astrophysics Data System (ADS)

    Björneholm, O.; Federmann, F.; Larsson, C.; Hahn, U.; Rieck, A.; Kakar, S.; Möller, T.; Beutler, A.; Fössing, F.

    1995-02-01

    The extreme ultraviolet beamline BW3 at Hasylab is a state of the art beamline for the energy range 15-2000 eV consisting of a triple undulator equipped with a modified high-flux SX-700 plane grating monochromator. The first three optical elements of the beamline are made of graphite coated with SiC to withstand the high heat load at the 4.5 GeV storage ring Doris III. Excellent spectral resolution of the order of 104 at the nitrogen K edge at 400 eV is obtained by replacing the elliptical focusing mirror of the original SX-700 design by a spherical mirror with very small tangent errors and with a large focal length in order to suppress spherical aberrations. In the energy range 50-1700 eV a photon flux of 1011-1013/s is obtained in a bandpass of 0.1%. Photoionization and photoemission measurements on atoms, molecules, and clusters making use of time-of-flight techniques demonstrate the excellent performance of the beamline.

  12. Behavioural effects of selective tachykinin agonists in midbrain dopamine regions.

    PubMed

    Stoessl, A J; Szczutkowski, E; Glenn, B; Watson, I

    1991-11-29

    The effects of selective NK-1, NK-2 and NK-3 tachykinin agonists in midbrain dopamine cell containing regions were investigated in the rat. The NK-3 agonist senktide induced locomotion, rearing and sniffing following infusion into the substantia nigra pars compacta, and to a lesser extent in the ventral tegmental area. These behavioural responses were not seen following infusion of the selective NK-1 agonist [Sar9,Met (O2)11]SP or the NK-2 agonist [N1e10]NKA4-10. In contrast, grooming was induced only by the NK-1 agonist administered into the substantia nigra. Yawning, chewing mouth movements and wet dog shakes were all seen following infusion of senktide into the ventral tegmental area. These findings suggest that (i) dopamine-mediated behavioural responses seen following tachykinin administration into the midbrain are dependent upon stimulation of NK-3 tachykinin receptors, (ii) tachykinin-induced grooming is mediated by stimulation of NK-1 receptors and (iii) some of the previously described 5-HT mediated behaviours seen following administration of NK-3 tachykinin agonists are probably generated by stimulation of 5-HT cell bodies in the ventral tegmental area.

  13. Histamine H3-receptor inverse agonists as novel antipsychotics.

    PubMed

    Ito, Chihiro

    2009-06-01

    Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.

  14. 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

  15. 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

  16. Effects of energy restriction and fish oil supplementation on renal guanidino levels and antioxidant defences in aged lupus-prone B/W mice.

    PubMed

    Kim, You Jung; Yokozawa, Takako; Chung, Hae Young

    2005-06-01

    Energy restriction (ER) and dietary fish oil (FO) are known to reduce the severity of glomerulonephritis and increase the lifespan of lupus-prone (NZB x NZW) F1 (B/W) mice. In the present study, mice were fed either ad libitum or energy-restricted (a 40 % lower energy intake than the diet ad libitum), semi-purified diets containing 5 % maize oil or 5 % fish oil supplementation. To estimate the renal damage associated with oxidative stress, the total amounts of reactive oxygen species (ROS), cyclooxygenase-derived ROS and levels of guanidino compounds were measured. Additionally, we assessed the putative action of ER and FO on several key antioxidant enzymes measured in the kidney post-mitochondrial fraction. Results showed that the age-related increase in creatinine level was significantly reduced by ER and FO in old mice. In contrast, arginine and guanidino acetic acid levels showed a decrease with age but were increased by ER and FO. The GSH:GSSG ratio showed a significant decrease with age, whereas ER and FO feeding prevented the decrease. The age-related decrease in antioxidant scavenging superoxide dismutase, catalase and glutathione peroxidase activities were all reversed by ER and FO. The moderately decreased glutathione reductase and glutathione-S-transferase activities with age were significantly increased by ER and FO. Furthermore, the increased total ROS and cyclooxygenase-derived ROS levels were effectively reduced by ER and FO. In conclusion, our data strongly indicate that ER and FO maintain antioxidant status and GSH:GSSG ratio, thereby protecting against renal deterioration from oxidative insults during ageing.

  17. 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

  18. Impact of amino acid and CP restriction from 20 to 140 kg BW on performance and dynamics in empty body protein and lipid deposition of entire male, castrated and female pigs.

    PubMed

    Ruiz-Ascacibar, I; Stoll, P; Kreuzer, M; Boillat, V; Spring, P; Bee, G

    2017-03-01

    Breeding leaner pigs during the last decades may have changed pig's empty body (EB) composition, a key trait for elaborating feeding recommendations. This research aimed to provide new experimental data on changes in the chemical composition of the EB of pigs from 20 to 140 kg BW. In addition, the impact of a reduction in the dietary CP associated with lower lysine, methionine+cystine, threonine and tryptophan levels was determined. In total, 48 males, castrates and females weighing 20 kg BW were allocated either to a control grower-finisher diet formulated according to current Swiss feeding recommendations, or a low CP grower-finisher diet (80% of control). Feed intake was monitored and pigs were weighed weekly. The chemical composition of EB (blood, hairs and hoofs, offals, bile, carcass) was determined at 20, 40, 60, 80, 100, 120 and 140 kg BW on four pigs per gender and diet (eight pigs per gender at 20 kg). The five fractions were weighed and samples were analysed for dry matter, protein, fat and energy. Nutrient deposition rates and N efficiency were calculated by using the 20 kg BW category as reference. Analysis revealed an accurate feed optimisation for the aforementioned essential amino acids (EAA), whereas digestible isoleucine content in the low CP diet was at 70% of the control diet. Despite similar feed intake, daily gain and feed efficiency were impaired (P<0.01) from 20 to 100 kg BW in the low CP compared with the control pigs. In the same growth period, castrates had the greatest feed intake but, together with females, displayed the lowest (P<0.01) feed efficiency. Protein deposition was reduced (P<0.01) by up to 31% with low CP diet and was lower (P<0.01) in castrates and females than males at 100 kg BW. The greatest fat deposition rates were found with low CP diet and castrates. N efficiency improved (P<0.05) by 10% with the low CP diet from 100 to 140 kg. The males displayed the greatest (P<0.05) N efficiency. These findings suggest that the CP

  19. GABA receptor agonists: pharmacological spectrum and therapeutic actions.

    PubMed

    Bartholini, G

    1985-01-01

    From the data discussed in this review it appears that GABA receptor agonists exhibit a variety of actions in the central nervous system, some of which are therapeutically useful (Table V). GABA receptor agonists, by changing the firing rate of the corresponding neurons accelerate noradrenaline turnover without changes in postsynaptic receptor density and diminish serotonin liberation with an up-regulation of 5HT2 receptors. These effects differ from those of tricyclic antidepressants which primarily block monoamine re-uptake and cause down-regulation of beta-adrenergic and 5HT2 receptors. The GABA receptor agonist progabide has been shown to exert an antidepressant action which is indistinguishable from that of imipramine in patients with major affective disorders. The fact that: (a) GABA receptor agonists and tricyclic antidepressants affect noradrenergic and serotonergic transmission differently; and (b) tricyclic antidepressants alter GABA-related parameters challenges the classical monoamine hypothesis of depression and suggests that GABA-mediated mechanisms play a role in mood disorders. Decreases in cellular excitability produced by GABAergic stimulation leads to control of seizures in practically all animal models of epilepsy. GABA receptor agonists have a wide spectrum as they antagonize not only seizures which are dependent on decreased GABA synaptic activity but also convulsant states which are apparently independent of alterations in GABA-mediated events. These results in animals are confirmed in a wide range of human epileptic syndromes. GABA receptor agonists decrease dopamine turnover in the basal ganglia and antagonize neuroleptic-induced increase in dopamine release. On repeated treatment, progabide prevents or reverses the neuroleptic-induced up-regulation of dopamine receptors in the rat striatum and antagonizes the concomitant supersensitivity to dopaminomimetics. Behaviorally, GABA receptor agonists diminish the stereotypies induced by

  20. Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol

    SciTech Connect

    Buck, K.J.; Harris, R.A. )

    1990-05-01

    Mice were made tolerant to and dependent on ethanol by administration of a liquid diet. Gamma-aminobutyric acid (GABA) receptor-dependent uptake of 36Cl- by mouse cortical microsacs was used to study the actions of benzodiazepine (BZ) agonists and inverse agonists. Chronic exposure to ethanol attenuated the ability of a BZ agonist, flunitrazepam, to augment muscimol-stimulated uptake of 36Cl- and enhanced the actions of BZ inverse agonists, Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,4)-benzodiazepine - 3-carboxylate) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), to inhibit GABAA receptor-operated chloride channels. Augmentation of chloride flux by pentobarbital was not reduced by chronic ethanol exposure. Attenuation of flunitrazepam efficacy was transient and returned to control levels within 6 to 24 hr after withdrawal from ethanol, but increased sensitivity to Ro15-4513 was observed as long as 8 days after withdrawal. Chronic exposure to ethanol did not alter (3H)SR 95531 (2-(3'-carbethoxy-2'propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide) binding to low-affinity GABAA receptors or muscimol stimulation of chloride flux; and did not alter (3H)Ro15-4513 or (3H)flunitrazepam binding to central BZ receptors or allosteric modulation of this binding by muscimol (i.e., muscimol-shift). These results suggest that chronic exposure to ethanol reduces coupling between BZ agonist sites and the chloride channel, and may be responsible for the development of cross-tolerance between ethanol and BZ agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.

  1. Intracerebroventricular administration of kappa-agonists induces convulsions in mice.

    PubMed

    Bansinath, M; Ramabadran, K; Turndorf, H; Shukla, V K

    1991-07-01

    Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

  2. 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.

  3. Novel nonsecosteroidal VDR agonists with phenyl-pyrrolyl pentane skeleton.

    PubMed

    Shen, Wei; Xue, Jingwei; Zhao, Zekai; Zhang, Can

    2013-11-01

    In order to find the vitamin D receptor (VDR) ligand whose VDR agonistic activity is separated from the calcemic activity sufficiently, novel nonsecosteroidal analogs with phenyl-pyrrolyl pentane skeleton were synthesized and evaluated for the VDR binding affinity, antiproliferative activity in vitro and serum calcium raising ability in vivo (tacalcitol used as control). Among them, several compounds showed varying degrees of VDR agonistic and growth inhibition activities of the tested cell lines. The most effective compound 2g (EC₅₀: 1.06 nM) exhibited stronger VDR agonistic activity than tacalcitol (EC₅₀: 7.05 nM), inhibited the proliferations of HaCaT and MCF-7 cells with IC₅₀ of 2.06 μM and 0.307 μM (tacalcitol: 2.07 μM and 0.057 μM) and showed no significant effect on serum calcium.

  4. Compulsive eating and weight gain related to dopamine agonist use.

    PubMed

    Nirenberg, Melissa J; Waters, Cheryl

    2006-04-01

    Dopamine agonists have been implicated in causing compulsive behaviors in patients with Parkinson's disease (PD). These have included gambling, hypersexuality, hobbyism, and other repetitive, purposeless behaviors ("punding"). In this report, we describe 7 patients in whom compulsive eating developed in the context of pramipexole use. All of the affected patients had significant, undesired weight gain; 4 had other comorbid compulsive behaviors. In the 5 patients who lowered the dose of pramipexole or discontinued dopamine agonist treatment, the behavior remitted and no further weight gain occurred. Physicians should be aware that compulsive eating resulting in significant weight gain may occur in PD as a side-effect of dopamine agonist medications such as pramipexole. Given the known risks of the associated weight gain and obesity, further investigation is warranted.

  5. Captive female gorilla agonistic relationships with clumped defendable food resources.

    PubMed

    Scott, Jennifer; Lockard, Joan S

    2006-07-01

    Minimal feeding competition among female mountain gorillas (Gorilla gorilla beringei) has resulted in egalitarian social relationships with poorly defined agonistic dominance hierarchies. Thus, gorillas are generally viewed as non-competitive egalitarian folivores that have had little need to develop effective competitive strategies to access food resources. However, this generalization is inconsistent with more recent research indicating that most gorillas are frugivorous, feeding on patchily distributed food resources. The current study at Howletts Wild Animal Park, Kent, England, explores the effects of clumped and defendable foods on female gorilla agonistic relationships among three groups of western lowland gorillas (G. g. gorilla), conditions that are predicted to lead to well-differentiated agonistic dominance hierarchies among female primates. The Howletts gorillas foraged all day on low-energy/-nutrient, high-fiber foods widely distributed around their enclosure by the keepers. However, they also had periodic access to high-energy foods (e.g., nuts, raisins, strawberries, etc.) that the keepers would spread in a clumped and defendable patch. Frequencies of agonistic and submissive behaviors between females and proximity data were gathered. High-status females were found to monopolize the food patch and kept the low-status females at bay with cough-grunt threat vocalizations or by chasing them away. Agonistic interactions were initiated mostly by females of high status; these were directed towards females of low status and were generally not reciprocal. In addition, females of low status engaged in submissive behaviors the most often, which they directed primarily at females of high status, especially in response to aggression by the latter. Agonistic interactions between high- and low-status females had decided outcomes more often than not, with low-status females the losers. Competition over highly desirable foods distributed in defendable clumps at

  6. Supernova 1998bw In ESO 184-G82. Repr. from Central Bureau for Astronomical Telegrams, no. 6969,10 Jul. 1998

    NASA Technical Reports Server (NTRS)

    Kay, L. E.; Halpern, Jules P.; Leighly, K. M.; Heathcote, S.; Magalhaes, A. M.; Oliversen, Ronald (Technical Monitor)

    2001-01-01

    Over the wavelength range 390-750 nm, we measure intrinsic linear polarization of 0.53 +/- 0.08 percent at position angle 49 +/- 3 deg, after correcting for Galactic interstellar polarization using the star HD 184100, which has polarization of 0.75 +/- 0.01 percent at p.a. 176.5 +/- 2.5 deg. This measured interstellar polarization is consistent with the Galactic extinction in this direction, estimated to be E(B-V) = 0.059 from IRAS maps, or E(B-V) = 0.079 from 21-cm H I. Interstellar polarization in the host galaxy ESO 184-G82 is expected to be negligible based on the relative absence of Na I D absorption at z = 0.00841 +/- 0.00005, the redshift of the environment of the supernova from narrow H II region emission lines in its spectrum. Polarization appears highest in between emission features in the total flux spectrum, which strengthens the interpretation of the polarization as intrinsic to the supernova. This modest polarization is less than that of some type-II supernovae, but greater than that of type-Ia supernovae, which are generally unpolarized. This supports the interpretation of SN 1998bw, a peculiar type-Ic supernova, as a core-collapse event in which the observed polarization is due to moderate asymmetry in either the photosphere of the ejecta or an overlying scattering envelope. However, this result does not strongly constrain arguments about whether some supernovae emit gamma-ray bursts, since such emission may come from a mildly relativistic shock associated with the radio emission and above the optical photosphere, without any requirements on beaming or orientation." A. V. Filippenko, University of California at Berkeley, comments on the total flux spectrum obtained above: "The spectrum most closely resembles those of the peculiar SN 1997ef, but perhaps evolving more slowly. It is not typical of type-Ic supernovae; indeed, the spectrum does not match any of the known spectral classes, but perhaps 'peculiar type Ic' is the best choice at this time

  7. Importance of dam BW change and calf birth weight in double-muscled Belgian Blue cattle and its relationship with parity and calving interval.

    PubMed

    Fiems, L O; Ampe, B

    2015-01-01

    Factors affecting calving interval (CI) in double-muscled Belgian Blue (DMBB) beef cows were investigated with regard to the BW yield (BWY) of the cow-calf pair, using 834 CI records from 386 females with parities 1 to 6. The effect of parity and CI on BWY was also studied. Cow-calf pair BWY was defined as calf birth weight plus dam BWY per CI. CI (mean±s.e.: 404±1.9 days) was affected by parity, calving season, suckling and calf birth weight/dam weight. Primiparous cows had a shorter CI than cows with three or more calvings (P<0.05), with an intermediate CI for second-calf cows. Spring calvings resulted in a shorter CI than summer and autumn calvings, with intermediate values for winter calvings. Suckling dams had longer CIs than non-suckling dams. There were interactions (P<0.05) between calving season and suckling, and between calving season and mating system. Shortest CIs were observed for spring calvings in case of non-suckling and for summer calvings in case of suckling. Longest CIs were observed for autumn calvings in case of natural service (NS) and for winter calvings in case of artificial insemination (AI). Calf birth weight/dam weight of 6% to 10% resulted in shorter CI than a ratio of <6% (P<0.05). Body condition and mating system (NS v. AI) did not affect CI. Daily cow-calf pair BWY was affected by parity (P<0.001) and CI (P=0.013), with a tendency for an interaction (P=0.094). Daily cow-calf pair BWY did not differ for CIs of <12 to 16 months in primiparous cows and was lowest for a CI of 13 to 15 months in second-calf cows, whereas the effect of CI was more variable in older cows. Dam contribution to cow-calf pair BWY was larger than calf birth weight in first- and second-calf cows, and increased with increasing CI. Dam contribution to cow-calf pair BWY was smaller than calf birth weight in older cows, varying from 0.2 to 1.0 depending on CI. A short CI is advised for DMBB cows because of a larger BWY and more efficient nutrient utilisation.

  8. Switching cannabinoid response from CB(2) agonists to FAAH inhibitors.

    PubMed

    Tourteau, Aurélien; Leleu-Chavain, Natascha; Body-Malapel, Mathilde; Andrzejak, Virginie; Barczyk, Amélie; Djouina, Madjid; Rigo, Benoit; Desreumaux, Pierre; Chavatte, Philippe; Millet, Régis

    2014-03-01

    A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.

  9. Partial agonistic action of endomorphins in the mouse spinal cord.

    PubMed

    Mizoguchi, H; Wu, H E; Narita, M

    2001-09-07

    The partial agonistic properties of endogenous mu-opioid peptides endomorphin-1 and endomorphin-2 for G-protein activation were determined in the mouse spinal cord, monitoring the increases in guanosine-5'-o-(3-[35S]thio)triphosphate binding. The G-protein activation induced by endogenous opioid peptide beta-endorphin in the spinal cord was significantly, but partially, attenuated by co-incubation with endomorphin-1 or endomorphin-2. The data indicates that endomorphin-1 and endomorphin-2 are endogenous partial agonists for mu-opioid receptor in the mouse spinal cord.

  10. Synthesis and activity of small molecule GPR40 agonists.

    PubMed

    Garrido, Dulce M; Corbett, David F; Dwornik, Kate A; Goetz, Aaron S; Littleton, Thomas R; McKeown, Steve C; Mills, Wendy Y; Smalley, Terrence L; Briscoe, Celia P; Peat, Andrew J

    2006-04-01

    The first report on the identification and structure-activity relationships of a novel series of GPR40 agonists based on a 3-(4-{[N-alkyl]amino}phenyl)propanoic acid template is described. Structural modifications to the original screening hit yielded compounds with a 100-fold increase in potency at the human GPR40 receptor and pEC(50)s in the low nanomolar range. The carboxylic acid moiety is not critical for activity but typically elicits an agonistic response higher than those observed with carboxamide replacements. These compounds may prove useful in unraveling the therapeutic potential of this receptor for the treatment of Type 2 diabetes.

  11. 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.

  12. 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…

  13. Once-weekly glucagon-like peptide 1 receptor agonists.

    PubMed

    Kalra, Sanjay; Gupta, Yashdeep

    2015-07-01

    The once-weekly glucagon-like peptide 1 receptor agonists (QW GLP1RA) represent a major advancement in diabetes pharmaco-therapeutics. This review describes the basic, clinical, and comparative pharmacology of this novel class of drugs. It highlights the clinical placement and posology of these drugs.

  14. Use of ß-adrenergic agonists in hybrid catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

  15. Dopamine agonists in prevention of ovarian hyperstimulation syndrome.

    PubMed

    Kasum, Miro; Vrčić, Hrvoje; Stanić, Patrik; Ježek, Davor; Orešković, Slavko; Beketić-Orešković, Lidija; Pekez, Marijeta

    2014-01-01

    The aim of this review is to analyze the efficacy of different dopamine agonists in the prevention of ovarian hyperstimulation syndrome (OHSS). Cabergoline, quinagolide and bromocriptine are the most common dopamine agonists used. There are wide clinical variations among the trials in the starting time (from the day of human chorionic gonadotrophin (hCG) to the day following oocyte retrieval); the duration of the treatment (4-21 days), the dose of cabergoline (0.5 mg or 0.25 mg orally) and in the regimens used. At present, the best known effective regimen is 0.5 mg of cabergoline for 8 days or rectal bromocriptine at a daily dose of 2.5 mg for 16 days. Dopamine agonists have shown significant evidences of their efficacy in the prevention of moderate and early-onset OHSS (9.41%), compared with a placebo (21.45%), which cannot be confirmed for the treatment of late OHSS. It would be advisable to start with the treatment on the day of hCG injection or preferably a few hours earlier. The use of dopamine agonists should be indicated in patients at high risk of OHSS, as well as in patients with a history of previous OHSS even without evident signs of the syndrome.

  16. [Alpha 2-adrenoceptor agonists for the treatment of chronic pain].

    PubMed

    Kulka, P J

    1996-04-25

    The antinociceptive effect of alpha(2)-adrenoceptor agonists is mediated by activation of descending inhibiting noradrenergic systems, which modulates 'wide-dynamic-range' neurones. Furthermore, they inhibit the liberation of substance P and endorphines and activate serotoninergic neurones. Despite this variety of antinociceptive actions, there is still little experience with alpha(2)-adrenoceptor agonists as therapeutic agents for use in chronic pain syndromes. Studies in animals and patients have shown that the transdermal, epidural and intravenous administration of the alpha(2)-adrenoceptor agonist clonidine reduces pain intensity in neuropathic pain syndromes for periods varying from some hours up to 1 month. Patients suffering from lancinating or sharp pain respond best to this therapy. Topically applied clonidine (200-300 microg) relieves hyperalgesia in sympathetically maintained pain. Epidural administration of 300 microg clonidine dissolved in 5 ml NaCl 0.9 % has also been shown to be effective. In patients suffering from cancer pain tolerant to opioids, pain control has proved possible again with combinations of opioids and clonidine. In isolated cases clonidine has been administered epidurally at a dose of 1500 microg/day for almost 5 months without evidence for any histotoxic property of clonidine. Side effects often observed during administration of alpha(2)-adrenoceptor agonists are dry mouth, sedation, hypotension and bradycardia. Therapeutic interventions are usually not required.

  17. Role of nicotine receptor partial agonists in tobacco cessation

    PubMed Central

    Maity, Nivedita; Chand, Prabhat; Murthy, Pratima

    2014-01-01

    One in three adults in India uses tobacco, a highly addictive substance in one or other form. In addition to prevention of tobacco use, offering evidence-based cessation services to dependent tobacco users constitutes an important approach in addressing this serious public health problem. A combination of behavioral methods and pharmacotherapy has shown the most optimal results in tobacco dependence treatment. Among currently available pharmacological agents, drugs that preferentially act on the α4 β2-nicotinic acetyl choline receptor like varenicline and cytisine appear to have relatively better cessation outcomes. These drugs are in general well tolerated and have minimal drug interactions. The odds of quitting tobacco use are at the very least doubled with the use of partial agonists compared with placebo and the outcomes are also superior when compared to nicotine replacement therapy and bupropion. The poor availability of partial agonists and specifically the cost of varenicline, as well as the lack of safety data for cytisine has limited their use world over, particularly in developing countries. Evidence for the benefit of partial agonists is more robust for smoking rather than smokeless forms of tobacco. Although more studies are needed to demonstrate their effectiveness in different populations of tobacco users, present literature supports the use of partial agonists in addition to behavioral methods for optimal outcome in tobacco dependence. PMID:24574554

  18. Dopamine receptor agonists for protection and repair in Parkinson's disease.

    PubMed

    Ferrari-Toninelli, Giulia; Bonini, Sara A; Cenini, Giovanna; Maccarinelli, Giuseppina; Grilli, Mariagrazia; Uberti, Daniela; Memo, Maurizio

    2008-01-01

    Dopamine agonists have been usually used as adjunctive therapy for the cure of Parkinson's disease. It is generally believed that treatment with these drugs is symptomatic rather than curative and it does not stop or delay the progression of neuronal degeneration. However, several dopamine agonists of the D2-receptor family have recently been shown to possess neuroprotective properties in different in vitro and in vivo experimental Parkinson's disease models. Here we summarize some recent molecular evidences underlining the wide pharmacological spectrum of dopamine agonists currently used for treating Parkinson's disease patients. In particular, the mechanism of action of different dopamine agonists does not always appear to be restricted to the stimulation of selective dopamine receptor subtypes since at least some of these drugs are endowed with antioxidant, antiapoptotic or neurotrophic properties. These neuroprotective activities are molecule-specific and may contribute to the clinical efficacy of these drugs for the treatment of chronic and progressive neurodegenerative diseases in which oxidative injury and/or protein misfolding and aggregation exert a primary role.

  19. Amylin and Amylin Agonists for Treating Psychiatric Diseases and Disorders

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Methods and compositions for treating psychiatric diseases and disorders are disclosed. The methods provided generally involve the administration of an amylin or an amylin agonist to a subject in order to treat psychiatric diseases and disorders, and conditions associated with psychiatric diseases a...

  20. Melatonin receptor agonists: new options for insomnia and depression treatment.

    PubMed

    Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco

    2011-12-01

    The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT₁ or MT₂ subtype-selective compounds are available up to now. Administration of the MT₂-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT₂ receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT₁ or MT₂ receptors are expected in coming years.

  1. Identification of raloxifene as a novel CB2 inverse agonist.

    PubMed

    Kumar, Pritesh; Song, Zhao-Hui

    2013-05-24

    The purpose of the current study was to apply a high throughput assay to systematically screen a library of food and drug administration (FDA)-approved drugs as potential ligands for the cannabinoid receptor 2 (CB2). A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring changes in intracellular cAMP levels was validated and found to be suitable for testing ligands that may act on CB2. Among the 640 FDA-approved drugs screened, raloxifene, a drug used to treat/prevent post-menopausal osteoporosis, was identified for the first time to be a novel CB2 inverse agonist. Our results demonstrated that by acting on CB2, raloxifene enhances forskolin-stimulated cAMP accumulation in a concentration-dependant manner. Furthermore, our data showed that raloxifene competes concentration-dependently for specific [(3)H]CP-55,940 binding to CB2. In addition, raloxifene pretreatment caused a rightward shift of the concentration-response curves of the cannabinoid agonists CP-55,940, HU-210, and WIN55,212-2. Raloxifene antagonism is most likely competitive in nature, as these rightward shifts were parallel and were not associated with any changes in the efficacy of cannabinoid agonists on CB2. Our discovery that raloxfiene is an inverse agonist for CB2 suggests that it might be possible to repurpose this FDA-approved drug for novel therapeutic indications for which CB2 is a target. Furthermore, identifying raloxifene as a CB2 inverse agonist also provides important novel mechanisms of actions to explain the known therapeutic effects of raloxifene.

  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. Effects of an intrathecally administered benzodiazepine receptor agonist, antagonist and inverse agonist on morphine-induced inhibition of a spinal nociceptive reflex.

    PubMed Central

    Moreau, J. L.; Pieri, L.

    1988-01-01

    1. The effects of an intrathecally administered benzodiazepine receptor (BZR) agonist (midazolam, up to 50 micrograms), antagonist (flumazenil, Ro 15-1788, 5 micrograms) and inverse agonist (Ro 19-4603, 15 micrograms) on nociception and on morphine-induced antinociception were studied in rats. 2. By themselves, none of these compounds significantly altered pain threshold. 3. The BZR agonist midazolam enhanced the morphine-induced antinociceptive effect whereas the antagonist flumazenil did not alter it. In contrast, the BZR inverse agonist Ro 19-4603 decreased the morphine-induced antinociceptive effect. 4. Naloxone (1 mg kg-1 i.p.) completely reversed all these effects. 5. These results demonstrate that BZR agonists and inverse agonists are able to affect, by allosteric up- or down-modulation of gamma-aminobutyric acidA (GABAA)-receptors, the transmission of nociceptive information at the spinal cord level, when this transmission is depressed by mu-opioid receptor activation. PMID:2898960

  4. 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.

  5. Agonist-antagonist combinations in opioid dependence: a translational approach

    PubMed Central

    Mannelli, P.

    2011-01-01

    Summary The potential therapeutic benefits of co-administering opiate agonist and antagonist agents remain largely to be investigated. This paper focuses on the mechanisms of very low doses of naltrexone that help modulate the effects of methadone withdrawal and review pharmacological properties of the buprenorphine/naltrexone combination that support its clinical investigation. The bench-to-bedside development of the very low dose naltrexone treatment can serve as a translational paradigm to investigate and treat drug addiction. Further research on putative mechanisms elicited by the use of opioid agonist-antagonist combinations may lead to effective pharmacological alternatives to the gold standard methadone treatment, also useful for the management of the abuse of non opioid drugs and alcohol. PMID:22448305

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

    PubMed

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

    2013-10-01

    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.

  7. Integrating costimulatory agonists to optimize immune-based cancer therapies.

    PubMed

    Pardee, Angela D; Wesa, Amy K; Storkus, Walter J

    2009-03-01

    While immunotherapy for cancer has become increasingly popular, clinical benefits for such approaches remain limited. This is likely due to tumor-associated immune suppression, particularly in the advanced-disease setting. Thus, a major goal of novel immunotherapeutic design has become the coordinate reversal of existing immune dysfunction and promotion of specific tumoricidal T-cell function. Costimulatory members of the TNF-receptor family are important regulators of T-cell-mediated immunity. Notably, agonist ligation of these receptors restores potent antitumor immunity in the tumor-bearing host. Current Phase I/II evaluation of TNF-receptor agonists as single-modality therapies will illuminate their safety, mechanism(s) of action, and best use in prospective combinational immunotherapy approaches capable of yielding superior benefits to cancer patients.

  8. Integrating costimulatory agonists to optimize immune-based cancer therapies

    PubMed Central

    Pardee, Angela D; Wesa, Amy K

    2009-01-01

    While immunotherapy for cancer has become increasingly popular, clinical benefits for such approaches remain limited. This is likely due to tumor-associated immune suppression, particularly in the advanced-disease setting. Thus, a major goal of novel immunotherapeutic design has become the coordinate reversal of existing immune dysfunction and promotion of specific tumoricidal T-cell function. Costimulatory members of the TNF-receptor family are important regulators of T-cell-mediated immunity. Notably, agonist ligation of these receptors restores potent antitumor immunity in the tumor-bearing host. Current Phase I/II evaluation of TNF-receptor agonists as single-modality therapies will illuminate their safety, mechanism(s) of action, and best use in prospective combinational immunotherapy approaches capable of yielding superior benefits to cancer patients. PMID:20046961

  9. Dopamine agonists and the suppression of impulsive motor actions in Parkinson disease.

    PubMed

    Wylie, Scott A; Claassen, Daniel O; Huizenga, Hilde M; Schewel, Kerilyn D; Ridderinkhof, K Richard; Bashore, Theodore R; van den Wildenberg, Wery P M

    2012-08-01

    The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-BG circuitry. BG dysfunction caused by Parkinson disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD but can also provoke impulsive-compulsive behaviors (ICB). We investigated whether dopamine agonist medication has a beneficial or detrimental effect on impulsive action control in 38 PD patients, half of whom had current ICB. Participants performed the Simon conflict task, which measures susceptibility to acting on spontaneous action impulses as well as the proficiency of suppressing these impulses. Compared with an off-agonist state, patients on their agonists were no more susceptible to reacting impulsively but were less proficient at suppressing the interference from the activation of impulsive actions. Importantly, agonist effects depended on baseline performance in the off-agonist state; more proficient suppressors off agonist experienced a reduction in suppression on agonist, whereas less-proficient suppressors off agonist showed improved suppression on agonist. Patients with active ICB were actually less susceptible to making fast, impulsive response errors than patients without ICB, suggesting that behavioral problems in this subset of patients may be less related to impulsivity in motor control. Our findings provide further evidence that dopamine agonist medication impacts specific cognitive control processes and that the direction of its effects depends on individual differences in performance off medication.

  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. 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.

  12. Newspapers and Newspaper Ink Contain Agonists for the Ah Receptor

    PubMed Central

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

    2010-01-01

    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 [3H]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

  13. Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?

    PubMed

    Lertxundi, Unax; Domingo-Echaburu, Saioa; Peral, Javier; García, Montserrat

    2011-09-15

    Published literature shows that dopamine agonists can reverse antipsychotic-induced hyperprolactinemia without worsening psychotic symptoms in the majority of schizophrenic patients. However, psychiatrists have been reluctant to use drugs with dopaminergic properties for fear of exacerbating psychiatric symptoms. There are reported cases of psychosis worsening published for both cabergoline and bromocriptine. Cabergoline has proven to be more effective and safe when used to treat hyperprolactinemia, but whether cabergoline is also safer than bromocriptine in antipsychotic induced hyperprolactinemia remains unproven.

  14. Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?

    PubMed Central

    Lertxundi, Unax; Domingo-Echaburu, Saioa; Peral, Javier; García, Montserrat

    2011-01-01

    Published literature shows that dopamine agonists can reverse antipsychotic-induced hyperprolactinemia without worsening psychotic symptoms in the majority of schizophrenic patients. However, psychiatrists have been reluctant to use drugs with dopaminergic properties for fear of exacerbating psychiatric symptoms. There are reported cases of psychosis worsening published for both cabergoline and bromocriptine. Cabergoline has proven to be more effective and safe when used to treat hyperprolactinemia, but whether cabergoline is also safer than bromocriptine in antipsychotic induced hyperprolactinemia remains unproven. PMID:27738363

  15. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

    PubMed

    Xia, Yang; Kellems, Rodney E

    2013-06-21

    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These

  16. Glucagon-like peptide-1 receptors agonists (GLP1 RA).

    PubMed

    Kalra, Sanjay

    2013-10-01

    The glucagon-like peptide-1 receptors agonists (GLP1RA) are a relatively new class of drugs, used for management of type 2 diabetes. This review studies the characteristics of these drugs, focusing upon their mechanism of action, intra-class differences, and utility in clinical practice. It compares them with other incretin based therapies, the dipeptidyl peptidase-IV inhibitors, and predicts future developments in the use of these molecules, while highlighting the robust indications for the use of these drugs.

  17. 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

  18. Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

    DTIC Science & Technology

    2010-07-01

    or 9), although these compounds still showed anti-DHT effects (lanes 2 vs. 6, 8, or 10). Figure 4 . The effects of DHEA derivatives on PSA...2009 - 30 JUN 2010 4 . TITLE AND SUBTITLE Dehydroepiandrosterone Derivatives as Potent Antiandrogens 5a. CONTRACT NUMBER with Marginal Agonist...words) We hypothesized that dehydroepiandrosterone ( DHEA ) metabolites or their synthetic derivatives are able to bind to the androgen receptor with

  19. Thermodynamic analysis of antagonist and agonist interactions with dopamine receptors.

    PubMed

    Duarte, E P; Oliveira, C R; Carvalho, A P

    1988-03-01

    The binding of [3H]spiperone to dopamine D-2 receptors and its inhibition by antagonists and agonists were examined in microsomes derived from the sheep caudate nucleus, at temperatures between 37 and 1 degree C, and the thermodynamic parameters of the binding were evaluated. The affinity of the receptor for the antagonists, spiperone and (+)-butaclamol, decreased as the incubation temperature decreased; the affinity for haloperidol did not further decrease at temperatures below 15 degrees C. The binding of the antagonists was associated with very large increases in entropy, as expected for hydrophobic interactions. The enthalpy and entropy changes associated with haloperidol binding were dependent on temperature, in contrast to those associated with spiperone and (+)-butaclamol. The magnitude of the entropy increase associated with the specific binding of the antagonists did not correlate with the degree of lipophilicity of these drugs. The data suggest that, in addition to hydrophobic forces, other forces are also involved in the antagonist-dopamine receptor interactions, and that a conformational change of the receptor could occur when the antagonist binds. Agonist binding data are consistent with a two-state model of the receptor, a high-affinity state (RH) and a low-affinity state (RL). The affinity of dopamine binding to the RH decreased with decreasing temperatures below 20 degrees C, whereas the affinity for the RL increased at low temperatures. In contrast, the affinity of apomorphine for both states of receptor decreased as the temperature decreased from 30 to 8 degrees C. A clear distinction between the energetics of high-affinity and low-affinity agonist binding was observed. The formation of the high-affinity complex was associated with larger increases in enthalpy and entropy than the interaction with the low-affinity state was. The results suggest that the interaction of the receptor with the G-proteins, induced or stabilized by the binding of

  20. Neuroprotective effects mediated by dopamine receptor agonists against malonate-induced lesion in the rat striatum.

    PubMed

    Fancellu, R; Armentero, M-T; Nappi, G; Blandini, F

    2003-10-01

    In rats, intrastriatal injection of malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces a lesion similar to that observed following focal ischemia or in Huntington's disease. In this study we used the malonate model to explore the neuroprotective potential of dopamine agonists. Rats were injected intraperitoneally with increasing concentrations of D1, D2, or mixed D1/D2 dopamine agonists prior to intrastriatal injection of malonate. Administration of increasing doses of the D2-specific agonist quinpirole resulted in increased protection against malonate toxicity. Conversely, the D1-specific agonist SKF-38393, as well as the mixed D1/D2 agonist apomorphine, conferred higher neuroprotection at lower than at higher drug concentrations. Our data suggest that malonate- induced striatal toxicity can be attenuated by systemic administration of dopamine agonists, with D1 and D2 agonists showing different profiles of efficacy.

  1. 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.

  2. Contact- and agonist-regulated microvesiculation of human platelets.

    PubMed

    Zhang, Yanjun; Liu, Xiao; Liu, Li; Zaske, Ana-Maria; Zhou, Zhou; Fu, Yuanyuan; Yang, Xi; Conyers, Jodie L; Li, Min; Dong, Jing-fei; Zhang, Jianning

    2013-08-01

    After exposure to an agonist, platelets are activated and become aggregated. They also shed membrane microparticles that participate in the pathogenesis of thrombosis, hyper-coagulation and inflammation. However, microvesiculation can potentially disrupt the integrity of platelet aggregation by shedding the membrane receptors and phosphatidylserine critical for forming and stabilising a platelet clot. We tested the hypothesis that adhesion and microvesiculation are functions of different subsets of platelets at the time of haemostasis by real-time monitoring of agonist-induced morphological changes and microvesiculation of human platelets.We identified two types of platelets that are adherent to fibrinogen: a high density bubble shape (HDBS) and low-density spread shape (LDSS). Adenosine diphosphate (ADP) predominantly induced HDBS platelets to vesiculate, whereas LDSS platelets were highly resistant to such vesiculation. Thrombin-receptor activating peptide (TRAP) stabilised platelets against microvesiculation by promoting a rapid HDBS-to-LDSS morphological transition. These activities of ADP and TRAP were reversed for platelets in suspension, independent of an engagement integrin αIIbβ3. As the result of membrane contact, LDSS platelets inhibited the microvesiculation of HDBS platelets in response to ADP. Aspirin and clopidogrel inhibited ADP-induced microvesiculation through different mechanisms. These results suggest that platelet aggregation and microvesiculation occur in different subsets of platelets and are differently regulated by agonists, platelet-platelets and platelet-fibrinogen interactions.

  3. Pharmacophore-driven identification of PPARγ agonists from natural sources

    NASA Astrophysics Data System (ADS)

    Petersen, Rasmus K.; Christensen, Kathrine B.; Assimopoulou, Andreana N.; Fretté, Xavier; Papageorgiou, Vassilios P.; Kristiansen, Karsten; Kouskoumvekaki, Irene

    2011-02-01

    In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery.

  4. 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

  5. LHRH Agonists for the Treatment of Prostate Cancer: 2012

    PubMed Central

    Lepor, Herbert; Shore, Neal D

    2012-01-01

    The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge (“clinical flare”) and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT. PMID:23172994

  6. 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

  7. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease.

    PubMed

    Landreth, Gary; Jiang, Qingguang; Mandrekar, Shweta; Heneka, Michael

    2008-07-01

    Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid within the brain parenchyma and is accompanied by the impairment of neuronal metabolism and function, leading to extensive neuronal loss. The disease involves the perturbation of synaptic function, energy, and lipid metabolism. The development of amyloid plaques results in the induction of a microglial-mediated inflammatory response. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor whose biological actions are to regulate glucose and lipid metabolism and suppress inflammatory gene expression. Thus, agonists of this receptor represent an attractive therapeutic target for AD. There is now an extensive body of evidence that has demonstrated the efficacy of PPARgamma agonists in ameliorating disease-related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPARgamma agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPARgamma represents an important new therapeutic target in treating AD.

  8. 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.

  9. 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.

  10. TLR agonists: our best frenemy in cancer immunotherapy

    PubMed Central

    Kaczanowska, Sabina; Joseph, Ann Mary; Davila, Eduardo

    2013-01-01

    Various TLR agonists are currently under investigation in clinical trials for their ability to orchestrate antitumor immunity. The antitumor responses are largely attributed to their aptitude to stimulate APCs such as DCs which in turn, activate tumor-specific T cell responses. However, there is a potential for TLR signaling to occur on cells other than professional APCs that could negate antitumor responses or even worse, promote tumor growth. The impetus for this review is twofold. First, there is accumulating data demonstrating that the engagement of TLRs on different T cell subsets and different cancer types could promote tumor growth or conversely, contribute to antitumor responses. Second, the efficacy of TLR agonists as monotherapies to treat cancer patients has been limited. In this review, we discuss how TLR signaling within different T cell subsets and cancer cells can potentially impact the generation of antitumor responses. Based on evidence from preclinical models and clinical trials, we draw attention to several criteria that we believe must be considered when selecting TLR agonists for developing effective immunotherapeutic strategies against cancer. PMID:23475577

  11. LHRH Agonists for the Treatment of Prostate Cancer: 2012.

    PubMed

    Lepor, Herbert; Shore, Neal D

    2012-01-01

    The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge ("clinical flare") and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT.

  12. Pregnane X receptor agonists impair postprandial glucose tolerance.

    PubMed

    Rysä, J; Buler, M; Savolainen, M J; Ruskoaho, H; Hakkola, J; Hukkanen, J

    2013-06-01

    We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of the pregnane X receptor (PXR) agonist rifampin on an oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for 7 days, and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration-time curves (AUC(incr)) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin, and C-peptide, and the homeostasis model assessment for insulin resistance, were not affected. The glucose AUC(incr) during OGTT was significantly increased in rats after 4-day treatment with pregnenolone 16α-carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was downregulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia, suggesting a detrimental role of PXR activation on glucose tolerance.

  13. Beta2-Agonist Doping Control and Optical Isomer Challenges.

    PubMed

    Jacobson, Glenn A; Fawcett, J Paul

    2016-12-01

    The World Anti-Doping Agency (WADA) currently allows therapeutic use of the beta2-agonists salbutamol, formoterol and salmeterol when delivered via inhalation despite some evidence suggesting these anti-asthma drugs may be performance enhancing. Beta2-agonists are usually administered as 50:50 racemic mixtures of two enantiomers (non-superimposable mirror images), one of which demonstrates significant beta2-adrenoceptor-mediated bronchodilation while the other appears to have little or no pharmacological activity. For salbutamol and formoterol, urine thresholds have been adopted to limit supratherapeutic dosing and to discriminate between inhaled (permitted) and oral (prohibited) use. However, chiral switches have led to the availability of enantiopure (active enantiomer only) preparations of salbutamol and formoterol, which effectively doubles their urine thresholds and provides a means for athletes to take supratherapeutic doses for doping purposes. Given the availability of these enantiopure beta2-agonists, the analysis of these drugs using enantioselective assays should now become routine. For salmeterol, there is currently only a therapeutic dose threshold and adoption of a urinary threshold should be a high priority for doping control.

  14. The β2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis.

    PubMed

    Wills, Lauren P; Trager, Richard E; Beeson, Gyda C; Lindsey, Christopher C; Peterson, Yuri K; Beeson, Craig C; Schnellmann, Rick G

    2012-07-01

    Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the β-adrenoceptor (β-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple β-AR agonists: isoproterenol (nonselective β-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective β(3)-AR agonist), and formoterol (selective β(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the β-AR antagonist propranolol and the β(2)-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor γ coactivator 1α, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1β subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet

  15. Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)α agonist fenofibrate and the PPARγ agonist pioglitazone

    PubMed Central

    Syversen, Unni; Stunes, Astrid K; Gustafsson, Björn I; Obrant, Karl J; Nordsletten, Lars; Berge, Rolf; Thommesen, Liv; Reseland, Janne E

    2009-01-01

    Background All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO) and the PPARγ agonist pioglitazone (PIO) on bone in intact female rats. Methods Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied. Results The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1. Conclusion We show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation. PMID:19331671

  16. Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT3) Subunit A Receptors.

    PubMed

    Alix, Katie; Khatri, Shailesh; Mosier, Philip D; Casterlow, Samantha; Yan, Dong; Nyce, Heather L; White, Michael M; Schulte, Marvin K; Dukat, Małgorzata

    2016-11-16

    Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT3) receptor ligands resulted in a broad spectrum of functionally-active ligands from antagonist to superagonist. For example, (i) introduction of an additional Cl-substituent(s) to our lead full agonist N-(3-chlorophenyl)guanidine (mCPG, 2; efficacy % = 106) yielded superagonists 7-9 (efficacy % = 186, 139, and 129, respectively), (ii) a positional isomer of 2, p-Cl analog 11, displayed partial agonist actions (efficacy % = 12), and (iii) replacing the halogen atom at the meta or para position with an electron donating OCH3 group or a stronger electron withdrawing (i.e., CF3) group resulted in antagonists 13-16. We posit based on combined mutagenesis, crystallographic, and computational analyses that for the 5-HT3 receptor, the arylguanidines that are better able to simultaneously engage the primary and complementary subunits, thus keeping them in close proximity, have greater agonist character while those that are deficient in this ability are antagonists.

  17. Virtual screening of CB(2) receptor agonists from bayesian network and high-throughput docking: structural insights into agonist-modulated GPCR features.

    PubMed

    Renault, Nicolas; Laurent, Xavier; Farce, Amaury; El Bakali, Jamal; Mansouri, Roxane; Gervois, Philippe; Millet, Régis; Desreumaux, Pierre; Furman, Christophe; Chavatte, Philippe

    2013-04-01

    The relevance of CB(2)-mediated therapeutics is well established in the treatment of pain, neurodegenerative and gastrointestinal tract disorders. Recent works such as the crystallization of class-A G-protein-coupled receptors in a range of active states and the identification of specific anchoring sites for CB(2) agonists challenged us to design a reliable agonist-bound homology model of CB(2) receptor. Docking-scoring enrichment tests of a high-throughput virtual screening of 140 compounds led to 13 hits within the micromolar affinity range. Most of these hits behaved as CB(2) agonists, among which two novel full agonists emerged. Although the main challenge was a high-throughput docking run targeting an agonist-bound state of a CB(2) model, a prior 2D ligand-based Bayesian network was computed to enrich the input commercial library for 3D screening. The exclusive discovery of agonists illustrates the reliability of this agonist-bound state model for the identification of polar and aromatic amino acids as new agonist-modulated CB(2) features to be integrated in the wide activation pathway of G-protein-coupled receptors.

  18. Effect of AVE 0991 angiotensin-(1-7) receptor agonist treatment on elemental and biomolecular content and distribution in atherosclerotic plaques of apoE-knockout mice

    NASA Astrophysics Data System (ADS)

    Kowalska, J.; Gajda, M.; Jawień, J.; Kwiatek, W. M.; Appel, K.; Dumas, P.

    2013-12-01

    Gene-targeted apolipoprotein E-knockout (apoE-KO) mice display early and highly progressive vascular lesions containing lipid deposits and they became a reliable animal model to study atherosclerosis. The aim of the present study was to investigate the effect of AVE 0991 angiotensin-(1-7) receptor agonist on the distribution of selected pro- and anti- inflammatory elements as well as biomolecules in atherosclerotic plaques of apoE-knockout mice. Synchrotron radiation-based X-ray fluorescence (micro-XRF) and Fourier Transform Infrared (micro-FTIR) microspectroscopies were applied. Two-month-old apoE-KO mice were fed for following four months diet supplemented with AVE 0991 (0.58 μmol/kg b.w. per day). Histological sections of ascending aortas were analyzed spectroscopically. The distribution of P, Ca, Fe and Zn were found to correspond with histological structure of the lesion. Significantly lower contents of P, Ca, Zn and significantly higher content of Fe were observed in animals treated with AVE 0991. Biomolecular analysis showed lower lipids saturation level and lower lipid to protein ratio in AVE 0991 treated group. Protein secondary structure was studied according to the composition of amide I band (1660 cm-1) and it demonstrated higher proportion of β-sheet structure as compared to α-helix in both studied groups.

  19. PPARgamma agonist pioglitazone does not enhance performance in mice.

    PubMed

    Sanchis-Gomar, Fabian; Pareja-Galeano, Helios; Martinez-Bello, Vladimir E

    2014-09-01

    Peroxisome-proliferator-activated receptor (PPAR) delta and adenosine monophosphate (AMP)-activated protein kinases (AMPKs) regulate the metabolic and contractile characteristics of myofibres. PPAR proteins are nuclear receptors that function as transcription factors and regulate the expression of multiple genes. AMPK has been described as a master metabolic regulator which also controls gene expression through the direct phosphorylation of some nuclear proteins. Since it was discovered that both PPARdelta agonists (GW1516) and AMPK activators (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, known as AICAR) are very effective performance-enhancing substances in sedentary mice, the World Anti-doping Agency (WADA) included AICAR and GW1516 in the prohibited list of substances as metabolic modulators in the class 'Hormone and metabolic modulators'. Thiazolidinediones are PPARgamma agonists that can induce similar biological effects to those of PPARdelta and PPARdelta-AMPK agonists. Thus in this study, the effects of pioglitazone on mitochondrial biogenesis and performance were evaluated. Blood glucose levels and the protein expression of the intermediates involved in the mitochondrial biogenesis pathway and the citrate synthase activity were determined in both gastrocnemius and soleus muscles. Maximal aerobic velocity (MAV), endurance capacity, and grip strength before and after the training period were also determined. The MAV endurance capacity and grip strength of trained animals significantly increased. We found that the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and the nuclear respiratory factor-1 (NRF-1) protein content and citrate synthase activity significantly increased in the soleus muscle of trained animals. No effect of treatment was found. Therefore in our study, pioglitazone administration did not affect mitochondrial biogenesis signaling pathway.

  20. 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

  1. Biased signaling by peptide agonists of protease activated receptor 2.

    PubMed

    Jiang, Yuhong; Yau, Mei-Kwan; Kok, W Mei; Lim, Junxian; Wu, Kai-Chen; Liu, Ligong; Hill, Timothy A; Suen, Jacky Y; Fairlie, David P

    2017-02-07

    Protease activated receptor 2 (PAR2) is associated with metabolism, obesity, inflammatory, respiratory and gastrointestinal disorders, pain, cancer and other diseases. The extracellular N-terminus of PAR2 is a common target for multiple proteases, which cleave it at different sites to generate different N-termini that activate different PAR2-mediated intracellular signaling pathways. There are no synthetic PAR2 ligands that reproduce the same signaling profiles and potencies as proteases. Structure-activity relationships here for 26 compounds spanned a signaling bias over 3 log units, culminating in three small ligands as biased agonist tools for interrogating PAR2 functions. DF253 (2f-LAAAAI-NH2) triggered PAR2-mediated calcium release (EC50 2 μM) but not ERK1/2 phosphorylation (EC50 > 100 μM) in CHO cells transfected with hPAR2. AY77 (Isox-Cha-Chg-NH2) was a more potent calcium-biased agonist (EC50 40 nM, Ca2+; EC50 2 μM, ERK1/2), while its analogue AY254 (Isox-Cha-Chg-A-R-NH2) was an ERK-biased agonist (EC50 2 nM, ERK1/2; EC50 80 nM, Ca2+). Signaling bias led to different functional responses in human colorectal carcinoma cells (HT29). AY254, but not AY77 or DF253, attenuated cytokine-induced caspase 3/8 activation, promoted scratch-wound healing and induced IL-8 secretion, all via PAR2-ERK1/2 signaling. Different ligand components were responsible for different PAR2 signaling and functions, clues that can potentially lead to drugs that modulate different pathway-selective cellular and physiological responses.

  2. 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.

  3. 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.

  4. Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

    DTIC Science & Technology

    2013-07-01

    DATES COVERED 01 July 2012 – 30 June 2013 4 . TITLE AND SUBTITLE Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist...Page Introduction…………………………………………………………….………..….. 1 Body………………………………………………………………………………….. 1- 4 Key Research...In addition, we previously found that androstenediol (Adiol), a physiological metabolite from dehydroepiandrosterone ( DHEA ) and a precursor of

  5. 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.

  6. Is there a justification for classifying GLP-1 receptor agonists as basal and prandial?

    PubMed

    Miñambres, Inka; Pérez, Antonio

    2017-01-01

    Several GLP-1 receptor agonists are currently available for treatment of type 2 diabetic patients. Based on their pharmacokinetic/pharmacodynamic profile, these drugs are classified as short-acting GLP-1 receptor agonists (exenatide and lixisenatide) or long-acting GLP-1 receptor agonists (exenatide-LAR, liraglutide, albiglutide, and dulaglutide). In clinical practice, they are also classified as basal or prandial GLP-1 receptor agonists to differentiate between patients who would benefit more from one or another based on characteristics such as previous treatment and the predominance of fasting or postprandial hyperglycemia. In the present article we examine available data on the pharmacokinetic characteristics of the various GLP-1 agonists and compare their effects with respect to the main parameters used to evaluate glycemic control. The article also analyzes whether the differences between the different GLP-1 agonists justify their classification as basal or prandial.

  7. Antidepressant-like Effects of δ Opioid Receptor Agonists in Animal Models

    PubMed Central

    Saitoh, Akiyoshi; Yamada, Mitsuhiko

    2012-01-01

    Recently, δ opioid receptor agonists have been proposed to be attractive targets for the development of novel antidepressants. Several studies revealed that single treatment of δ opioid receptor agonists produce antidepressant-like effects in the forced swimming test, which is one of the most popular animal models for screening antidepressants. In addition, subchronic treatment with δ opioid receptor agonists has been shown to completely attenuate the hyperemotional responses found in olfactory bulbectomized rats. This animal model exhibits hyperemotional behavior that may mimic the anxiety, aggression, and irritability found in depressed patients, suggesting that δ opioid receptor agonists could be effective in the treatment of these symptoms in depression. On the other hand, prototype δ opioid receptor agonists produce convulsive effects, which limit their therapeutic potential and clinical development. In this review, we presented the current knowledge regarding the antidepressant-like effects of δ opioid receptor agonists, which include some recently developed drugs lacking convulsive effects. PMID:23449756

  8. Tissue specificity of aryl hydrocarbon receptor (AhR) mediated responses and relative sensitivity of white sturgeon (Acipenser transmontanus) to an AhR agonist.

    PubMed

    Doering, Jon A; Wiseman, Steve; Beitel, Shawn C; Tendler, Brett J; Giesy, John P; Hecker, Markus

    2012-06-15

    Sturgeons are endangered in some parts of the world. Due to their benthic nature and longevity sturgeon are at greater risk of exposure to bioaccumulative contaminants such as dioxin-like compounds that are associated with sediments. Despite their endangered status, little research has been conducted to characterize the relative responsiveness of sturgeon to dioxin-like compounds. In an attempt to study the biological effects and possible associated risks of exposure to dioxin-like compounds in sturgeon, the molecular and biochemical responses of white sturgeon (Acipenser transmontanus) to a model aryl hydrocarbon receptor (AhR) agonist, β-naphthoflavone (βNF) were investigated. White sturgeon were injected intraperitoneally with one of three doses of βNF (0, 50, or 500mg/kg, bw). Rainbow trout (Oncorhynchus mykiss) were used as a reference species since their responses have been well characterized in the past. Three days following injection with βNF, fish were euthanized and livers, gills, and intestines collected for biochemical and molecular analyses. White sturgeon exposed to βNF had significantly greater ethoxyresorufin O-deethylase (EROD) activity in liver (up to 37-fold), gill (up to 41-fold), and intestine (up to 36-fold) than did unexposed controls. Rainbow trout injected with βNF exhibited EROD activity that was significantly greater in liver (88-fold), than that of controls, but was undetectable in gills or intestine. Abundance of CYP1A transcript displayed a comparable pattern of tissue-specific induction with intestine (up to 189-fold), gills (up to 53-fold), and liver (up to 21-fold). Methoxyresorufin O-deethylase (MROD) and pentoxyresorufin O-deethylase (PROD) activities were undetectable in unexposed white sturgeon tissues while exposed tissues displayed MROD activity that was only moderately greater than the activity that could be detected. Differential inducibility among liver, gill, and intestine following exposure to an AhR agonist is

  9. Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan.

    PubMed

    Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Takagi, Mai; Sei, Kazunari; Yang, Min; Hirotsuji, Junji; Hu, Jianying; Nishikawa, Jun-ichi; Nakanishi, Tsuyoshi; Ike, Michihiko

    2010-04-01

    This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) alpha in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan. To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARalpha agonist contamination in the river basins. RARalpha agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARalpha agonists are always present and widespread in the rivers. Comparative investigation of RARalpha and estrogen receptor alpha agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARalpha agonist contamination was entirely different from that of the estrogenic compound contamination. This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARalpha agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARalpha agonists in the rivers. Although a trial conducted to identify RARalpha agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARalpha agonistic activity were not RAs (natural RAR ligands) and 4-oxo-RAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China. These findings suggest that there are unknown RARalpha agonists with high

  10. β‐Arrestin 2 dependence of δ opioid receptor agonists is correlated with alcohol intake

    PubMed Central

    Chiang, T; Sansuk, K

    2016-01-01

    Background and Purpose δ Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co‐morbid with alcohol use disorders. Yet we have previously shown that δ receptor agonists range widely in their ability to modulate alcohol intake; certain δ receptor agonists actually increase alcohol consumption in mice. We propose that variations in β‐arrestin 2 recruitment contribute to the differential behavioural profile of δ receptor agonists. Experimental Approach We used three diarylmethylpiperazine‐based non‐peptidic δ receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse δ receptor agonists (TAN‐67, KNT127 and NIH11082). We tested these agonists in cAMP and β‐arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used β‐arrestin 2 knockout mice and a model of depression‐like behaviour to further study the role of β‐arrestin 2 in δ receptor pharmacology. Key Results All six tested δ receptor agonists were full agonists in the cAMP assay but displayed distinct β‐arrestin 2 recruitment efficacy. The efficacy of δ receptor agonists to recruit β‐arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression‐like behaviour were β‐arrestin 2‐dependent. Conclusions and Implications Our finding that δ receptor agonists that strongly recruit β‐arrestin 2 can increase alcohol intake carries important ramifications for drug development of δ receptor agonists for treatment of alcohol use disorders and depressive disorders. © 2015 The British Pharmacological Society PMID:26507558

  11. Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.

    PubMed

    Papke, Roger L; Trocmé-Thibierge, Caryn; Guendisch, Daniela; Al Rubaiy, Shehd Abdullah Abbas; Bloom, Stephen A

    2011-05-01

    Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of α4β2* [(α4)(2)(β2)(3), (α4)(3)(β2)(2), and (α4)(2)(β2)(2)α5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of α7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, "run-up" of α7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of α7 responses by α4β2 partial agonists and decreases in α4β2* responses by α7-selective agonists. These data indicate the dual effects expected for α4β2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development.

  12. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment.

    PubMed

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T; Abbruscato, Thomas J

    2015-06-03

    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype.

  13. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment

    PubMed Central

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T.; Abbruscato, Thomas J.

    2015-01-01

    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10 nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10 nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype. PMID:25801116

  14. Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. I. Acute effects of ethanol

    SciTech Connect

    Buck, K.J.; Harris, R.A. )

    1990-05-01

    Acute exposure to ethanol was found to enhance the ability of a benzodiazepine (BZ) inverse agonist, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), to reduce muscimol-activated 36Cl- uptake by membranes isolated from mouse cerebral cortex. Pretreatment in vivo with a hypnotic dose of ethanol (but not a subhypnotic dose), or exposure to a corresponding concentration in vitro, was effective. This increase in sensitivity of gamma-aminobutyric acid receptor-operated chloride channels to the actions of DMCM was due to an increase in both the potency and efficacy of DMCM. Sensitization to DMCM was reversible and was not observed 24 hr after a single injection of ethanol. Pretreatment with ethanol (10, 50 and 100 mM) in vitro produced sensitization to DMCM in a concentration-dependent manner, similar to that produced by in vivo exposure; this increase in sensitivity did not develop if the membranes were pretreated with ethanol at 0 degrees C. Similarly, in vitro exposure to pentobarbital (200 microM) or flunitrazepam (1 microM) enhanced the actions of the inverse agonist Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5a)(1,4)BZ-3- carboxylate). Acute ethanol exposure did not alter low-affinity gamma-aminobutyric acidA receptor binding or muscimol action, or the ability of a BZ agonist, flunitrazepam, to augment muscimol-activated chloride flux. Ethanol exposure did not alter (3H)flumazenil (Ro15-1788) binding to central BZ receptors, its displacement by DMCM or allosteric modulation of DMCM binding by muscimol (muscimol-shift).

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

    PubMed

    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

    2016-03-01

    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.

  16. Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

    SciTech Connect

    Molenaar, P.; Malta, E.

    1986-04-01

    In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-(/sup 125/I)iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants.

  17. The pharmacology of epanolol (ICI 141292)--a new beta 1-selective adrenoceptor partial agonist.

    PubMed

    Bilski, A J; Hadfield, S E; Wale, J L

    1988-08-01

    The clinical benefit of beta-adrenoceptor partial agonists is still debated. To clarify the situation, epanolol, ICI 141,292 [N-[-2-(3-o-cyanophenoxy-2-hydroxypropylamino)ethyl]-4- hydroxyphenylactamide], has been developed to assess the role of modest beta-adrenoceptor partial agonist activity in humans. Animal studies have shown that epanolol is a potent beta-adrenoceptor partial agonist with a greater affinity for beta 1- than beta 2-adrenoceptors. In vitro, the PA2 values obtained for espanolol at atrial and tracheal beta-adrenoceptors were 8.42 and 6.33, respectively (isoproterenol as agonist), giving a selectivity ratio of 123. The potency was studied in vivo in the dog, where it was also shown that as an antagonist at the cardiac beta 1-adrenoceptor, it was 18 and 40 times more potent than atenolol and practolol, respectively. Espanolol has less partial agonist activity in the rat than pindolol, but more than practolol. In this species, it is also a classical partial agonist, exhibiting agonist activity at all beta-adrenoceptor blocking doses. This is in contrast to pindolol, which caused predominantly beta-adrenoceptor blockade at low doses and partial agonist activity at higher doses. These differences were confirmed in haemodynamic studies in the dog. In contrast to many other partial agonists, the partition coefficient, log P, of epanolol in octanol and water is low (0.92).

  18. 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

  19. Agonist signalling properties of radiotracers used for imaging of dopamine D2/3 receptors

    PubMed Central

    2014-01-01

    Background Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists are more sensitive to detect dopamine release than antagonist radiopharmaceuticals, but this theory has been challenged. Interestingly, not all agonists similarly activate the classic cyclic adenosine mono phosphate (cAMP) and the ?-arrestin-2 pathway, some stimulate preferentially one of these pathways; a phenomenon called biased agonism. Because these pathways can be affected separately by pathologies or drugs (including dopamine releasers), it is important to know how agonist radiotracers act on these pathways. Therefore, we characterized the intracellular signalling of the well-known D2/3R agonist radiopharmaceuticals NPA and PHNO and of several novel D2/3R agonists. Methods cAMP accumulation and ?-arrestin-2 recruitment were measured on cells expressing human D2R. Results All tested agonists showed (almost) full agonism in both pathways. Conclusions The tested D2/3R agonist radiopharmaceuticals did not exhibit biased agonism in vitro. Consequently, it is likely that drugs (including psychostimulants like amphetamines) and/or pathologies that influence the cAMP and/or the ?-arrestin-2 pathway may influence the binding of these radiopharmaceuticals. PMID:25977878

  20. Melatonin and melatonin agonist for delirium in the elderly patients.

    PubMed

    Chakraborti, Dwaipayan; Tampi, Deena J; Tampi, Rajesh R

    2015-03-01

    The objective of this review is to summarize the available data on the use of melatonin and melatonin agonist for the prevention and management of delirium in the elderly patients from randomized controlled trials (RCTs). A systematic search of 5 major databases PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library was conducted. This search yielded a total of 2 RCTs for melatonin. One study compared melatonin to midazolam, clonidine, and control groups for the prevention and management of delirium in individuals who were pre- and posthip post-hip arthroplasty. The other study compared melatonin to placebo for the prevention of delirium in older adults admitted to an inpatient internal medicine service. Data from these 2 studies indicate that melatonin may have some benefit in the prevention and management of delirium in older adults. However, there is no evidence that melatonin reduces the severity of delirium or has any effect on behaviors or functions in these individuals. Melatonin was well tolerated in these 2 studies. The search for a melatonin agonist for delirium in the elderly patients yielded 1 study of ramelteon. In this study, ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo. Ramelteon was well tolerated in this study.

  1. GLP-1 receptor agonist-induced polyarthritis: a case report.

    PubMed

    Ambrosio, Maria Luisa; Monami, Matteo; Sati, Lavinia; Marchionni, Niccolò; Di Bari, Mauro; Mannucci, Edoardo

    2014-08-01

    Occasional cases of bilateral, symmetrical, seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase-4 inhibitors (Crickx et al. in Rheumatol Int, 2013). We report here a similar case observed during treatment with a GLP-1 receptor agonist. A 42-year-old man with type 2 diabetes treated with metformin 1,500 mg/day and liraglutide 1.8 mg/day. After 6 months from the beginning of treatment, the patient complained of bilateral arthralgia (hands, feet, ankles, knees, and hips). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and leukocytes were increased. Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear antibodies, anti-Borrelia, and burgdorferi antibodies were all negative, and myoglobin and calcitonin were normal. Liraglutide was withdrawn, and the symptoms completely disappeared within 1 week, with normalization of ESR, CRP, fibrinogen, and leukocytes. Previously described cases of polyarthritis associated with DPP4 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme. The present case, occurred during treatment with a GLP-1 receptor agonists, suggests a possibly different mechanism, mediated by GLP-1 receptor stimulation, which deserved further investigation.

  2. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    PubMed Central

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

  3. Agonist-stimulated alveolar macrophages: apoptosis and phospholipid signaling.

    PubMed

    Lütjohann, J; Spiess, A N; Gercken, G

    1998-08-01

    Bovine alveolar macrophages (BAM) were labeled with [3H]-choline or [3H]-ethanolamine and exposed to quartz dust, metal oxide-coated silica particles, Escherichia coli-derived lipopolysaccharide (LPS) or tumor promotor 12-O-tetradecanoyl phorbol 13-acetate (PMA). The activation of phospholipases A2, C and D (PLA2, PLC and PLD) acting on phosphatidylcholine and phosphatidylethanolamine was determined by high performance liquid chromatography (HPLC) separation and liquid scintillation counting of water- and lipid-soluble phospholipid metabolites. Exposure of BAM to quartz dust, metal oxide-coated silica particles, and LPS led to a transient PLD activation while treatment with PMA caused a prolonged rise in PLD activity. LPS and quartz dust induced a short-term increase of PLC cleavage products. All agonists caused a transient activation of PLA2. To induce apoptosis, BAM were stimulated with C8-ceramide, calcium-ionophore 23187, or gliotoxin. Apoptosis was investigated by qualitative and quantitative methods like flow cytometry, propidium iodide/Hoechst 33258 double staining, Cell Death Detection ELISA, and electrophoretical detection of DNA fragmentation. All three agonists led to apoptosis of BAM in a time- and concentration-dependent manner. After stimulation with gliotoxin an increase in ceramide and a drastic decrease in sphingosine-1-phosphate levels were observed, suggesting an involvement of these sphingolipids in gliotoxin-mediated apoptosis.

  4. The evolution of histamine H₃ antagonists/inverse agonists.

    PubMed

    Lebois, Evan P; Jones, Carrie K; Lindsley, Craig W

    2011-01-01

    This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H₃ antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H₃R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H₃ ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H₃ ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H₃R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists.

  5. Trial Watch: Toll-like receptor agonists in oncological indications.

    PubMed

    Aranda, Fernando; Vacchelli, Erika; Obrist, Florine; Eggermont, Alexander; Galon, Jérôme; Sautès-Fridman, Catherine; Cremer, Isabelle; Henrik Ter Meulen, Jan; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2014-01-01

    Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.

  6. Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists

    PubMed Central

    Quera Salva, M.A.; Hartley, S.

    2012-01-01

    Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse. PMID:23650464

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. Coupling between agonist and chloride ionophore sites of the GABA(A) receptor: agonist/antagonist efficacy of 4-PIOL.

    PubMed

    Rabe, H; Picard, R; Uusi-Oukari, M; Hevers, W; Lüddens, H; Korpi, E R

    2000-12-15

    Eight gamma-aminobutyric acid (GABA) mimetics were tested on their ability to differentiate native GABA(A) receptor subtypes present in various rat brain regions. In rat brain cryostat sections, little regional variations by the agonistic actions of muscimol, thiomuscimol, 4,5,6,7-tetrahydroisoazolo(5,4-c)pyridin-3-ol, piperidine-4-sulphonic acid, taurine and beta-alanine on [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to GABA(A) receptor channels were found. They were very similar to those found for GABA itself and indicated no direct correlation with single subunit distributions for any of these compounds. Only the low-efficacy GABA mimetic 5-(4-piperidyl)isoxazol-3-ol (4-PIOL) acted like a weak partial agonist or antagonist depending on the brain area. As the cerebellar granule cell layer was relatively insensitive to both modes of action, we tested 4-PIOL in recombinant alpha1beta2gamma2 (widespread major subtype) and alpha6beta2gamma2 (cerebellar granule cell restricted) receptors where it had different effects on GABA-modulated [35S]TBPS binding and on electrophysiological responses. 4-PIOL may thus serve as a potential lead for receptor subtype selective compounds.

  12. Discriminative stimulus properties of indorenate, a serotonin agonist.

    PubMed Central

    Velázquez-Martínez, D N; López Cabrera, M; Sánchez, H; Ramírez, J I; Hong, E

    1999-01-01

    OBJECTIVE: To determine whether indorenate, a serotonin-receptor agonist, can exert discriminative control over operant responses, to establish the temporal course of discriminative control and to compare its stimulus properties to a (5-HT)IA receptor agonist. [3H]-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT). DESIGN: Prospective animal study. ANIMALS: Ten male Wistar rats. INTERVENTIONS: Rats were trained to press either of 2 levers for sucrose solution according to a fixed ratio schedule, which was gradually increased. Rats were given injections of either indorenate or saline solution during discrimination training. Once they had achieved an 83% accuracy rate, rats underwent generalization tests after having received a different dose of indorenate, the training dose of indorenate at various intervals before the test, various doses of 8-OH-DPT, or NAN-190 administered before indorenate or 8-OH-DPAT. OUTCOME MEASURES: Distribution of responses between the 2 levers before the first reinforcer of the session, response rate for all the responses in the session, and a discrimination index that expressed the drug-appropriate responses as a proportion of the total responses. RESULTS: Indorenate administration resulted in discriminative control over operant responses, maintained at fixed ratio 10, at a dose of 10.0 mg/kg (but not 3.0 mg/kg). When the interval between the administration of indorenate and the start of the session was varied, the time course of its cue properties followed that of its described effects on 5-HT turnover. In generalization tests, the discrimination index was a function of the dose of indorenate employed; moreover, administration of 8-OH-DPAT (from 0.1 to 1.0 mg/kg) fully mimicked the stimulus properties of indorenate in a dose-dependent way. The (5-HT)IA antagonist NAN-190 prevented the stimulus generalization from indorenate to 8-OH-DPAT. Also, NAN-190 antagonized the stimulus control of indorenate when administered 45 minutes before

  13. New Small Molecule Agonists to the Thyrotropin Receptor

    PubMed Central

    Ali, M. Rejwan; Ma, Risheng; David, Martine; Morshed, Syed A.; Ohlmeyer, Michael; Felsenfeld, Dan P.; Lau, Zerlina; Mezei, Mihaly; Davies, Terry F.

    2015-01-01

    Background Novel small molecular ligands (SMLs) to the thyrotropin receptor (TSHR) have potential as improved molecular probes and as therapeutic agents for the treatment of thyroid dysfunction and thyroid cancer. Methods To identify novel SMLs to the TSHR, we developed a transcription-based luciferase-cAMP high-throughput screening system and we screened 48,224 compounds from a 100K library in duplicate. Results We obtained 62 hits using the cut-off criteria of the mean±three standard deviations above the baseline. Twenty molecules with the greatest activity were rescreened against the parent CHO-luciferase cell for nonspecific activation, and we selected two molecules (MS437 and MS438) with the highest potency for further study. These lead molecules demonstrated no detectible cross-reactivity with homologous receptors when tested against luteinizing hormone (LH)/human chorionic gonadotropin receptor and follicle stimulating hormone receptor–expressing cells. Molecule MS437 had a TSHR-stimulating potency with an EC50 of 13×10−8 M, and molecule MS438 had an EC50 of 5.3×10−8 M. The ability of these small molecule agonists to bind to the transmembrane domain of the receptor and initiate signal transduction was suggested by their activation of a chimeric receptor consisting of an LHR ectodomain and a TSHR transmembrane. Molecular modeling demonstrated that these molecules bound to residues S505 and E506 for MS438 and T501 for MS437 in the intrahelical region of transmembrane helix 3. We also examined the G protein activating ability of these molecules using CHO cells co-expressing TSHRs transfected with luciferase reporter vectors in order to measure Gsα, Gβγ, Gαq, and Gα12 activation quantitatively. The MS437 and MS438 molecules showed potent activation of Gsα, Gαq, and Gα12 similar to TSH, but neither the small molecule agonists nor TSH showed activation of the Gβγ pathway. The small molecules MS437 and MS438 also showed upregulation of

  14. Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes.

    PubMed

    Katritch, Vsevolod; Reynolds, Kimberly A; Cherezov, Vadim; Hanson, Michael A; Roth, Christopher B; Yeager, Mark; Abagyan, Ruben

    2009-01-01

    The 2.4 A crystal structure of the beta(2)-adrenergic receptor (beta(2)AR) in complex with the high-affinity inverse agonist (-)-carazolol provides a detailed structural framework for the analysis of ligand recognition by adrenergic receptors. Insights into agonist binding and the corresponding conformational changes triggering G-protein coupled receptor (GPCR) activation mechanism are of special interest. Here we show that while the carazolol pocket captured in the beta(2)AR crystal structure accommodates (-)-isoproterenol and other agonists without steric clashes, a finite movement of the flexible extracellular part of TM-V helix (TM-Ve) obtained by receptor optimization in the presence of docked ligand can further improve the calculated binding affinities for agonist compounds. Tilting of TM-Ve towards the receptor axis provides a more complete description of polar receptor-ligand interactions for full and partial agonists, by enabling optimal engagement of agonists with two experimentally identified anchor sites, formed by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Further, receptor models incorporating a flexible TM-V backbone allow reliable prediction of binding affinities for a set of diverse ligands, suggesting potential utility of this approach to design of effective and subtype-specific agonists for adrenergic receptors. Systematic differences in capacity of partial, full and inverse agonists to induce TM-V helix tilt in the beta(2)AR model suggest potential role of TM-V as a conformational "rheostat" involved in the whole spectrum of beta(2)AR responses to small molecule signals.

  15. Impact of efficacy at the μ-opioid receptor on antinociceptive effects of combinations of μ-opioid receptor agonists and cannabinoid receptor agonists.

    PubMed

    Maguire, David R; France, Charles P

    2014-11-01

    Cannabinoid receptor agonists, such as Δ(9)-tetrahydrocannabinol (Δ(9)-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, Δ(9)-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 Δ(9)-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. Δ(9)-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 Δ(9)-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.

  16. Sensitivity of GBM cells to cAMP agonist-mediated apoptosis correlates with CD44 expression and agonist resistance with MAPK signaling

    PubMed Central

    Daniel, Paul M; Filiz, Gulay; Mantamadiotis, Theo

    2016-01-01

    In some cell types, activation of the second messenger cAMP leads to increased expression of proapoptotic Bim and subsequent cell death. We demonstrate that suppression of the cAMP pathway is a common event across many cancers and that pharmacological activation of cAMP in glioblastoma (GBM) cells leads to enhanced BIM expression and apoptosis in specific GBM cell types. We identified the MAPK signaling axis as the determinant of cAMP agonist sensitivity in GBM cells, with high MAPK activity corresponding to cAMP resistance and low activity corresponding to sensitization to cAMP-induced apoptosis. Sensitive cells were efficiently killed by cAMP agonists alone, while targeting both the cAMP and MAPK pathways in resistant GBM cells resulted in efficient apoptosis. We also show that CD44 is differentially expressed in cAMP agonist-sensitive and -resistant cells. We thus propose that CD44 may be a useful biomarker for distinguishing tumors that may be sensitive to cAMP agonists alone or cAMP agonists in combination with other pathway inhibitors. This suggests that using existing chemotherapeutic compounds in combination with existing FDA-approved cAMP agonists may fast track trials toward improved therapies for difficult-to-treat cancers, such as GBM. PMID:27906173

  17. Modulation of [3H]diazepam binding in rat cortical membranes by GABAA agonists.

    PubMed

    Wong, E H; Iversen, L L

    1985-04-01

    GABAA receptor agonists modulate [3H]diazepam binding in rat cortical membranes with different efficacies. At 23 degrees C, the relative potencies for enhancement of [3H]diazepam binding by agonists parallel their potencies in inhibiting [3H]gamma-aminobutyric acid [( 3H]GABA) binding. The agonist concentrations needed for enhancement of [3H]diazepam binding are up to 35 times higher than for [3H]GABA binding and correspond closely to the concentrations required for displacement of [3H]bicuculline methochloride (BMC) binding. The maximum enhancement of [3H]diazepam varied among agonists: muscimol = GABA greater than isoguvacine greater than 3-aminopropane sulphonic acid (3APS) = imidazoleacetic acid (IAA) greater than 4,5,6,7-tetrahydroisoxazolo (4,5,6)-pyridin-3-ol (THIP) = taurine greater than piperidine 4-sulphonic acid (P4S). At 37 degrees C, the potencies of agonists remained unchanged, but isoguvacine, 3 APS, and THIP acquired efficacies similar to GABA, whereas IAA, taurine, and P4S maintained their partial agonist profiles. At both temperatures the agonist-induced enhancement of [3H]diazepam binding was reversible by bicuculline methobromide and by the steroid GABA antagonist RU 5135. These results stress the importance of studying receptor-receptor interaction under near-physiological conditions and offer an in vitro assay that may predict the agonist status of putative GABA receptor ligands.

  18. Use-dependent inhibition of P2X3 receptors by nanomolar agonist.

    PubMed

    Pratt, Emily B; Brink, Thaddeus S; Bergson, Pamela; Voigt, Mark M; Cook, Sean P

    2005-08-10

    P2X3 receptors desensitize within 100 ms of channel activation, yet recovery from desensitization requires several minutes. The molecular basis for this slow rate of recovery is unknown. We designed experiments to test the hypothesis that this slow recovery is attributable to the high affinity (< 1 nM) of desensitized P2X3 receptors for agonist. We found that agonist binding to the desensitized state provided a mechanism for potent inhibition of P2X3 current. Sustained applications of 0.5 nM ATP inhibited > 50% of current to repetitive applications of P2X3 agonist. Inhibition occurred at 1000-fold lower agonist concentrations than required for channel activation and showed strong use dependence. No inhibition occurred without previous activation and desensitization. Our data are consistent with a model whereby inhibition of P2X3 by nanomolar [agonist] occurs by the rebinding of agonist to desensitized channels before recovery from desensitization. For several ATP analogs, the concentration required to inhibit P2X3 current inversely correlated with the rate of recovery from desensitization. This indicates that the affinity of the desensitized state and recovery rate primarily depend on the rate of agonist unbinding. Consistent with this hypothesis, unbinding of [32P]ATP from desensitized P2X3 receptors mirrored the rate of recovery from desensitization. As expected, disruption of agonist binding by site-directed mutagenesis increased the IC50 for inhibition and increased the rate of recovery.

  19. Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rats.

    PubMed

    Li, Su-Min; Collins, Gregory T; Paul, Noel M; Grundt, Peter; Newman, Amy H; Xu, Ming; Grandy, David K; Woods, James H; Katz, Jonathan L

    2010-05-01

    Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss-Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000-10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [(+/-)-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.

  20. 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

  1. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice

    PubMed Central

    Sharma, Pawan; Yi, Roslyn; Nayak, Ajay P.; Wang, Nadan; Tang, Francesca; Knight, Morgan J.; Pan, Shi; Oliver, Brian; Deshpande, Deepak A.

    2017-01-01

    Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.

  2. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview

    PubMed Central

    Soltani, Hoda; Pardakhty, Abbas

    2016-01-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of “new drug delivery systems” is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today. PMID:27882209

  3. Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120).

    PubMed

    Sparks, Steven M; Chen, Grace; Collins, Jon L; Danger, Dana; Dock, Steven T; Jayawickreme, Channa; Jenkinson, Stephen; Laudeman, Christopher; Leesnitzer, M Anthony; Liang, Xi; Maloney, Patrick; McCoy, David C; Moncol, David; Rash, Vincent; Rimele, Thomas; Vulimiri, Padmaja; Way, James M; Ross, Sean

    2014-07-15

    The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.

  4. 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.

  5. Dopamine receptor agonists mediate neuroprotection in malonate-induced striatal lesion in the rat.

    PubMed

    Armentero, Marie-Thérèse; Fancellu, Roberto; Nappi, Giuseppe; Blandini, Fabio

    2002-12-01

    Mitochondrial bioenergetic defects are involved in neurological disorders associated with neuronal damage in the striatum, such as Huntington's disease and cerebral ischemia. The striatal release of neurotransmitters, in particular dopamine, may contribute to the development of the neuronal damage. Recent studies have shown that dopamine agonists may exert neuroprotective effects via multiple mechanisms, including modulation of dopamine release from nigrostriatal dopaminergic terminals. In rats, intrastriatal injection of malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces a lesion similar to that observed following focal ischemia or in Huntington's disease. In this study, we used the malonate model to explore the neuroprotective potential of dopamine agonists. Sprague-Dawley rats were injected systemically with increasing concentrations of D(1), D(2), or mixed D(1)/D(2) dopamine agonists prior to malonate intrastriatal insult. Administration of increasing doses of the D(2)-specific agonist quinpirole resulted in increased protection against malonate toxicity. Conversely, the D(1)-specific agonist SKF-38393, as well as the mixed D(1)/D(2) agonist apomorphine, conferred higher neuroprotection at lower than at higher concentrations. Our data suggest that malonate-induced striatal toxicity can be attenuated by systemic administration of dopamine agonists, with D(1) and D(2) agonists showing different profiles of efficacy.

  6. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview.

    PubMed

    Soltani, Hoda; Pardakhty, Abbas

    2016-04-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of "new drug delivery systems" is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  7. 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

  8. 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

  9. [Safety and tolerability of GLP-1 receptor agonists].

    PubMed

    Soldevila, Berta; Puig-Domingo, Manel

    2014-01-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer.

  10. [Safety and tolerability of GLP-1 receptor agonists].

    PubMed

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer.

  11. Locomotion induced by ventral tegmental microinjections of a nicotinic agonist.

    PubMed

    Museo, E; Wise, R A

    1990-03-01

    Bilateral microinjections of the nicotinic agonist cytisine (0.1, 1 or 10 nanomoles per side) into the ventral tegmental area increased locomotor activity. This increase in locomotion was antagonized by mecamylamine (2 mg/kg, IP), a nicotinic antagonist that readily crosses the blood-brain barrier, and by pimozide (0.3 mg/kg, IP), a central dopaminergic antagonist. Hexamethonium (2 mg/kg, IP), a nicotinic antagonist that, unlike mecamylamine, does not cross the blood-brain barrier, had no effect; this suggests that mecamylamine's attenuation of cytisine-induced locomotor activity resulted from a blockade of central and not peripheral nicotinic receptors. The data support the notion that nicotinic and dopaminergic substrates interact at the level of the VTA to produce increases in locomotor activity.

  12. Basal Insulin Use With GLP-1 Receptor Agonists.

    PubMed

    Anderson, Sarah L; Trujillo, Jennifer M

    2016-08-01

    IN BRIEF The combination of basal insulin and a glucagon-like peptide 1 receptor agonist is becoming increasingly common and offers several potential benefits to patients with type 2 diabetes. Clinical studies have demonstrated improved glycemic control and low risks of hypoglycemia and weight gain with the combination, which provides a safe and effective alternative to basal-bolus insulin with less treatment burden. Fixed-ratio combination products that administer both agents in a single injection are in the pipeline and will offer additional options for clinicians and patients. This review focuses on the rationale for, clinical evidence on, and implications of using this combination of therapies in the treatment of type 2 diabetes.

  13. 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.

  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. Differential opioid agonist regulation of the mouse mu opioid receptor.

    PubMed

    Blake, A D; Bot, G; Freeman, J C; Reisine, T

    1997-01-10

    Mu opioid receptors mediate the analgesia induced by morphine. Prolonged use of morphine causes tolerance development and dependence. To investigate the molecular basis of tolerance and dependence, the cloned mouse mu opioid receptor with an amino-terminal epitope tag was stably expressed in human embryonic kidney (HEK) 293 cells, and the effects of prolonged opioid agonist treatment on receptor regulation were examined. In HEK 293 cells the expressed mu receptor showed high affinity, specific, saturable binding of radioligands and a pertussis toxin-sensitive inhibition of adenylyl cyclase. Pretreatment (1 h, 3 h, or overnight) of cells with 1 microM morphine or [D-Ala2MePhe4,Gly(ol)5]enkephalin (DAMGO) resulted in no apparent receptor desensitization, as assessed by opioid inhibition of forskolin-stimulated cAMP levels. In contrast, the morphine and DAMGO pretreatments (3 h) resulted in a 3-4-fold compensatory increase in forskolin-stimulated cAMP accumulation. The opioid agonists methadone and buprenorphine are used in the treatment of addiction because of a markedly lower abuse potential. Pretreatment of mu receptor-expressing HEK 293 cells with methadone or buprenorphine abolished the ability of opioids to inhibit adenylyl cyclase. No compensatory increase in forskolin-stimulated cAMP accumulation was found with methadone or buprenorphine; these opioids blocked the compensatory effects observed with morphine and DAMGO. Taken together, these results indicate that methadone and buprenorphine interact differently with the mouse mu receptor than either morphine or DAMGO. The ability of methadone and buprenorphine to desensitize the mu receptor and block the compensatory rise in forskolin-stimulated cAMP accumulation may be an underlying mechanism by which these agents are effective in the treatment of morphine addiction.

  16. Kappa Agonists as a Novel Therapy for Menopausal Hot Flashes

    PubMed Central

    Oakley, Amy E.; Steiner, Robert A.; Chavkin, Charles; Clifton, Donald K.; Ferrara, Laura K.; Reed, Susan D.

    2015-01-01

    Objective Postmenopausal hot flash etiology is poorly understood, making it difficult to develop and target ideal therapies. A network of hypothalamic estrogen-sensitive neurons producing Kisspeptin, Neurokinin B, and Dynorphin (KNDy neurons), located adjacent to the thermoregulatory center, regulate pulsatile secretion of GnRH and LH. Dynorphin may inhibit this system by binding kappa opioid receptors within the vicinity of KNDy neurons. We hypothesize that hot flashes are reduced by KNDy neuron manipulation. Methods A double-blind, cross-over, placebo-controlled pilot study evaluated the effect of a kappa agonist (KA).Hot flash frequency was the primary outcome. Twelve healthy postmenopausal women with moderate-severe hot flashes, ages 48-60 years, were randomized. Eight women with sufficient baseline hot flashes for statistical analysis completed all 3 interventions: placebo, standard Pentazocine/Naloxone (50/0.5 mg) or low-dose Pentazocine/Naloxone (25/0.25 mg). In an inpatient research setting, each participant received the 3 interventions, in randomized order, on 3 separate days. On each day, an intravenous catheter was inserted for luteinizing hormone (LH) blood sampling, and skin conductance and Holter monitors were placed. Subjective hot flash frequency and severity were recorded. Results Mean hot flash frequency 2-7 hours following therapy initiation was lower than that for placebo (KA standard-dose: 4.75 ± 0.67; KA low-dose: 4.50 ± 0.57; and placebo: 5.94 ± 0.78 hot flashes/5 hours; p =0.025). Hot flash intensity did not vary between interventions. LH pulsatility mirrored objective hot flashes in some, but not all women. Conclusions This pilot suggests that kappa agonists may affect menopausal vasomotor symptoms. PMID:25988798

  17. Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra).

    PubMed

    Simons, Rudy; Vincken, Jean-Paul; Mol, Loes A M; The, Susan A M; Bovee, Toine F H; Luijendijk, Teus J C; Verbruggen, Marian A; Gruppen, Harry

    2011-07-01

    The roots of licorice (Glycyrrhiza glabra) are a rich source of flavonoids, in particular, prenylated flavonoids, such as the isoflavan glabridin and the isoflavene glabrene. Fractionation of an ethyl acetate extract from licorice root by centrifugal partitioning chromatography yielded 51 fractions, which were characterized by liquid chromatography-mass spectrometry and screened for activity in yeast estrogen bioassays. One third of the fractions displayed estrogenic activity towards either one or both estrogen receptors (ERs; ERα and ERβ). Glabrene-rich fractions displayed an estrogenic response, predominantly to the ERα. Surprisingly, glabridin did not exert agonistic activity to both ER subtypes. Several fractions displayed higher responses than the maximum response obtained with the reference compound, the natural hormone 17β-estradiol (E(2)). The estrogenic activities of all fractions, including this so-called superinduction, were clearly ER-mediated, as the estrogenic response was inhibited by 20-60% by known ER antagonists, and no activity was found in yeast cells that did not express the ERα or ERβ subtype. Prolonged exposure of the yeast to the estrogenic fractions that showed superinduction did, contrary to E(2), not result in a decrease of the fluorescent response. Therefore, the superinduction was most likely the result of stabilization of the ER, yeast-enhanced green fluorescent protein, or a combination of both. Most fractions displaying superinduction were rich in flavonoids with single prenylation. Glabridin displayed ERα-selective antagonism, similar to the ERα-selective antagonist RU 58668. Whereas glabridin was able to reduce the estrogenic response of E(2) by approximately 80% at 6 × 10(-6) M, glabrene-rich fractions only exhibited agonistic responses, preferentially on ERα.

  18. 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

  19. Cardiovascular selectivity of adenosine receptor agonists in anaesthetized dogs.

    PubMed Central

    Gerencer, R. Z.; Finegan, B. A.; Clanachan, A. S.

    1992-01-01

    1. In order to determine the relevance of adenosine (Ado) receptor classification obtained from in vitro methods to the cardiovascular actions of Ado agonists in vivo, the cardiovascular effects of adenosine 5'-monophosphate (AMP), N6-cyclohexyladenosine (CHA, 400 fold A1-selective), 5'-N-ethyl-carboxamidoadenosine (NECA, A1 approximately A2) and 2-phenylaminoadenosine (PAA, 5 fold A2-selective) were compared in open-chest, fentanyl-pentobarbitone anaesthetized dogs. 2. Graded doses of CHA (10 to 1000 micrograms kg-1), NECA (0.5 to 100 micrograms kg-1) or PAA (0.1 to 20 micrograms kg-1) were administered intravenously and changes in haemodynamics and myocardial contractility were assessed 10 min following each dose. The effects of graded infusions of AMP (200 to 1000 micrograms kg-1 min-1) were also evaluated. 3. AMP and each of the Ado analogues (NECA > PAA > CHA) increased the systemic vascular conductance index (SVCI) in a dose-dependent manner and reduced mean arterial pressure (MAP). At doses causing similar increases in SVCI, these agonists caused (i) similar reflex increases in heart rate (HR) and cardiac index (CI) and decreases in AV conduction interval (AVi) and (ii) similar increases in coronary vascular conductance (CVC). 4. After cardiac autonomic blockade with atropine (0.2 mg kg-1) and propranolol (1 mg kg-1), AMP, CHA and PAA still increased SVCI and CVC and decreased MAP. CHA and PAA had no marked effects on HR, CI or AVi. As in the absence of cardiac autonomic blockade, equieffective vasodilator doses of CHA and PAA had identical effects on CVC, CI and AVi.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1467827

  20. GITR agonist enhances vaccination responses in lung cancer.

    PubMed

    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

    2015-04-01

    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.

  1. Influence of beta-adrenoceptor agonists and antagonists on baclofen-induced memory impairment in mice.

    PubMed

    Zarrindast, M R; Haidari, H; Jafari, M R; Djahanguiri, B

    2004-07-01

    Post-training administration of different doses of baclofen (a GABAB agonist) has been shown to impair memory retention, in a step-down passive avoidance test in mice. We have studied the effects of beta-adrenergic agonists and antagonists on baclofen-induced memory impairment in mice. Dobutamine (a beta 1-agonist) or salbutamol (a beta 2-agonist) reversed the memory impairment induced by baclofen without exhibiting intrinsic actions on memory when administered alone. The administration of atenolol (a beta 1-antagonist) or propranolol (a beta-antagonist) produced a memory impairment. When co-administered with baclofen, both atenolol and propranolol exacerbated the memory impairment induced by the GABAB agonist. It is concluded that beta-adrenergic mechanisms may be involved in the modulation of memory via GABAB receptors.

  2. Rate constants of agonist binding to muscarinic receptors in rat brain medulla. Evaluation by competition kinetics

    SciTech Connect

    Schreiber, G.; Henis, Y.I.; Sokolovsky, M.

    1985-07-25

    The method of competition kinetics, which measures the binding kinetics of an unlabeled ligand through its effect on the binding kinetics of a labeled ligand, was employed to investigate the kinetics of muscarinic agonist binding to rat brain medulla pons homogenates. The agonists studied were acetylcholine, carbamylcholine, and oxotremorine, with N-methyl-4-(TH)piperidyl benzilate employed as the radiolabeled ligand. Our results suggested that the binding of muscarinic agonists to the high affinity sites is characterized by dissociation rate constants higher by 2 orders of magnitude than those of antagonists, with rather similar association rate constants. Our findings also suggest that isomerization of the muscarinic receptors following ligand binding is significant in the case of antagonists, but not of agonists. Moreover, it is demonstrated that in the medulla pons preparation, agonist-induced interconversion between high and low affinity bindings sites does not occur to an appreciable extent.

  3. Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations.

    PubMed

    Carris, Nicholas W; Taylor, James R; Gums, John G

    2014-12-01

    Most patients with diabetes mellitus require multiple medications to achieve glycemic goals. Considering this and the increasing incidence of type 2 diabetes worldwide, the need for effective combination therapy is pressing. Basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. Though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. This review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin-GLP-1 receptor agonist regimen. Basal insulin added to a GLP-1 receptor agonist reduces hemoglobin A1c (HbA1c) without weight gain or significantly increased hypoglycemia. A GLP-1 receptor agonist added to basal insulin reduces HbA1c and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA1c, weight loss instead of weight gain, and less hypoglycemia. Gastrointestinal adverse events are common with GLP-1 receptor agonists, especially during initiation and titration. However, combination with basal insulin is not expected to augment expected adverse events that come with using a GLP-1 receptor agonist. Basal insulin can be added to a GLP-1 receptor agonist with a slow titration to target goal fasting plasma glucose. In patients starting a GLP-1 receptor agonist, the dose of basal insulin should be decreased by 20 % in patients with an HbA1c ≤8 %. The evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes.

  4. Dissemination of Solid and Liquid BW Agents

    DTIC Science & Technology

    experiments on the characteristics of powders are presented including investigations of frictional forces between powders and channel walls and dynamic angle ...of repose of Sm powder. Theoretical studies of load transmission in particulate materials and several specific cases of force transmission were

  5. Final Report BW Sample Collection& Preparation Device

    SciTech Connect

    Koopman, R P; Belgrader, P; Meyer, G; Benett, W J; Richards, J B; Hadley, D R; Stratton, P L; Milanovich, F P

    2002-01-31

    The objective of this project was to develop the technique needed to prepare a field collected sample for laboratory analysis and build a portable integrated biological detection instrument with new miniaturized and automated sample purification capabilities. The device will prepare bacterial spores, bacterial vegetative cells, and viral particles for PCR amplification.

  6. 360 degree b/w 'Monster Pan'

    NASA Technical Reports Server (NTRS)

    1997-01-01

    This 360 degree 'monster' panorama was taken by the deployed Imager for Mars Pathfinder (IMP) on Sol 3. All three petals, the perimeter of the deflated airbags, deployed rover Sojourner, forward and backward ramps and prominent surface features are visible. The IMP stands 1.8 meters over the Martian surface. The curvature and misalignment of several sections are due to image parallax.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  7. Withdrawal of GnRH agonist decreases oestradiol and VEGF concentrations in high responders.

    PubMed

    Ding, Li-Jun; Wang, Bin; Shen, Xiao-Yue; Yan, Gui-Jun; Zhang, Ning-Yuan; Hu, Ya-Li; Sun, Hai-Xiang

    2013-08-01

    This study evaluated whether the withdrawal of a gonadotrophin-releasing hormone (GnRH) agonist before triggering ovulation reduces the incidence of ovarian hyperstimulation syndrome (OHSS) in high-risk infertility patients who were treated with gonadotrophins. GnRH agonist was withdrawn for 2 or 3 days when dominant follicles were ≥14 mm in diameter, according to the GnRH agonist long protocol. Non-withdrawal of GnRH agonist was used as control. The serum concentration of oestradiol on the ovulation trigger day was significantly decreased in the GnRH agonist withdrawal group compared with the control group (5750.78 ± 2344.77 pg/ml versus 8076.43 ± 1981.67 pg/ml); however, the number of retrieved oocytes and the fertilization rate were similar between the groups. In addition, the concentrations of vascular endothelial growth factor in plasma on day of human chorionic gonadotrophin administration and follicular fluid on the oocyte retrieval day were decreased following GnRH agonist withdrawal. In fresh embryo transfer cycles, rates of clinical pregnancy, implantation and OHSS were not different between the groups. When GnRH agonist withdrawal was followed by total embryos cryopreserved, the rate of OHSS was decreased compared with the control group (0% versus 8.70%). Clinical pregnancy rates in cryopreserved embryo transfer cycles were comparable between the two groups.

  8. The glycine transport inhibitor sarcosine is an NMDA receptor co-agonist that differs from glycine

    PubMed Central

    Zhang, Hai Xia; Hyrc, Krzysztof; Thio, Liu Lin

    2009-01-01

    Sarcosine is an amino acid involved in one-carbon metabolism and a promising therapy for schizophrenia because it enhances NMDA receptor (NMDAR) function by inhibiting glycine uptake. The structural similarity between sarcosine and glycine led us to hypothesize that sarcosine is also an agonist like glycine. We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons. We found that sarcosine is an NMDAR co-agonist at the glycine binding site. However, sarcosine differed from glycine because less NMDAR desensitization occurred with sarcosine than with glycine as the co-agonist. This finding led us to examine whether the physiological effects of NMDAR activation with these two co-agonists are the same. The difference in desensitization probably accounts for rises in intracellular Ca2+, as assessed by the fluorescent indicator fura-FF, being larger when NMDAR activation occurred with sarcosine than with glycine. In addition, Ca2+-activated K+ currents following NMDAR activation were larger with sarcosine than with glycine. Compared to glycine, NMDAR-mediated autaptic currents decayed faster with sarcosine suggesting that NMDAR deactivation also differs with these two co-agonists. Despite these differences, NMDAR-dependent neuronal death as assessed by propidium iodide was similar with both co-agonists. The same was true for neuronal bursting. Thus, sarcosine may enhance NMDAR function by more than one mechanism and may have different effects from other NMDAR co-agonists. PMID:19433577

  9. Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria

    PubMed Central

    Brust, Tarsis F.; Morgenweck, Jenny; Kim, Susy A.; Rose, Jamie H.; Locke, Jason L.; Schmid, Cullen L.; Zhou, Lei; Stahl, Edward L.; Cameron, Michael D.; Scarry, Sarah M.; Aubé, Jeffrey; Jones, Sara R.; Martin, Thomas J.; Bohn, Laura M.

    2016-01-01

    Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain. Unlike typical opioid narcotics, KOR agonists do not produce euphoria or lead to respiratory suppression or overdose. However, they do produce dysphoria and sedation, side effects that have precluded their clinical development as therapeutics. KOR signaling can be fine-tuned to preferentially activate certain pathways over others, such that agonists can bias signaling so that the receptor signals through G proteins rather than other effectors such as βarrestin2. We evaluated a newly developed G protein signaling–biased KOR agonist in preclinical models of pain, pruritis, sedation, dopamine regulation, and dysphoria. We found that triazole 1.1 retained the antinociceptive and antipruritic efficacies of a conventional KOR agonist, yet it did not induce sedation or reductions in dopamine release in mice, nor did it produce dysphoria as determined by intracranial self-stimulation in rats. These data demonstrated that biased agonists may be used to segregate physiological responses downstream of the receptor. Moreover, the findings suggest that biased KOR agonists may present a means to treat pain and intractable itch without the side effects of dysphoria and sedation and with reduced abuse potential. PMID:27899527

  10. Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists.

    PubMed

    Kangas, Brian D; Delatte, Marcus S; Vemuri, V Kiran; Thakur, Ganesh A; Nikas, Spyridon P; Subramanian, Kumara V; Shukla, Vidyanand G; Makriyannis, Alexandros; Bergman, Jack

    2013-03-01

    Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB(1) inverse agonist SR141716A (rimonabant) and the CB(1) neutral antagonist AM4113 were compared for their ability to modify CB(1) receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054. Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB(1) neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB(1) receptors.

  11. Evaluation of the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages.

    PubMed

    Gill, Sharonjit K; Marriott, Helen M; Suvarna, S Kim; Peachell, Peter T

    2016-12-15

    The principal mechanism by which bronchodilator β-adrenoceptor agonists act is to relax airways smooth muscle although they may also be anti-inflammatory. However, the extent of anti-inflammatory activity and the cell types affected by these agonists are uncertain. The purpose of this study was to evaluate whether β-adrenoceptor agonists prevent pro-inflammatory cytokine generation from activated human lung macrophages. Macrophages were isolated and purified from human lung. The cells were pre-treated with both short-acting (isoprenaline, salbutamol, terbutaline) and long-acting (formoterol, salmeterol, indacaterol) β-agonists before activation with lipopolysaccharide (LPS) to induce cytokine (TNFα, IL-6, IL-8 and IL-10) generation. The experiments showed that short-acting β-agonists were poor inhibitors of cytokine generation. Of the long-acting β-agonists studied, formoterol was also a weak inhibitor of cytokine generation whereas only indacaterol and salmeterol showed moderate inhibitory activity. Further experiments using the β2-adrenoceptor antagonist ICI-118,551 suggested that the effects of indacaterol were likely to be mediated by β2-adrenoceptors whereas those of salmeterol were not. These findings were corroborated by functional desensitization studies in which the inhibitory effects of indacaterol appeared to be receptor-mediated whereas those of salmeterol were not. Taken together, the data indicate that the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages are modest.

  12. 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.

  13. 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.

  14. Potency and characterization of estrogen-receptor agonists in United Kingdom estuarine sediments.

    PubMed

    Thomas, Kevin V; Balaam, Jan; Hurst, Mark; Nedyalkova, Zoya; Mekenyan, Ovanes

    2004-02-01

    The activity of estrogen-receptor (ER) agonists in sediments collected from the United Kingdom (UK) estuaries was assessed using the in vitro recombinant yeast estrogen screen (YES assay). The YES assay was successfully used to determine the in vitro ER agonist potency of pore waters and solvent extracts of sediments collected from UK estuaries. Estrogen-receptor agonists were detected in 66% of the pore water samples and in 91% of the sediment solvent extracts tested. The pore waters tested had ER agonist potencies from less than 2 to 68 ng 17beta-estradiol (E2) L(-1), whereas sediment extracts had potencies from less than 0.2 to 13 microg E2 kg(-1). A toxicity identification evaluation approach using bioassay-directed fractionation was used in an attempt to identify the ER agonists in extracts of sediments collected from the Tyne and Tees estuaries (UK). Gas chromatography-mass spectrometry was used to provide lists of compounds in the fractions obtained that were evaluated for known ER agonist activity using published data and an ER quantitative structure-activity relationship model. Toxicity identification evaluation characterization failed to identify any ER agonists in pore water extracts; however, three compounds in sediment solvent extracts were identified as ER agonists. Nonylphenol, cinnarizine, and cholesta-4,6-dien-3-one were identified in the sample collected from the Tyne estuary. Important ER agonist substances that contaminate marine sediments remain unidentified. The present study as well as previous work on effluents point toward the involvement of natural products in the estrogenic burdens of marine sediments. Further work is required to establish the relative contribution of natural products and anthropogenic chemicals to current environmental impacts in the context of the Oslo and Paris Commission strategy to eliminate hazardous substances by 2020.

  15. CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity.

    PubMed

    Baillie, Gemma L; Horswill, James G; Anavi-Goffer, Sharon; Reggio, Patricia H; Bolognini, Daniele; Abood, Mary E; McAllister, Sean; Strange, Phillip G; Stephens, Gary J; Pertwee, Roger G; Ross, Ruth A

    2013-02-01

    We have previously identified allosteric modulators of the cannabinoid CB(1) receptor (Org 27569, PSNCBAM-1) that display a contradictory pharmacological profile: increasing the specific binding of the CB(1) receptor agonist [(3)H]CP55940 but producing a decrease in CB(1) receptor agonist efficacy. Here we investigated the effect one or both compounds in a broad range of signaling endpoints linked to CB(1) receptor activation. We assessed the effect of these compounds on CB(1) receptor agonist-induced [(35)S]GTPγS binding, inhibition, and stimulation of forskolin-stimulated cAMP production, phosphorylation of extracellular signal-regulated kinases (ERK), and β-arrestin recruitment. We also investigated the effect of these allosteric modulators on CB(1) agonist binding kinetics. Both compounds display ligand dependence, being significantly more potent as modulators of CP55940 signaling as compared with WIN55212 and having little effect on [(3)H]WIN55212 binding. Org 27569 displays biased antagonism whereby it inhibits: agonist-induced guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding, simulation (Gα(s)-mediated), and inhibition (Gα(i)-mediated) of cAMP production and β-arrestin recruitment. In contrast, it acts as an enhancer of agonist-induced ERK phosphorylation. Alone, the compound can act also as an allosteric agonist, increasing cAMP production and ERK phosphorylation. We find that in both saturation and kinetic-binding experiments, the Org 27569 and PSNCBAM-1 appeared to influence only orthosteric ligand maximum occupancy rather than affinity. The data indicate that the allosteric modulators share a common mechanism whereby they increase available high-affinity CB(1) agonist binding sites. The receptor conformation stabilized by the allosterics appears to induce signaling and also selectively traffics orthosteric agonist signaling via the ERK phosphorylation pathway.

  16. Order-disorder in In{sup 3+} perovskites: The example of A(In{sub 2/3}B''{sub 1/3})O{sub 3} (A=Ba, Sr; B''=W, U)

    SciTech Connect

    Larregola, S.A. Alonso, J.A.; Pinacca, R.M.; Viola, M.C.; Pedregosa, J.C.

    2008-10-15

    We describe the preparation and structural characterization of four In-containing perovskites from neutron powder diffraction (NPD) and X-ray powder diffraction (XRPD) data. Sr{sub 3}In{sub 2}B''O{sub 9} and Ba(In{sub 2/3}B''{sub 1/3})O{sub 3} (B''=W, U) were synthesized by standard ceramic procedures. The crystal structure of the W-containing perovskites and Ba(In{sub 2/3}U{sub 1/3})O{sub 3} have been revisited based on our high-resolution NPD and XRPD data, while for the new U-containing perovskite Sr{sub 3}In{sub 2}UO{sub 9} the structural refinement was carried out from high-resolution XRPD data. At room temperature, the crystal structure for the two Sr phases is monoclinic, space group P2{sub 1}/n, where the In atoms occupy two different sites Sr{sub 2}[In]{sub 2d}[In{sub 1/3}B''{sub 2/3}]{sub 2c}O{sub 6}, with a=5.7548(2) A, b=5.7706(2) A, c=8.1432(3) A, {beta}=90.01(1){sup o} for B''=W and a=5.861(1) A, b=5.908(1) A, c=8.315(2) A, {beta}=89.98(1){sup o} for B''=U. The two phases with A=Ba should be described in a simple cubic perovskite unit cell (S.G. Pm3-bar m) with In and B'' distributed at random at the octahedral sites, with a=4.16111(1) A and 4.24941(1) A for W and U compounds, respectively. - Graphical abstract: The structure of the new uranium-based double perovskite Sr{sub 3}In{sub 2}UO{sub 9} is described and the true symmetry of the other title compounds are revisited. The presence of long-range ordering in the Sr samples, by contrast with the Ba perovskites, is related with the smaller unit cell and B-B distances in the Sr oxides, promoting the electrostatic repulsions between highly charged W{sup 6+} and U{sup 6+} cations as driving force for the long-range B-site ordering.

  17. The most effective influence of 17-(3-ethoxypropyl) substituent on the binding affinity and the agonistic activity in KNT-127 derivatives, δ opioid receptor agonists.

    PubMed

    Nemoto, Toru; Ida, Yoshihiro; Iihara, Yusuke; Nakajima, Ryo; Hirayama, Shigeto; Iwai, Takashi; Fujii, Hideaki; Nagase, Hiroshi

    2013-12-15

    We investigated the structure-activity relationship of KNT-127 (opioid δ agonist) derivatives with various 17-substituents which are different in length and size. The 17-substituent in KNT-127 derivatives exerted a great influence on the affinity and agonistic activity for the δ receptor. While the compounds with electron-donating 17-substituents showed higher affinities for the δ receptor than those with electron-withdrawing groups, KNT-127 derivatives with 17-fluoroalkyl groups (the high electron-withdrawing groups) showed high selectivities for the δ receptor among evaluated compounds. In addition, the basicity of nitrogen as well as the structure of the 17-N substituent such as the length and configuration at an asymmetric carbon atom contributed to agonist properties for the δ receptor. Thus, the analog with a 17-(3-ethoxypropyl) group showed the best selectively and potent agonistic activity for the δ receptor among KNT-127 derivatives. These findings should be useful for designing novel δ selective agonists.

  18. Differential behavioral effect of the TRPM8/TRPA1 channel agonist icilin (AG-3-5).

    PubMed

    Rawls, Scott M; Gomez, Teresa; Ding, Zhe; Raffa, Robert B

    2007-12-01

    Molecular identification of two new transient receptor potential (TRP) channels, TRPM8 and TRPA1, has prompted an intense interest in their functional roles. We report that an acute exposure to the TRPM8/TRPA1 agonist icilin (0.01-100 microM), but not TRPV1 agonist capsaicin (10 microM), causes an atypical dose-related increase in planarian motility. This is the first demonstration of a TRPM8/TRPA1 channel subtype agonist-induced differential pharmacological effect in invertebrates and provides a novel sensitive, quantifiable end-point for studying TRP channel pharmacology.

  19. GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice.

    PubMed

    Arai, Sawako; Takuma, Kazuhiro; Mizoguchi, Hiroyuki; Ibi, Daisuke; Nagai, Taku; Kamei, Hiroyuki; Kim, Hyoung-Chun; Yamada, Kiyofumi

    2009-01-05

    In this study, we investigated the effects of GABA(A) and GABA(B) receptor agonists on the methamphetamine-induced impairment of recognition memory in mice. Repeated treatment with methamphetamine at a dose of 1 mg/kg for 7 days induced an impairment of recognition memory. Baclofen, a GABA(B) receptor agonist, ameliorated the repeated methamphetamine-induced cognitive impairment, although gaboxadol, a GABA(A) receptor agonist, had no significant effect. GABA(B) receptors may constitute a putative new target in treating cognitive deficits in patients suffering from schizophrenia, as well as methamphetamine psychosis.

  20. Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function

    PubMed Central

    Perroy, Julie; Walwyn, Wendy M.; Smith, Monique L.; Vicente-Sanchez, Ana; Segura, Laura; Bana, Alia; Kieffer, Brigitte L.; Evans, Christopher J.

    2016-01-01

    Ligand-specific recruitment of arrestins facilitates functional selectivity of G-protein-coupled receptor signaling. Here, we describe agonist-selective recruitment of different arrestin isoforms to the delta opioid receptor in mice. A high-internalizing delta opioid receptor agonist (SNC80) preferentially recruited arrestin 2 and, in arrestin 2 knock-outs (KOs), we observed a significant increase in the potency of SNC80 to inhibit mechanical hyperalgesia and decreased acute tolerance. In contrast, the low-internalizing delta agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3 with unaltered behavioral effects in arrestin 2 KOs. Surprisingly, arrestin 3 KO revealed an acute tolerance to these low-internalizing agonists, an effect never observed in wild-type animals. Furthermore, we examined delta opioid receptor–Ca2+ channel coupling in dorsal root ganglia desensitized by ARM390 and the rate of resensitization was correspondingly decreased in arrestin 3 KOs. Live-cell imaging in HEK293 cells revealed that delta opioid receptors are in pre-engaged complexes with arrestin 3 at the cell membrane and that ARM390 strengthens this membrane interaction. The disruption of these complexes in arrestin 3 KOs likely accounts for the altered responses to low-internalizing agonists. Together, our results show agonist-selective recruitment of arrestin isoforms and reveal a novel endogenous role of arrestin 3 as a facilitator of resensitization and an inhibitor of tolerance mechanisms. SIGNIFICANCE STATEMENT Agonists that bind to the same receptor can produce highly distinct signaling events and arrestins are a major mediator of this ligand bias. Here, we demonstrate that delta opioid receptor agonists differentially recruit arrestin isoforms. We found that the high-internalizing agonist SNC80 preferentially recruits arrestin 2 and knock-out (KO) of this protein results in increased efficacy of SNC80. In contrast, low-internalizing agonists (ARM390 and JNJ20788560

  1. Agonist actions of neonicotinoids on nicotinic acetylcholine receptors expressed by cockroach neurons.

    PubMed

    Tan, Jianguo; Galligan, James J; Hollingworth, Robert M

    2007-07-01

    The agonist actions of seven commercial neonicotinoid insecticides and nicotine were studied on nicotinic acetylcholine receptors (nAChRs) expressed by neurons isolated from the three thoracic ganglia of the American cockroach, Periplaneta americana. Single electrode voltage clamp recording was used to measure agonist-induced inward currents. Acetylcholine, nicotine and all neonicotinoids tested, except thiamethoxam, caused inward currents which were blocked reversibly by methyllycaconitine, a nAChR antagonist. Based on maximum inward currents, neonicotinoids could be divided into two subgroups: (1) those with a heterocyclic ring in their electronegative pharmacophore moiety (i.e. nicotine, imidacloprid and thiacloprid) were relatively weak partial agonists causing only 20-25% of the maximum ACh current and (2) open chain compounds (i.e. acetamiprid, dinotefuran, nitenpyram, and clothiandin) which were much more effective agonists producing 60-100% of the maximum ACh current. These compounds also elicited different symptoms of poisoning in American cockroaches with excitatory responses evident for the low efficacy agonists but depressive and paralytic responses predominating for the most efficacious agonists. No correlation was observed between agonist affinity and efficacy on these nAChRs. Thiamethoxam, even at 100 microM, failed to cause an inward current and showed no competitive interaction with other neonicotinoids on nAChRs, indicating that it is not a direct-acting agonist or antagonist. Despite the probable presence of multiple subtypes of nAChRs on cockroach neurons, competition studies between neonicotinoids did not reveal evidence that separate binding sites exist for the tested compounds. The size of inward currents induced by co-application of neonicotinoid pairs at equal concentration (100 microM) were predominantly determined by the one with higher binding affinity as indicated by EC(50) values, rather than by the one with higher binding efficacy as

  2. PPAR Agonists for the Prevention and Treatment of Lung Cancer

    PubMed Central

    Banno, Asoka

    2017-01-01

    Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPARα, PPARβ/δ, and PPARγ, display distinct biological activities and varied influences on lung cancer biology. PPARα activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARγ is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPARα and PPARγ, whether PPARβ/δ activation is anti- or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease. PMID:28316613

  3. Mechanical stress activates NMDA receptors in the absence of agonists.

    PubMed

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K; Sachs, Frederick; Hua, Susan Z

    2017-01-03

    While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca(2+) entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca(2+) influx. Extracellular Mg(2+) at 2 mM did not significantly affect the shear induced Ca(2+) influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.

  4. Basic understanding of gonadotropin-releasing hormone-agonist triggering.

    PubMed

    Casper, Robert F

    2015-04-01

    A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle-stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (≥6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles.

  5. Mechanical stress activates NMDA receptors in the absence of agonists

    PubMed Central

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

    2017-01-01

    While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca2+ influx. Extracellular Mg2+ at 2 mM did not significantly affect the shear induced Ca2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI. PMID:28045032

  6. Can the sigma-1 receptor agonist fluvoxamine prevent schizophrenia?

    PubMed

    Hashimoto, Kenji

    2009-12-01

    In the past decade there has been increasing interest in the potential benefit of early pharmacological intervention in schizophrenia. Patients with schizophrenia show nonpsychotic and nonspecific prodromal symptoms (e.g., depression and cognitive deficits) for several years preceding the onset of frank psychosis. Several studies have demonstrated that medication with atypical antipsychotic drugs in people with prodromal symptoms may reduce the risk of subsequent transition to schizophrenia. Furthermore, a naturalistic treatment study in young people with prodromal symptoms demonstrated that medication with antidepressants could prevent the development of psychosis. Although the sample in this study was small, the results were striking. Some antidepressants, including selective serotonin reuptake inhibitors (SSRIs), had high to moderate affinities at the endoplasmic reticulum protein sigma-1 receptors, which are implicated in neuroprotection and neuronal plasticity. Among all antidepressants, fluvoxamine was the most potent sigma-1 receptor agonist. Since the effects of fluroxaming were antagonized by the selective sigma-1 receptor antagonist NE-100. Based on the role of sigma-1 receptors in the pathophysiology of cognition and depression, the author would like to propose a hypothesis that SSRIs (e.g., fluvoxamine) with sigma-1 receptor agonism may reduce the risk of subsequent transition to schizophrenia.

  7. 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.

  8. [Treatment of hyperprolactinemic anovulation with the dopamin-agonist quinagolide].

    PubMed

    Koloszár, S; Keresztúri, A; Kovács, L

    2000-07-16

    Quinagolide has a strong dopaminerg activity, suppresses prolactin secretion and restores gonadal function in women with hyperprolactinemic anovulation. The aim of our study was to investigate the effectiveness of quinagolide in the treatment of 16 hyperprolactinemic patients. The clinical diagnosis was functional hyperprolactinemia in 13 patients, microprolactinoma in 2 and empty sella syndrome in 1. The drug was administered orally and initially daily dose was 0.025 mg for the first three days, 0.050 mg for the next three days and 0.075 mg for the following 6 months. The serum prolactin level was measured monthly before pregnancy, three monthly during the pregnancy and six weeks after delivery. Serum prolactin levels decreased in most of the patients during the first month and only in one case remained in the pathological range after six months quinagolide++ treatment. Prolactin secretion changed (mean and range) from 3120 (780-5790) mU/l to 370 (84-1076) mU/l. Out of 16 hyperprolactinemic patients nine women were infertile. During quinagolide treatment 5 pregnancies occurred. In conclusion, our results show that quinagolide has a good efficacy on regulation of prolactin secretion and it is a well tolerated dopamin-agonist drug.

  9. Object-horning in goitered gazelle: agonistic or marking behaviour?

    PubMed

    Blank, David; Yang, Weikang

    2014-03-01

    We studied object-horning behaviour in goitered gazelles in the natural, arid environment of Kazakhstan over a 6-year period. We found that object-horning was used by adult males mostly as a threat display during territorial conflicts. Therefore object-horning was observed most frequently in territorial single males during the rut in November-December. Object-horning, though, also had a marking effect, with the males' use of this behaviour leaving visible traces that advertized the location of preorbital and urination-defecation scent marks. Therefore, this pattern also was observed linked with preorbital marking and urination-defecation marking behaviours, especially during the rut. Goitered gazelle males chose the most abundant and eatable shrubs for object horning. In contrast to other gazelle species, object-horning in goitered gazelle was observed much more frequently and at the same rate as preorbital and urination-defecation scent markings. This, then, proved a more vigorous and aggressive level of rutting behaviour of the goitered gazelle compared to tropical gazelles, and most likely connected to the short rutting period in the studied species. We concluded, therefore, that object-horning was a manifold phenomenon that played a very important role in goitered gazelle agonistic displays, but without loosing the marking intention of this behaviour.

  10. Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

    PubMed

    Fredrickson, Paul; Boules, Mona; Stennett, Bethany; Richelson, Elliott

    2014-03-01

    Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a "gateway drug". Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

  11. Publicity and reports of behavioral addictions associated with dopamine agonists

    PubMed Central

    Gendreau, Katherine E.; Potenza, Marc N.

    2016-01-01

    Background The development of behavioral addictions (BAs) in association with dopamine agonists (DAs, commonly used to treat Parkinson’s disease) has been reported. A recent report presented data that these associations are evident in the US Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS), a database containing information on adverse drug event and medication error reports submitted to the FDA. However, given that vulnerability to publicity-stimulated reporting is a potential limitation of spontaneous reporting systems like the FAERS, the potential impact of publicity on reporting in this case remains unclear. Method and aims To investigate the potential impact of publicity on FAERS reporting of BAs in association with DAs (BAs w/DAs) as presented by Moore, Glenmullen, and Mattison (2014), news stories covering a BA/DA association were identified and compared with BA w/DA and other reporting data in the FAERS. Results Fluctuations in the growth of BA w/DA reporting to the FAERS between 2003 and 2012 appear to coincide with multiple periods of intensive media coverage of a BA/DA association, a pattern that is not evident in other reporting data in the FAERS. Discussion/Conclusions Publicity may stimulate reporting of adverse events and premature dismissal of the potential influence of publicity on reporting may lead to mistaking an increased risk of an adverse event being reported for an increased risk of an adverse event occurring. PMID:26690325

  12. Juvenile hormone agonists affect the occurrence of male Daphnia.

    PubMed

    Tatarazako, Norihisa; Oda, Shigeto; Watanabe, Hajime; Morita, Masatoshi; Iguchi, Taisen

    2003-12-01

    The water flea Daphnia magna reproduces primarily by cyclic parthenogenesis. Environmental stimuli that signal a change to adverse conditions induce the organisms to switch from parthenogenesis to gamogenetic reproduction. During the gamogenetic period, they produce male daphnids and dormant resting eggs, which can survive prolonged periods of environmental adversity. However, little is known about the mechanisms associated with the switch from parthenogenesis to gamogenetic reproduction. We investigated the effects of several juvenoids on sex determination in Daphnia. Females less than 24 h old were exposed to various concentrations of the test substance and were observed for 21 days. It was found that they can trigger the appearance of male daphnids: the percentage of males in the population increases to a level greater than what occurs under ordinary environmental conditions. We found that methylfarnesoate, juvenile hormone III, methoprene, and the phenoxyphenoxy derivatives pyriproxyfen and fenoxycarb (both insecticides) reduced the production of offspring and produced sex ratios dominated by male daphnids. Pyriproxyfen and fenoxycarb showed striking effects at low concentrations. Exposure to either of these chemicals at a concentration of 330 ngl(-1) caused adult females to produce almost all male neonates. Methylfarnesoate, juvenile hormone III, and methoprene showed an effect in inducing male production at higher concentrations (3.7 x 10(3), 3.3 x 10(5), and 1.3 x 10(5) ngl(-1), respectively). Our findings suggest that juvenile hormone agonists, including some insecticides, affect the chemical signaling responsible for inducing the production of male offspring.

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

    PubMed Central

    Amarante-Mendes, Gustavo P.; Griffith, Thomas S.

    2016-01-01

    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

  14. Intracellular calcium strongly potentiates agonist-activated TRPC5 channels

    PubMed Central

    Blair, Nathaniel T.; Kaczmarek, J. Stefan

    2009-01-01

    TRPC5 is a calcium (Ca2+)-permeable nonselective cation channel expressed in several brain regions, including the hippocampus, cerebellum, and amygdala. Although TRPC5 is activated by receptors coupled to phospholipase C, the precise signaling pathway and modulatory signals remain poorly defined. We find that during continuous agonist activation, heterologously expressed TRPC5 currents are potentiated in a voltage-dependent manner (∼5-fold at positive potentials and ∼25-fold at negative potentials). The reversal potential, doubly rectifying current–voltage relation, and permeability to large cations such as N-methyl-d-glucamine remain unchanged during this potentiation. The TRPC5 current potentiation depends on extracellular Ca2+: replacement by Ba2+ or Mg2+ abolishes it, whereas the addition of 10 mM Ca2+ accelerates it. The site of action for Ca2+ is intracellular, as simultaneous fura-2 imaging and patch clamp recordings indicate that potentiation is triggered at ∼1 µM [Ca2+]. This potentiation is prevented when intracellular Ca2+ is tightly buffered, but it is promoted when recording with internal solutions containing elevated [Ca2+]. In cell-attached and excised inside-out single-channel recordings, increases in internal [Ca2+] led to an ∼10–20-fold increase in channel open probability, whereas single-channel conductance was unchanged. Ca2+-dependent potentiation should result in TRPC5 channel activation preferentially during periods of repetitive firing or coincident neurotransmitter receptor activation. PMID:19398778

  15. Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

    DTIC Science & Technology

    2012-07-01

    July 2011 - 30 June 2012 4 . TITLE AND SUBTITLE Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity 5a...Introduction…………………………………………………………….………..….. 1 Body………………………………………………………………………………….. 1 Key Research Accomplishments………………………………………….…….. 4 ...Reportable Outcomes……………………………………………………………… 4 Conclusion…………………………………………………………………………… 8 References……………………………………………………………………………. 9

  16. Agonist photoaffinity label for the. beta. -adrenergic receptor

    SciTech Connect

    Resek, J.F.; Ruoho, A.E.

    1987-05-01

    An iodinated photosensitive derivative of norepinephrine, N-(p-azido-m-iodophenethylamidoisobutyryl)norepinephrine (NAIN), has been synthesized and characterized. Carrier-free radioiodinated NAIN ((/sup 125/I)-NAIN) was used at 1-2 x 10/sup -9/ M to photoaffinity label the ..beta..-adrenergic receptor in guinea pig lung membranes. SDS-PAGE analysis of (-)-alprenolol (10/sup -5/M) protectable (/sup 125/I)-NAIN labeling showed the same molecular weight polypeptide (65 kDa) that was specifically derivatized with the antagonist photolabel, (/sup 125/I)-IABP. Specific labeling of the ..beta..-adrenergic receptor with (/sup 125/I)-NAIN was dependent on the presence of MgCl/sub 2/ and the absence of guanyl nucleotide. GTP..gamma..S (10/sup -4/ M) abolished specific receptor labeling by (/sup 125/I)-NAIN. N-ethylmaleimide (2 mm) in the presence of (/sup 125/I)-NAIN protected against the guanyl nucleotide effect. These data are consistent with photolabeling by (/sup 125/I)-NAIN while the agonist, receptor, and GTP binding protein are in a high affinity complex.

  17. Agonist Derived Molecular Probes for A2A Adenosine Receptors

    PubMed Central

    Jacobson, Kenneth A.; Pannell, Lewis K.; Ji, Xiao-duo; Jarvis, Michael F.; Williams, Michael; Hutchison, Alan J.; Barrington, William W.; Stiles, Gary L.

    2011-01-01

    The adenosine agonist 2-(4-(2-carboxyethyl)phenylethylamino)-5′-N-ethylcarboxamidoadenosine (CGS21680) was recently reported to be selective for the A2A adenosine receptor subtype, which mediates its hypotensive action. To investigate structurelactivity relationships at a distal site, CGS21680 was derivatized using a functionalized congener approach. The carboxylic group of CGS21680 has been esterified to form a methyl ester, which was then treated with ethylenediamine to produce an amine congener. The amine congener was an intermediate for acylation reactions, in which the reactive acyl species contained a reported group, or the precursor for such. For radioiodination, derivatives of p-hydroxyphenylpropionic, 2-thiophenylacetic, and p-aminophenylacetic acids were prepared. The latter derivative (PAPA-APEC) was iodinated electrophilically using [125I]iodide resulting in a radioligand which was used for studies of competition of binding to striatal A, adenosine receptors in bovine brain. A biotin conjugate and an aryl sulfonate were at least 350-fold selective for A, receptors. For spectroscopic detection, a derivative of the stable free radical tetramethyl-1-piperidinyloxy (TEMPO) was prepared. For irreversible inhibition of receptors, meta- and para-phenylenediisothiocyanate groups were incorporated in the analogs. We have demonstrated that binding at A2A receptors is relatively insensitive to distal structural changes at the 2-position, and we report high affinity molecular probes for receptor characterization by radioactive, spectroscopic and affinity labelling methodology. PMID:2561548

  18. Ingestion of TRP channel agonists attenuates exercise-induced muscle cramps.

    PubMed

    Craighead, Daniel H; Shank, Sean W; Gottschall, Jinger S; Passe, Dennis H; Murray, Bob; Alexander, Lacy M; Kenney, W Larry

    2017-02-13

    Exercise associated muscle cramping (EAMC) is a poorly understood problem that is neuromuscular in origin. Ingestion of transient receptor potential (TRP) channel agonists has been efficacious in attenuating electrically-induced muscle cramps.

  19. Alpha 2-adrenoceptor agonists potentiate responses mediated by alpha 1-adrenoceptors in the cat nictitating membrane.

    PubMed Central

    Shepperson, N. B.

    1984-01-01

    Alpha 1 but not alpha 2-adrenoceptors mediate contractions of the cat nictitating membrane. The contractions of this tissue evoked by alpha 1-adrenoceptor agonists, but not those evoked by angiotensin II, are potentiated by pre-dosing with alpha 2-adrenoceptor agonists. This potentiation is reversed by the alpha 2-adrenoceptor antagonist, WY 26392. Pressor responses evoked by alpha 1-adrenoceptor agonists or angiotensin II were not affected by alpha 2-adrenoceptor agonists. Contractions of the nictitating membrane evoked by noradrenaline were reduced by pretreatment with WY 26392. These results suggest that in some tissues the role of alpha 2-adrenoceptors may be to modulate responses to alpha 1-adrenoceptors, rather than to evoke a discrete response themselves. PMID:6148985

  20. 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.

  1. Dopaminergic agonists: possible neurorescue drugs endowed with independent and synergistic multisites of action.

    PubMed

    Uberti, Daniela; Bianchi, Irene; Olivari, Luca; Ferrari-Toninelli, Giulia; Bonini, Sara A; Memo, Maurizio

    2007-10-01

    Dopaminergic agonists have been usually used as adjunctive therapy for the cure of Parkinson's disease (PD). It is generally believed that treatment with these drugs is symptomatic rather then curative and does not stop or delay the progression of neuronal degeneration. However, several DA agonists of the DA D2-receptor family (including D2, D3 and D4-subtypes) have recently been shown to possess neuroprotective properties in different in vitro and in vivo experimental PD models. Here we summarize some recent data from our and other groups underlining the wide pharmacological spectrum of DA agonists currently used for treating PD patients. In particular, the mechanism of action of different DA agonists does not appear to be restricted to the stimulation of selective DA receptor subtypes being these drugs endowed with intrinsic, independent, and peculiar antioxidant effects. This activity may represent an additional pharmacological property contributing to their clinical efficacy in PD.

  2. Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.

    PubMed

    Ryabtsova, Oksana; Joossens, Jurgen; Van Der Veken, Pieter; Vanden Berghe, Wim; Augustyns, Koen; De Winter, Hans

    2016-10-15

    The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.

  3. Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3.

    PubMed

    Milanos, Lampros; Brox, Regine; Frank, Theresa; Poklukar, Gašper; Palmisano, Ralf; Waibel, Reiner; Einsiedel, Jürgen; Dürr, Maximilian; Ivanović-Burmazović, Ivana; Larsen, Olav; Hjortø, Gertrud Malene; Rosenkilde, Mette Marie; Tschammer, Nuska

    2016-03-10

    In this work we report a design, synthesis, and detailed functional characterization of unique strongly biased allosteric agonists of CXCR3 that contain tetrahydroisoquinoline carboxamide cores. Compound 11 (FAUC1036) is the first strongly biased allosteric agonist of CXCR3 that selectively induces weak chemotaxis and leads to receptor internalization and the β-arrestin 2 recruitment with potency comparable to that of the chemokine CXCL11 without any activation of G proteins. A subtle structural change (addition of a methoxy group, 14 (FAUC1104)) led to a contrasting biased allosteric partial agonist that activated solely G proteins, induced chemotaxis, but failed to induce receptor internalization or β-arrestin 2 recruitment. Concomitant structure-activity relationship studies indicated very steep structure-activity relationships, which steer the ligand bias between the β-arrestin 2 and G protein pathway. Overall, the information presented provides a powerful platform for further development and rational design of strongly biased allosteric agonists of CXCR3.

  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.

  5. Selection of multiple agonist antibodies from intracellular combinatorial libraries reveals that cellular receptors are functionally pleiotropic.

    PubMed

    Yea, Kyungmoo; Xie, Jia; Zhang, Hongkai; Zhang, Wei; Lerner, Richard A

    2015-06-01

    The main purpose of this perspective is to build on the unexpected outcomes of previous laboratory experiments using antibody agonists to raise questions concerning how activation of a given receptor can be involved in inducing differentiation of cells along different pathways some of which may even derive from different lineages. While not yet answered, the question illustrates how the advent of agonists not present in nature may give a different dimension to the important problem of signal transduction. Thus, if one studies a natural agonist-receptor system one can learn details about its signal transduction pathway. However, if one has a set of orthogonal agonists, one may learn about the yet undiscovered potential of the system that, in the end, may necessitate refinements to the currently used models. Thus, we wonder why receptors conventionally linked to a given pathway induce a different pattern of differentiation when agonized in another way.

  6. 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

  7. SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist.

    PubMed

    Sard, Howard; Kumaran, Govindaraj; Morency, Cynthia; Roth, Bryan L; Toth, Beth Ann; He, Ping; Shuster, Louis

    2005-10-15

    An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT(2C) receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive-compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT(2C) agonists with applications for drug discovery.

  8. Differential agonist sensitivity of glycine receptor alpha2 subunit splice variants.

    PubMed

    Miller, Paul S; Harvey, Robert J; Smart, Trevor G

    2004-09-01

    1. The glycine receptor (GlyR) alpha2A and alpha2B splice variants differ by a dual, adjacent amino acid substitution from alpha2A(V58,T59) to alpha2B(I58,A59) in the N-terminal extracellular domain. 2. Comparing the effects of the GlyR agonists, glycine, beta-alanine and taurine, on the GlyR alpha2 isoforms, revealed a significant increase in potency for all three agonists at the alpha2B variant. 3. The sensitivities of the splice variants to the competitive antagonist, strychnine, and to the biphasic modulator Zn(2+), were comparable. In contrast, the allosteric inhibitor picrotoxin was more potent on GlyR alpha2A compared to GlyR alpha2B receptors. 4. Coexpression of alpha2A or alpha2B subunits with the GlyR beta subunit revealed that the higher agonist potencies observed with the alpha2B homomer were retained for the alpha2Bbeta heteromer. 5. The identical sensitivity to strychnine combined with a reduction in the maximum current induced by the partial agonist taurine at the GlyR alpha2A homomer, suggested that the changed sensitivity to agonists is in accordance with a modulation of agonist efficacy rather than agonist affinity. 6. An effect on agonist efficacy was also supported by using a structural model of the GlyR, localising the region of splice variation to the proposed docking region between GlyR loop 2 and the TM2-3 loop, an area associated with channel activation. 7. The existence of a spasmodic mouse phenotype linked to a GlyR alpha1(A52S) mutation, the equivalent position to the source of the alpha2 splice variation, raises the possibility that the GlyR alpha2 splice variants may be responsible for distinct roles in neuronal function.

  9. Discovery of a novel series of potent S1P1 agonists.

    PubMed

    Crosignani, Stefano; Bombrun, Agnes; Covini, David; Maio, Maurizio; Marin, Delphine; Quattropani, Anna; Swinnen, Dominique; Simpson, Don; Sauer, Wolfgang; Françon, Bernard; Martin, Thierry; Cambet, Yves; Nichols, Anthony; Martinou, Isabelle; Burgat-Charvillon, Fabienne; Rivron, Delphine; Donini, Cristina; Schott, Olivier; Eligert, Valerie; Novo-Perez, Laurence; Vitte, Pierre-Alain; Arrighi, Jean-François

    2010-03-01

    The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.

  10. Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders

    PubMed Central

    Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Müller-Lissner, S; Quigley, E M M; Schuurkes, J; Maeyer, J H; Stanghellini, V

    2012-01-01

    Summary Background The nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride). Conclusions 5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility. PMID:22356640

  11. The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor.

    PubMed

    Westaway, Susan M; Brown, Samantha L; Conway, Elizabeth; Heightman, Tom D; Johnson, Christopher N; Lapsley, Kate; Macdonald, Gregor J; MacPherson, David T; Mitchell, Darren J; Myatt, James W; Seal, Jon T; Stanway, Steven J; Stemp, Geoffrey; Thompson, Mervyn; Celestini, Paolo; Colombo, Andrea; Consonni, Alessandra; Gagliardi, Stefania; Riccaboni, Mauro; Ronzoni, Silvano; Briggs, Michael A; Matthews, Kim L; Stevens, Alexander J; Bolton, Victoria J; Boyfield, Izzy; Jarvie, Emma M; Stratton, Sharon C; Sanger, Gareth J

    2008-12-15

    Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.

  12. [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

    2014-01-06

    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.

  13. Retinoic Acid Receptor β2 Agonists Restore Glycemic Control In Diabetes and Reduce Steatosis

    PubMed Central

    Trasino, Steven E.; Tang, Xiao-Han; Jessurun, Jose; Gudas, Lorraine J.

    2016-01-01

    Aims Retinoids (vitamin A (retinol), and structurally related molecules) possess metabolic modulating properties, prompting new interest in their role in the treatment of diabetes and fatty liver disease, but little is known about the effects of specific retinoic acid receptor (RAR) agonists in these diseases. Materials and Methods Synthetic agonists for retinoic acid receptor RARβ2 were administered to wild type (wt) mice in a model of high fat diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D). Results We demonstrate that administration of synthetic agonists for the retinoic acid receptor RARβ2 to either wild type (wt) mice in a model of high fat diet (HFD)-induced type 2 diabetes (T2D) or to ob/ob and db/db mice (genetic models of obesity-associated T2D) reduces hyperglycemia, peripheral insulin resistance, and body weight. Furthermore, RARβ2 agonists dramatically reduce steatosis, lipid peroxidation, and oxidative stress in the liver, pancreas, and kidneys of obese, diabetic mice. RARβ2 agonists also lower levels of mRNAs involved in lipogenesis, such as SREBP1 and FASN (fatty acid synthase), and increase mRNAs that mediate mitochondrial fatty acid β-oxidation, such as CPT1α, in these organs. RARβ2 agonists lower triglyceride levels in these organs, and in muscle. Conclusions Collectively, our data show that orally active, rapidly acting, high affinity pharmacological agonists for RARβ2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RARβ2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis. PMID:26462866

  14. Rapid kinetics of 2-adrenergic agonist binding and inhibition of adenylate cyclase

    SciTech Connect

    Thomsen, W.; Neubig, R.R.

    1987-05-01

    Activation of 2-adrenergic receptors in human platelets results in inhibition of adenylate cyclase (AC). To elucidate the relation between agonist binding and response, the authors have used a novel rapid-mix quench method to compare the kinetics of binding and response. At functionally effective concentrations, the time course of binding of the full 2-agonist, (TH)UK14,304 (UK), to purified platelet membranes was faster than could be measured manually. Using the rapid-mix quench method, agonist binding was quantitated for times for 0.3 to 60 seconds. UK binding exhibited biexponential kinetics. The rate constant of the fast binding component increases linearly with agonist concentration from 1 to 100 nM with a second order rate constant and 7 x 10WM s (at 25C). The slow rate constant was nearly independent of agonist concentration. The half times of the fast and slow components of binding for 100 nM UK are 1.5 seconds and approximately 2 minutes respectively. The rate and magnitude of the fast binding was unaffected by 10 M GTP whereas the magnitude of the slow phase was markedly reduced. Inhibition of forskolin stimulated AC by 100 M epinephrine occurs with a lag of 5-10 seconds in the presence of 10 M GTP. At lower GTP concentrations, this lag is prolonged. The observation that the fast component of agonist binding precedes inhibition even at agonist concentrations 20-fold lower than the EC40 for responses indicates that the rate limiting step in inhibition of AC is distal to the binding of agonist.

  15. 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.

  16. Effects of dopamine D1 receptor full agonists in rats trained to discriminate SKF 38393.

    PubMed

    Gleason, S D; Witkin, J M

    2004-02-01

    Although the dopaminergic pharmacology of the D1 receptor full agonists, dinapsoline, dihydrexidine and the prodrug ABT-431 have been studied, no information is available on the ability of these agonists to substitute for the D1 agonist SKF 38393 in rats trained to discriminate this compound from vehicle. The present study was designed to characterize the potential D1 discriminative stimulus effects of these compounds. The selective dopamine D1-receptor agonists dihydrexidine [(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride], ABT-431 [(-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride], the diacetyl prodrug derivative of A-86929, and dinapsoline [9-dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline] were studied in rats trained to discriminate racemic SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol], a selective D1 receptor partial agonist from vehicle. All of the agonists substituted fully for the discriminative stimulus effects of SKF 38393. The rank order of potency for substitution was ABT-431 > dinapsoline > dihydrexidine > SKF 38393. The D1 receptor antagonist, SCH 23390, blocked the discriminative stimulus effects of SKF 38393. The D3/D2-receptor agonist PD 128,907 [S(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano[4,3-b]-1,4-oxazin-9-ol] did not substitute up to doses that produced profound rate-suppressant effects. Thus, consistent with their D1 receptor pharmacology, the full D1-receptor agonists substituted completely for the discriminative stimulus of SKF 38393.

  17. Discovery and dimeric approach of novel Natriuretic Peptide Receptor A (NPR-A) agonists.

    PubMed

    Iwaki, Takehiko; Oyama, Yoshiaki; Tomoo, Toshiyuki; Tanaka, Taisaku; Okamura, Yoshihiko; Sugiyama, Masako; Yamaki, Akira; Furuya, Mayumi

    2017-03-15

    Novel agonists of the Natriuretic Peptide Receptor A (NPR-A) were obtained through random screening and subsequent structural modification of triazine derivatives. The key structural feature to improve in vitro activity was the dimerization of triazine monomer derivatives. The non peptide derivative 7c and 13a showed highly potent NPR-A agonistic activity in vitro and diuretic activity in vivo. These results implied that non-peptidic small molecules open the possibility of new therapy for congestive heart failure.

  18. 5-HT(2C) agonists as therapeutics for the treatment of schizophrenia.

    PubMed

    Rosenzweig-Lipson, Sharon; Comery, Thomas A; Marquis, Karen L; Gross, Jonathan; Dunlop, John

    2012-01-01

    The 5-HT(2C) receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT(2C) receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT(2C) receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT(2C) agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT(2C) agonists in schizophrenia. To this end, the preclinical profile of 5-HT(2C) agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT(2C) agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT(2C) agonists are potential therapeutics for the treatment of psychiatric disorders.

  19. 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

  20. Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats.

    PubMed

    Frank, J A; Wang, Y; Osorio, O; Matthay, M A

    2000-10-01

    To determine whether beta-adrenergic agonist therapy increases alveolar liquid clearance during the resolution phase of hydrostatic pulmonary edema, we studied alveolar and lung liquid clearance in two animal models of hydrostatic pulmonary edema. Hydrostatic pulmonary edema was induced in sheep by acutely elevating left atrial pressure to 25 cmH(2)O and instilling 6 ml/kg body wt isotonic 5% albumin (prepared from bovine albumin) in normal saline into the distal air spaces of each lung. After 1 h, sheep were treated with a nebulized beta-agonist (salmeterol) or nebulized saline (controls), and left atrial pressure was then returned to normal. beta-Agonist therapy resulted in a 60% increase in alveolar liquid clearance over 3 h (P < 0.001). Because the rate of alveolar fluid clearance in rats is closer to human rates, we studied beta-agonist therapy in rats, with hydrostatic pulmonary edema induced by volume overload (40% body wt infusion of Ringer lactate). beta-Agonist therapy resulted in a significant decrease in excess lung water (P < 0.01) and significant improvement in arterial blood gases by 2 h (P < 0.03). These preclinical experimental studies support the need for controlled clinical trials to determine whether beta-adrenergic agonist therapy would be of value in accelerating the resolution of hydrostatic pulmonary edema in patients.

  1. Effects of cannabinoid and vanilloid receptor agonists and their interaction on learning and memory in rats.

    PubMed

    Shiri, Mariam; Komaki, Alireza; Oryan, Shahrbanoo; Taheri, Masoumeh; Komaki, Hamidreza; Etaee, Farshid

    2017-04-01

    Despite previous findings on the effects of cannabinoid and vanilloid systems on learning and memory, the effects of the combined stimulation of these 2 systems on learning and memory have not been studied. Therefore, in this study, we tested the interactive effects of cannabinoid and vanilloid systems on learning and memory in rats by using passive avoidance learning (PAL) tests. Forty male Wistar rats were divided into the following 4 groups: (1) control (DMSO+saline), (2) WIN55,212-2, (3) capsaicin, and (4) WIN55,212-2 + capsaicin. On test day, capsaicin, a vanilloid receptor type 1 (TRPV1) agonist, or WIN55,212-2, a cannabinoid receptor (CB1/CB2) agonist, or both substances were injected intraperitoneally. Compared to the control group, the group treated with capsaicin (TRPV1 agonist) had better scores in the PAL acquisition and retention test, whereas treatment with WIN55,212-2 (CB1/CB2 agonist) decreased the test scores. Capsaicin partly reduced the effects of WIN55,212-2 on PAL and memory. We conclude that the acute administration of a TRPV1 agonist improves the rats' cognitive performance in PAL tasks and that a vanilloid-related mechanism may underlie the agonistic effect of WIN55,212-2 on learning and memory.

  2. TRPA1 agonist activity of probenecid desensitizes channel responses: consequences for screening.

    PubMed

    McClenaghan, Conor; Zeng, Fanning; Verkuyl, Jan Martin

    2012-12-01

    The transient receptor potential channel subtype A member 1 (TRPA1) is a nonselective cation channel widely viewed as having therapeutic potential, particularly for pain-related indications. Realization of this potential will require potent, selective modulators; however, currently the pharmacology of TRPA1 is poorly defined. As TRPA1 is calcium permeable, calcium indicators offer a simple assay format for high-throughput screening. In this report, we show that probenecid, a uricosuric agent used experimentally in screening to increase loading of calcium-sensitive dyes, activates TRPA1. Prolonged probenecid incubation during the dye-loading process reduces agonist potency upon subsequent challenge. When Chinese Hamster Ovary (CHO)-hTRPA1 or STC-1 cells, which endogenously express TRPA1, were dye loaded in the presence of 2 mM probenecid TRPA1, agonists appeared less potent; EC(50) for allyl isothiocyante agonists in CHO-hTRPA1 was increased from 1.5±0.19 to 7.32±1.20 μM (P<0.01). No significant effect on antagonist potency was observed when using the agonist EC(80) concentration determined under the appropriate dye-loading conditions. We suggest an alternative protocol for calcium imaging using another blocker of anion transport, sulfinpyrazone. This blocker significantly augments indicator dye loading and the screening window, but is not a TRPA1 agonist and has no effect on agonist potency.

  3. 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

  4. A Systematic Approach to Identify Biased Agonists of the Apelin Receptor through High-Throughput Screening.

    PubMed

    McAnally, Danielle; Siddiquee, Khandaker; Sharir, Haleli; Qi, Feng; Phatak, Sharangdhar; Li, Jian-Liang; Berg, Eric; Fishman, Jordan; Smith, Layton

    2017-03-01

    Biased agonists are defined by their ability to selectively activate distinct signaling pathways of a receptor, and they hold enormous promise for the development of novel drugs that specifically elicit only the desired therapeutic response and avoid potential adverse effects. Unfortunately, most high-throughput screening (HTS) assays are designed to detect signaling of G protein-coupled receptors (GPCRs) downstream of either G protein or β-arrestin-mediated signaling but not both. A comprehensive drug discovery program seeking biased agonists must employ assays that report on the activity of each compound at multiple discrete pathways, particularly for HTS campaigns. Here, we report a systematic approach to the identification of biased agonists of human apelin receptor (APJ). We synthesized 448 modified versions of apelin and screened them against a cascade of cell-based assays, including intracellular cAMP and β-arrestin recruitment to APJ, simultaneously. The screen yielded potent and highly selective APJ agonists. Representative hits displaying preferential signaling via either G-protein or β-arrestin were subjected to a battery of confirmation assays. These biased agonists will be useful as tools to probe the function and pharmacology of APJ and provide proof of concept of our systematic approach to the discovery of biased ligands. This approach is likely universally applicable to the search for biased agonists of GPCRs.

  5. Substrate specificity of the agonist-stimulated release of polyunsaturated fatty acids from vascular endothelial cells

    SciTech Connect

    Rosenthal, M.D.; Garcia, M.C.; Sprecher, H. )

    1989-11-01

    Stimulation of vascular endothelial cells with agonists such as histamine and thrombin results in release of arachidonic acid from membrane lipids and subsequent eicosanoid synthesis. As shown previously, the agonist-stimulated deacylation is specific for arachidonate, eicosapentaenoate, and 5,8,11-eicosatrienoate. This study has utilized radiolabeled fatty acids differing in chain length and position of double bonds to further elucidate the fatty acyl specificity of agonist-stimulated deacylation. Replicate wells of confluent human umbilical vein endothelial cells were incubated with 14C-labeled fatty acids and then challenged with histamine, thrombin, or the calcium ionophore A23187. Comparison of the results obtained with isomeric eicosatetraenoic fatty acids with initial double bonds at carbons 4, 5, or 6 indicated that the deacylation induced by all three agonists exhibited marked specificity for the cis-5 double bond. Lack of stringent chain length specificity was indicated by agonist-stimulated release of 5,8,11,14- tetraenoic fatty acids with 18, 19, 20, and 21 carbons. Release of 5,8,14-(14C)eicosatrienoate was two-to threefold that of 5,11,14-(14C)eicosatrienoate, thus indicating that the cis-8 double bond may also contribute to the stringent recognition by the agonist-sensitive phospholipase. The present study has also demonstrated that histamine, thrombin, and A23187 do not stimulate release of docosahexaenoate from endothelial cells.

  6. Dopa-testotoxicosis: disruptive hypersexuality in hypogonadal men with prolactinomas treated with dopamine agonists.

    PubMed

    De Sousa, Sunita M C; Chapman, Ian M; Falhammar, Henrik; Torpy, David J

    2017-02-01

    Dopamine agonists are the first line of therapy for prolactinomas, with high rates of biochemical control and tumour shrinkage. Toxicity is considered to be low and manageable by switching of agents and dose reduction. Dopamine agonist-induced impulse control disorders are well described in the neurology setting, but further data are required regarding this toxicity in prolactinoma patients. We performed a multicenter retrospective cohort study of eight men with prolactinomas and associated central hypogonadism. The eight men had no prior history of psychiatric disease, but each developed disruptive hypersexuality whilst on dopamine agonist therapy at various doses. Cabergoline, bromocriptine and quinagolide were all implicated. Hypersexuality had manifold consequences, including relationship discord, financial loss, reduced work performance, and illicit activity. We hypothesise that this phenomenon is due to synergy between reward pathway stimulation by dopamine agonists, together with rapid restoration of the eugonadal state after prolonged hypogonadism. We refer here to this distinct drug toxicity as 'dopa-testotoxicosis'. Given the profound impact in these patients and their families, cessation of dopamine agonists should be considered in men who develop hypersexuality, and pituitary surgery may be required to facilitate this. Awareness of this distinct impulse control disorder should enable further research into the prevalence, natural history and management of dopa-testotoxicosis. The condition is likely under-reported due to the highly personal nature of the symptoms and we suggest a simple written questionnaire to screen for hypersexuality and other behavioural symptoms within the first six months of dopamine agonist treatment.

  7. 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.

  8. The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability.

    PubMed

    Lin, Ann P; Ko, Mei-Chuan

    2013-02-20

    Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans.

  9. 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

  10. 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.

  11. Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders.

    PubMed

    Williams, Wilbur P Trey; McLin, Dewey E; Dressman, Marlene A; Neubauer, David N

    2016-09-01

    Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs.

  12. 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

  13. 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.

  14. Metabolic mapping of A3 adenosine receptor agonist MRS5980

    PubMed Central

    Fang, Zhong-Ze; Tosh, Dilip K.; Tanaka, Naoki; Wang, Haina; Krausz, Kristopher W.; O'Connor, Robert; Jacobson, Kenneth A.; Gonzalez, Frank J.

    2015-01-01

    (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 of 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 group in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation for 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 major 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

  15. 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

  16. The pharmacologic basis for clinical differences among GLP-1 receptor agonists and DPP-4 inhibitors.

    PubMed

    Morales, Javier

    2011-11-01

    The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists-which can be dosed to pharmacologic levels-act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%-1.7%) compared with DPP-4 inhibitors (0.4%-1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater

  17. 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

  18. Nonlinear analysis of partial dopamine agonist effects on cAMP in C6 glioma cells.

    PubMed

    Avalos, M; Mak, C; Randall, P K; Trzeciakowski, J P; Abell, C; Kwan, S W; Wilcox, R E

    2001-01-01

    Most drugs have some efficacy so that improved methods to determine the relative intrinsic efficacy of partial agonists should be of benefit to preclinical and clinical investigators. We examined the effects of partial D(1) or partial D(2) dopamine agonists using a partial agonist interaction model. The dependent variable was the modulation of the dopamine-receptor-mediated cAMP response in C6 glioma cells selectively and stably expressing either D(1) or D(2) recombinant dopamine receptors. The dissociation constant (K(B)) and relative intrinsic efficacy (E(r)) for each partial agonist were calculated using a partial agonist interaction null model in which the effects of fixed concentrations of each partial agonist on the dopamine dose-response curve were evaluated. This model is an extension of the competitive antagonist null model to drugs with efficacy and assumes only that the log-dose--response curve is monotonic. Generally, the partial agonist interaction model fit the data, as well as fits of the independent logistic curves. Furthermore, the partial agonist K(B) values could be shared across partial agonist concentrations without worsening the model fit (by increasing the residual variance). K(B) values were also similar to drug affinities reported in the literature. The model was validated in three ways. First, we assumed a common tissue stimulus parameter (beta) and calculated the E(r) values. This provided a qualitative check on the interaction model results. Second, we calculated new relative efficacy values, E(r)(beta), using the beta estimate. Third, we calculated relative efficacy using relative maxima times midpoint shift ratios (J. Theor. Biol. 198 (1999) 347.). All three methods indicated that the present model yielded reasonable estimates of affinity and relative efficacy for the set of compounds studied. Our results provide a quick and convenient method of quantification of partial agonist efficacy. Special applications and limitations of the

  19. Radiatively corrected lepton energy distributions in top quark decays t→ bW +→ b( ℓ + ν ℓ ) and t→ bH +→ b( τ + ν τ ) and single-charged prong energy distributions from subsequent τ + decays

    NASA Astrophysics Data System (ADS)

    Ali, Ahmed; Kuraev, Eduard A.; Bystritskiy, Yury M.

    2010-06-01

    We calculate the QED and QCD radiative corrections to the charged lepton energy distributions in the dominant semileptonic decays of the top quark t→ bW +→ b( ℓ + ν ℓ ) ( ℓ= e, μ, τ) in the standard model (SM), and for the decay t→ bH +→ b( τ + ν τ ) in an extension of the SM having a charged Higgs boson H ± with m_{H^{±}}

  20. Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence.

    PubMed

    Neumeyer, J L; Bidlack, J M; Zong, R; Bakthavachalam, V; Gao, P; Cohen, D J; Negus, S S; Mello, N K

    2000-01-13

    This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.

  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.

  2. 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.

  3. Desensitization of functional µ-opioid receptors increases agonist off-rate.

    PubMed

    Williams, John T

    2014-07-01

    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-[Leu(5)]-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.

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

    PubMed

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

    2013-04-26

    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 IC50 values of 1.2 and 1.5mM, 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; IC50=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.

  5. Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists.

    PubMed

    Hiranita, Takato; Mereu, Maddalena; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

    2013-03-01

    Sigma(1) receptors (σ(1)Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective σ(1)R agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either σ(1)R agonist. In contrast, after subjects self-administered cocaine σ(1)R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both σ(1)R agonists, extinguished when injections were discontinued, and reconditioned when σ(1)R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of σ(1)R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the σR antagonist, BD1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive σ(1)R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced σ(1)R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse.

  6. 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

  7. 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.

  8. β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS).

    PubMed

    Bartus, Raymond T; Bétourné, Alexandre; Basile, Anthony; Peterson, Bethany L; Glass, Jonathan; Boulis, Nicholas M

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neuromuscular disease for which no cure exists and better treatment options are desperately needed. We hypothesize that currently approved β2-adrenoceptor agonists may effectively treat the symptoms and possibly slow the progression of ALS. Although β2-agonists are primarily used to treat asthma, pharmacologic data from animal models of neuromuscular diseases suggest that these agents may have pharmacologic effects of benefit in treating ALS. These include inhibiting protein degradation, stimulating protein synthesis, inducing neurotrophic factor synthesis and release, positively modulating microglial and systemic immune function, maintaining the structural and functional integrity of motor endplates, and improving energy metabolism. Moreover, stimulation of β2-adrenoceptors can activate a range of downstream signaling events in many different cell types that could account for the diverse array of effects of these agents. The evidence supporting the possible therapeutic benefits of β2-agonists is briefly reviewed, followed by a more detailed review of clinical trials testing the efficacy of β-agonists in a variety of human neuromuscular maladies. The weight of evidence of the potential benefits from treating these diseases supports the hypothesis that β2-agonists may be efficacious in ALS. Finally, ways to monitor and manage the side effects that may arise with chronic administration of β2-agonists are evaluated. In sum, effective, safe and orally-active β2-agonists may provide a novel and convenient means to reduce the symptoms of ALS and possibly delay disease progression, affording a unique opportunity to repurpose these approved drugs for treating ALS, and rapidly transforming the management of this serious, unmet medical need.

  9. Occurrence of aryl hydrocarbon receptor agonists and genotoxic compounds in the river systems in Southern Taiwan.

    PubMed

    Chou, Pei-Hsin; Liu, Tong-Cun; Ko, Fung-Chi; Liao, Mong-Wei; Yeh, Hsiao-Mei; Yang, Tse-Han; Wu, Chun-Ting; Chen, Chien-Hsun; Tsai, Tsung-Ya

    2014-07-01

    Water and sediment samples from river systems located in Southern Taiwan were investigated for the presence of aryl hydrocarbon receptor (AhR) agonists and genotoxicants by a combination of recombinant cell assays and gas chromatography-mass spectrometry analysis. AhR agonist activity and genotoxic response were frequently detected in samples collected during different seasons. In particular, dry-season water and sediment samples from Erren River showed strong AhR agonist activity (201-1423 ng L(-1) and 1374-5631 ng g(-1) β-naphthoflavone equivalents) and high genotoxic potential. Although no significant correlation was found between AhR agonist activity and genotoxicity, potential genotoxicants in sample extracts were suggested to be causative agents for yeast growth inhibition in the AhR-responsive reporter gene assay. After high performance liquid chromatography fractionation, AhR agonist candidates were detected in several fractions of Erren River water and sediment extracts, while possible genotoxicants were only found in water extracts. In addition, polycyclic aromatic hydrocarbons, the typical contaminants showing high AhR binding affinity, were only minor contributors to the AhR agonist activity detected in Erren River sediment extracts. Our findings displayed the usefulness of bioassays in evaluating the extent of environmental contamination, which may be helpful in reducing the chances of false-negative results obtained from chemical analysis of conventional contaminants. Further research will be undertaken to identify major candidates for xenobiotic AhR agonists and genotoxicants to better protect the aquatic environments in Taiwan.

  10. Luteinizing hormone-releasing hormone agonists in premenopausal hormone receptor-positive breast cancer.

    PubMed

    Tan, Sing-Huang; Wolff, Antonio C

    2007-02-01

    Ovarian function suppression for the treatment of premenopausal breast cancer was first used in the late 19th century. Traditionally, ovarian function suppression had been accomplished irreversibly via irradiation or surgery, but analogues of the luteinizing hormone-releasing hormone (LH-RH) have emerged as reliable and reversible agents for this purpose, especially the LH-RH agonists. Luteinizing hormone-releasing hormone antagonists are in earlier stages of development in breast cancer and are not currently in clinical use. Luteinizing hormonereleasing hormone agonists act by pituitary desensitization and receptor downregulation, thereby suppressing gonadotrophin release. Limited information is available comparing the efficacies of the depot preparations of various agonists, but pharmacodynamic studies have shown comparable suppressive capabilities on estradiol and luteinizing hormone. At present, only monthly goserelin is Food and Drug Administration-approved for the treatment of estrogen receptor-positive, premenopausal metastatic breast cancer in the United States. Luteinizing hormone-releasing hormone agonists have proven to be as effective as surgical oophorectomy in premenopausal advanced breast cancer. They offer similar outcomes compared with tamoxifen, but the endocrine combination appears to be more effective than LH-RH agonists alone. In the adjuvant setting, LH-RH agonists versus no therapy reduce the annual odds of recurrence and death in women aged>50 years with estrogen receptor-positive tumors. Luteinizing hormone-releasing hormone agonists alone or in combination with tamoxifen have shown disease-free survival rates similar to chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil). Outcomes of chemotherapy with or without LH-RH agonists are comparable, though a few trials favor the combination in young premenopausal women (aged<40 years). Adjuvant LH-RH agonists with or without tamoxifen might be as efficacious as tamoxifen alone

  11. Transcriptome analysis of endometrial tissues following GnRH agonist treatment in a mouse adenomyosis model

    PubMed Central

    Guo, Song; Lu, Xiaowei; Gu, Ruihuan; Zhang, Di; Sun, Yijuan; Feng, Yun

    2017-01-01

    Purpose Adenomyosis is a common, benign gynecological condition of the female reproductive tract characterized by heavy menstrual bleeding and dysmenorrhea. Gonadotropin-releasing hormone (GnRH) agonists are one of the medications used in adenomyosis treatment; however, their underlying mechanisms are poorly understood. Moreover, it is difficult to obtain endometrial samples from women undergoing such treatment. To overcome this, we generated an adenomyosis mouse model, which we treated with an GnRH agonist to determine its effect on pregnancy outcomes. We also analyzed endometrial gene expression following GnRH agonist treatment to determine the mechanisms that may affect pregnancy outcome in individuals with adenomyosis. Methods Neonatal female mice were divided into a control group, an untreated adenomyosis group, and an adenomyosis group treated with a GnRH agonist (n=6 each). The pregnancy outcome was observed and compared among the groups. Then, three randomly chosen transcriptomes from endometrial tissues from day 4 of pregnancy were analyzed between the adenomyosis group and the GnRH agonist treatment group by RNA sequencing and quantitative reverse transcription polymerase chain reaction (PCR). Results The litter size was significantly smaller in the adenomyosis group than in the control group (7±0.28 vs 11±0.26; P<0.05). However, the average live litter size was increased (10±0.28 vs 7±0.28; P<0.05) after GnRH agonist treatment. Three hundred and fifty-nine genes were differentially expressed in the GnRH agonist-treated group compared with the untreated group (218 were downregulated and 141 were upregulated). Differentially expressed genes were related to diverse biological processes, including estrogen metabolism, cell cycle, and metabolite biosynthesis. Conclusion GnRH agonist treatment appears to improve the pregnancy outcome of adenomyosis in a mouse model. Besides pituitary down-regulation, other possible mechanisms such as the regulation of cell

  12. In silico screening for agonists and blockers of the β2 adrenergic receptor: implications of inactive and activated state structures

    PubMed Central

    Costanzi, Stefano; Vilar, Santiago

    2011-01-01

    Ten crystal structures of the β2 adrenergic receptor (β2AR) have been published, reflecting different signaling states. Here, through controlled docking experiments, we examined the implications of using inactive or activated structures on the in silico screening for agonists and blockers of the receptor. Specifically, we targeted the crystal structures solved in complex with carazolol (2RH1), the neutral antagonist alprenalol (3NYA), the irreversible agonist FAUC50 (3PDS) and the full agonist BI-167017 (3P0G). Our results indicate that activated structures favor agonists over blockers while inactive structures favor blockers over agonists. This tendency is more marked for activated than for inactive structures. Additionally, agonists tend to receive more favorable docking scores when docked at activated rather than inactive structures, while blockers do the opposite. Hence, the difference between the docking scores attained with an activated and an inactive structure is an excellent means for the classification of ligands into agonists and blockers, as we determined through receiver operating characteristic (ROC) curves and linear discriminant analysis (LDA). With respect to virtual screening, all structures prioritized well agonists and blockers over non-binders. However, inactive structures worked better for blockers and activated structures worked better for agonists. Notably, the combination of individual docking experiments through receptor ensemble docking (RED) resulted in an excellent performance in the retrieval of both agonists and blockers. Finally, we demonstrated that the induced fit docking of agonists is a viable way of modifying an inactive crystal structure and bias it towards the in silico recognition of agonists rather than blockers. PMID:22170280

  13. The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

    PubMed Central

    Martin, Yvonne Connolly

    2011-01-01

    The novel selective D1 dopaminergic full agonists A-68930, A-77636 were discovered by the synthesis of molecules to probe the bioactive conformation of the partial agonist SKF-38393, by the use of this information to add D1 affinity and selectivity to a screening hit, and by traditional medicinal chemistry exploration of structure-activity relationships. The subsequent design of A-86929 and ABT-413 capitalized on these results, recently disclosed agonists, and traditional medicinal chemistry. PMID:25954518

  14. 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.

  15. Evaluation of the interaction of mu and kappa opioid agonists on locomotor behavior in the horse.

    PubMed Central

    Mama, K R; Pascoe, P J; Steffey, E P

    1993-01-01

    This study was designed to determine the interactive effects of mu and kappa opioid agonists on locomotor behavior in the horse. Three doses of a mu agonist, fentanyl (5, 10, 20 micrograms/kg) and a kappa agonist U50,488H (30, 60, 120 micrograms/kg) were administered in a random order to six horses. Locomotor activity was measured using a two minute footstep count. Each dose of U50,488H was then combined with 20 micrograms/kg of fentanyl to determine the interactive effects of the drugs on locomotor activity. A significant increase in locomotor activity was seen with 20 micrograms/kg of fentanyl and all the drug combinations. The combination of U50,488H with fentanyl resulted in an earlier onset of locomotor activity. At the highest doses of the combination (U50,488H 120 micrograms/kg, fentanyl 20 micrograms/kg), the duration of locomotor activity was significantly increased when compared to the other doses. We conclude that locomotor activity is maintained or enhanced in horses when a receptor specific kappa agonist is combined with a mu receptor agonist. PMID:8490803

  16. Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists

    PubMed Central

    Pertwee, R.G.

    2010-01-01

    It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Δ9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor agonists and CB1/CB2 antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB1 and CB2 receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB1, non-CB2 G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB1 and/or CB2 receptors. PMID:20166927

  17. Pharmacological Profiles of Alpha 2 Adrenergic Receptor Agonists Identified Using Genetically Altered Mice and Isobolographic Analysis

    PubMed Central

    Fairbanks, Carolyn A.; Stone, Laura S.; Wilcox, George L.

    2009-01-01

    Endogenous, descending noradrenergic fibers convey powerful analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (α2ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share similar a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express α2AAR and α2CAR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal α2ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of these six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal α2AR agonists featured. PMID:19393691

  18. GABAergic involvement in motor effects of an adenosine A(2A) receptor agonist in mice.

    PubMed

    Khisti, R T; Chopde, C T; Abraham, E

    2000-04-03

    Adenosine A(2A) agonists are known to induce catalepsy and inhibit dopamine mediated motor hyperactivity. An antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors is known to regulate GABA-mediated neurotransmission in striatopallidal neurons. Stimulation of adenosine A(2A) and dopamine D(2) receptors has been shown to increase and inhibit GABA release respectively in pallidal GABAergic neurons. However, the role of GABAergic neurotransmission in the motor effects of adenosine A(2A) receptors is not yet known. Therefore in the present study the effect of GABAergic agents on adenosine A(2A) receptor agonist (NECA- or CGS 21680) induced catalepsy and inhibition of amphetamine elicited motor hyperactivity was examined. Pretreatment with GABA, the GABA(A) agonist muscimol or the GABA(B) agonist baclofen potentiated whereas the GABA(A) antagonist bicuculline attenuated NECA- or CGS 21680-induced catalepsy. However, the GABA(B) antagonists phaclophen and delta-aminovaleric acid had no effect. Administration of NECA or CGS 21680 not only reduced spontaneous locomotor activity but also antagonized amphetamine elicited motor hyperactivity. These effects of NECA and CGS 21680 were potentiated by GABA or muscimol and antagonized by bicuculline. These findings provide behavioral evidence for the role of GABA in the motor effects of adenosine A(2A) receptor agonists. Activation of adenosine A(2A) receptors increases GABA release which could reduce dopaminergic tone and induce catalepsy or inhibit amphetamine mediated motor hyperactivity.

  19. 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

  20. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver

    PubMed Central

    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

  1. Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor

    PubMed Central

    2015-01-01

    Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci.2013, 22, 101−11323184890; Ahn, K. H. et al. Proteins2013, 81, 1304–131723408552] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists. PMID:26633590

  2. Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore.

    PubMed

    Balboni, Gianfranco; Salvadori, Severo; Trapella, Claudio; Knapp, Brian I; Bidlack, Jean M; Lazarus, Lawrence H; Peng, Xuemei; Neumeyer, John L

    2010-02-17

    Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.

  3. Agonist and antagonist protect sulfhydrals in the binding site of the D-1 dopamine receptor

    SciTech Connect

    Sidhu, A.; Kebabian, J.W.; Fishman, P.H.

    1986-05-01

    An iodinated compound (/sup 125/I)-SCH 23982 (8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) has been characterized as a specific, high affinity (Kd = 0.7 nM) ligand for the D-1 dopamine receptor. The ligand binding site of the D-1 receptor in rat striatum was inactivated by N-ethylmaleimide (NEM) in a time and concentration dependent manner. The inactivation was rapid and irreversible with a 70% net loss of binding sites. Scatchard analysis of binding to NEM-treated tissue showed a decrease both in receptor number and in radioligand affinity. The remaining receptors retained their selectivity for stereoisomers of both agonist and antagonist. Receptor occupancy by either a D-1 specific agonist or antagonist protected in a dose dependent manner the binding sites from inactivation by NEM; the agonist was more effective than the antagonist. The agonist high affinity site, however, was abolished in the absence or presence of protective compound, presumably because of inactivation of the GTP-binding component of adenylate cyclase. In this regard, there was a total loss of agonist- and forskolin-stimulated adenylate cyclase activity after NEM treatment. The authors conclude that the D-1 dopamine receptor contains NEM-sensitive sulfhydral group(s) at or near the vicinity of the ligand binding site.

  4. The atypical dopamine D1 receptor agonist SKF 83959 induces striatal Fos expression in rats.

    PubMed

    Wirtshafter, David; Osborn, Catherine V

    2005-12-28

    The effects of dopamine D1 receptor agonists are often presumed to result from an activation of adenylyl cyclase, but dopamine D1 receptors may also be linked to other signal transduction cascades and the relative importance of these various pathways is currently unclear. SKF 83959 is an agonist at dopamine D1 receptors linked to phospholipase C, but has been reported to be an antagonist at receptors linked to adenylyl cyclase. The current report demonstrates that SKF 83959 induces pronounced, nonpatchy, expression of the immediate-early gene product Fos in the striatum of intact rats which can be converted to a patchy pattern by pretreatment with the dopamine D2-like receptor agonist quinpirole. In rats with unilateral 6-hydroxydopamine lesions SKF 83959 induces strong behavioral rotation and a greatly potentiated Fos response. All of the responses to SKF 83959, in both intact and dopamine-depleted animals, can be blocked by pretreatment with the dopamine D1 receptor antagonist SCH-23390. In intact subjects, SKF 83959 induced Fos expression less potently than the standard dopamine D1 receptor agonist SKF 82958, but the two drugs were approximately equipotent in deinnervated animals. These results demonstrate for the first time that possession of full efficacy at dopamine D1 receptors linked to adenylyl cyclase is not a necessary requirement for the induction of striatal Fos expression in intact animals and suggest that alternative signal transduction pathways may play a role in dopamine agonist induced Fos expression, especially in dopamine-depleted subjects.

  5. 2-Dialkynyl derivatives of (N)-methanocarba nucleosides: 'Clickable' A(3) adenosine receptor-selective agonists.

    PubMed

    Tosh, Dilip K; Chinn, Moshe; Yoo, Lena S; Kang, Dong Wook; Luecke, Hans; Gao, Zhan-Guo; Jacobson, Kenneth A

    2010-01-15

    We modified a series of (N)-methanocarba nucleoside 5'-uronamides to contain dialkyne groups on an extended adenine C2 substituent, as synthetic intermediates leading to potent and selective A(3) adenosine receptor (AR) agonists. The proximal alkyne was intended to promote receptor recognition, and the distal alkyne reacted with azides to form triazole derivatives (click cycloaddition). Click chemistry was utilized to couple an octadiynyl A(3)AR agonist to azido-containing fluorescent, chemically reactive, biotinylated, and other moieties with retention of selective binding to the A(3)AR. A bifunctional thiol-reactive crosslinking reagent was introduced. The most potent and selective novel compound was a 1-adamantyl derivative (K(i) 6.5nM), although some of the click products had K(i) values in the range of 200-400nM. Other potent, selective derivatives (K(i) at A(3)AR innM) were intended as possible receptor affinity labels: 3-nitro-4-fluorophenyl (10.6), alpha-bromophenacyl (9.6), thiol-reactive isothiazolone (102), and arylisothiocyanate (37.5) derivatives. The maximal functional effects in inhibition of forskolin-stimulated cAMP were measured, indicating that this class of click adducts varied from partial to full A(3)AR agonist compared to other widely used agonists. Thus, this strategy provides a general chemical approach to linking potent and selective A(3)AR agonists to reporter groups of diverse structure and to carrier moieties.

  6. Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors.

    PubMed

    Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi

    2016-05-03

    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.

  7. 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.

  8. Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program.

    PubMed

    Klimas, Jan; Muench, John; Wiest, Katharina; Croff, Raina; Rieckman, Traci; McCarty, Dennis

    2015-01-01

    Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention, and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n = 208) and in an opioid treatment program (n = 204) over a two-year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. In the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counselors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested that organizational, structural, provider, patient, and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow.

  9. Functional selectivity of dopamine D1 receptor agonists in regulating the fate of internalized receptors *

    PubMed Central

    Ryman-Rasmussen, Jessica P.; Griffith, Adam; Oloff, Scott; Vaidehi, Nagarajan; Brown, Justin T.; Goddard, William A.; Mailman, Richard B.

    2007-01-01

    Recently, we demonstrated that D1 agonists can cause functionally selective effects when the endpoints of receptor internalization and adenylate cyclase activation are compared. The present study was designed to probe the phenomenon of functional selectivity at the D1 receptor further by testing the hypothesis that structurally dissimilar agonists with efficacies at these endpoints that equal or exceed those of dopamine would differ in ability to influence receptor fate after internalization, a functional endpoint largely unexplored for the D1 receptor. We selected two novel agonists of therapeutic interest that meet these criteria (the isochroman A-77636, and the isoquinoline dinapsoline), and compared the fates of the D1 receptor after internalization in response to these two compounds with that of dopamine. We found that dopamine caused the receptor to be rapidly recycled to the cell surface within 1 h of removal. Conversely, A-77636 caused the receptor to be retained intracellularly up to 48 h after agonist removal. Most surprisingly, the D1 receptor recovered to the cell surface 48 h after removal of dinapsoline. Taken together, these data indicate that these agonists target the D1 receptor to different intracellular trafficking pathways, demonstrating that the phenomenon of functional selectivity at the D1 receptor is operative for cellular events that are temporally downstream of immediate receptor activation. We hypothesize that these differential effects result from interactions of the synthetic ligands with aspects of the D1 receptor that are distal from the ligand binding domain. PMID:17067639

  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. 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.

  12. 3D-pharmacophore identification for kappa-opioid agonists using ligand-based drug-design techniques.

    PubMed

    Yamaotsu, Noriyuki; Hirono, Shuichi

    2011-01-01

    A selective kappa-opioid receptor (KOR) agonist might act as a powerful analgesic without the side effects of micro-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 kappa-opioid agonists and propose a new three-dimensional pharmacophore model that encompasses the kappa-activities of all classes. This utilizes conformational sampling of agonists by high-temperature molecular dynamics and pharmacophore extraction through a series of molecular superpositions.

  13. Comparison of the discriminative-stimulus effects of SKF 38393 with those of other dopamine receptor agonists.

    PubMed

    Desai, R I; Terry, P; Katz, J L

    2003-05-01

    The dopamine D(1)-like receptor agonists have traditionally been defined molecularly by their efficacy in stimulating adenylyl cyclase. However, evidence correlating the effectiveness of these drugs in behavioral assays and their effectiveness biochemically has not been forthcoming. The present study compared the discriminative-stimulus effects of the D(1)-like partial agonist SKF 38393 with several other D(1)-like agonists, an indirect agonist, cocaine, and a D(2)-like agonist, quinpirole. Rats were trained under a fixed-ratio 30-response schedule to discriminate SKF 38393 (5.6 mg/kg) from vehicle. Under this schedule, 30 consecutive responses on one of two keys were reinforced with food presentation after a pre-session injection of 5.6 mg/kg SKF 38393, and 30 consecutive responses on the alternative key were reinforced after saline injection. When daily performances were stable, substitution patterns for several compounds were assessed during test sessions in which 30 consecutive responses on either key were reinforced. Quinpirole and cocaine each produced saline-appropriate responding. In contrast, the D(1)-like agonists, SKF 75670 and SKF 77434, fully substituted for SKF 38393. Curiously, SKF 82958, which is considered a full agonist based on adenylyl cyclase assays, was less effective in substituting for SKF 38393 (maximum drug-appropriate responding 66%) than was the partial agonist SKF 75670. The present results suggest that second messenger effects other than stimulation of adenylyl cyclase may play an important role in the behavioral effects of dopamine D(1)-like agonists.

  14. 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.

  15. Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner.

    PubMed

    Blume, Lawrence C; Leone-Kabler, Sandra; Luessen, Deborah J; Marrs, Glen S; Lyons, Erica; Bass, Caroline E; Chen, Rong; Selley, Dana E; Howlett, Allyn C

    2016-11-01

    Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1 R) distal C-terminus-associated protein that modulates CB1 R signaling via G proteins, and CB1 R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1 R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB1 Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1 R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown clones to investigate gene dose effects of CRIP1a on CB1 R plasma membrane expression. Results indicate that CP55940 or WIN55212-2 (10 nM, 5 min) reduced cell surface CB1 R by a dynamin- and clathrin-dependent process, and this was attenuated by CRIP1a over-expression. CP55940-mediated cell surface CB1 R loss was followed by a cycloheximide-sensitive recovery of surface receptors (30-120 min), suggesting the requirement for new protein synthesis. In contrast, WIN55212-2-mediated cell surface CB1 Rs recovered only in CRIP1a knockdown cells. Changes in CRIP1a expression levels did not affect a transient rimonabant (10 nM)-mediated increase in cell surface CB1 Rs, which is postulated to be as a result of rimonabant effects on 'non-agonist-driven' internalization. These studies demonstrate a novel role for CRIP1a in agonist-driven CB1 R cell surface regulation postulated to occur by two mechanisms: 1) attenuating internalization that is agonist-mediated, but not that in the absence of exogenous agonists, and 2) biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface.

  16. beta2 adrenergic agonists in acute lung injury? The heart of the matter.

    PubMed

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of beta2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to increase the resolution of pulmonary edema. However, the results of clinical trials of beta agonist therapy for ALI/ARDS have been conflicting in terms of benefit. In the previous issue of Critical Care, Briot and colleagues present evidence that may help clarify the inconsistent results. The authors demonstrate that, in oleic acid lung injury in dogs, the inotropic effect of beta agonists may recruit damaged pulmonary capillaries, leading to increased lung endothelial permeability.

  17. 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

  18. Nicotinamide is an endogenous agonist for a C. elegans TRPV OSM-9 and OCR-4 channel

    PubMed Central

    Upadhyay, Awani; Pisupati, Aditya; Jegla, Timothy; Crook, Matt; Mickolajczyk, Keith J.; Shorey, Matthew; Rohan, Laura E.; Billings, Katherine A.; Rolls, Melissa M.; Hancock, William O.; Hanna-Rose, Wendy

    2016-01-01

    TRPV ion channels are directly activated by sensory stimuli and participate in thermo-, mechano- and chemo-sensation. They are also hypothesized to respond to endogenous agonists that would modulate sensory responses. Here, we show that the nicotinamide (NAM) form of vitamin B3 is an agonist of a Caenorhabditis elegans TRPV channel. Using heterologous expression in Xenopus oocytes, we demonstrate that NAM is a soluble agonist for a channel consisting of the well-studied OSM-9 TRPV subunit and relatively uncharacterized OCR-4 TRPV subunit as well as the orthologous Drosophila Nan-Iav TRPV channel, and we examine stoichiometry of subunit assembly. Finally, we show that behaviours mediated by these C. elegans and Drosophila channels are responsive to NAM, suggesting conservation of activity of this soluble endogenous metabolite on TRPV activity. Our results in combination with the role of NAM in NAD+ metabolism suggest an intriguing link between metabolic regulation and TRPV channel activity. PMID:27731314

  19. Cyclic AMP agonist inhibition increases at low levels of histamine release from human basophils

    SciTech Connect

    Tung, R.S.; Lichtenstein, L.M.

    1981-09-01

    The relationship between the intensity of the signal for antigen-induced immunoglobulin E-mediated histamine release from human basophils and the concentration of agonist needed to inhibit release has been determined. The agonists, prostaglandin E1, dimaprit, fenoterol, isobutylmethylxanthine and dibutyryl cyclic AMP, all act by increasing the cyclic AMP level. Each agonist was 10- to 1000-fold more potent (relative ID50) at low levels of histamine release (5-10% of total histamine) than at high levels (50-80%). Thus, the inhibitory potential of a drug is a function of the concentration of antigen used to initiate the response. Our results are now more in accord with the inhibitory profile of these drugs in human lung tissue. It is suggested that in vivo release is likely to be low and that this is the level at which to evaluate drugs in vitro.

  20. Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists.

    PubMed

    Sasmal, Pradip K; Krishna, C Vamsee; Adabala, S Sudheerkumar; Roshaiah, M; Rawoof, Khaji Abdul; Thadi, Emima; Sukumar, K Pavan; Cheera, Srisailam; Abbineni, Chandrasekhar; Rao, K V L Narasimha; Prasanthi, A; Nijhawan, Kamal; Jaleel, Mahaboobi; Iyer, Lakshmi Ramachandran; Chaitanya, T Krishna; Tiwari, Nirbhay Kumar; Krishna, N Lavanya; Potluri, Vijay; Khanna, Ish; Frimurer, Thomas M; Lückmann, Michael; Rist, Øystein; Elster, Lisbeth; Högberg, Thomas

    2015-02-15

    Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.

  1. Synthesis of quinolinomorphinan-4-ol derivatives as δ opioid receptor agonists.

    PubMed

    Ida, Yoshihiro; Nemoto, Toru; Hirayama, Shigeto; Fujii, Hideaki; Osa, Yumiko; Imai, Masayuki; Nakamura, Takashi; Kanemasa, Toshiyuki; Kato, Akira; Nagase, Hiroshi

    2012-01-15

    The previously reported morphinan derivative SN-28 showed high selectivity and agonist activity for the δ opioid receptor. In the course of examining the structure-activity relationship of SN-28 derivatives, the derivatives with the 4-hydroxy group (SN-24, 26, 27) showed higher selectivities for the δ receptor over the μ receptor than the corresponding SN-28 derivatives with the 3-hydroxy group (SN-11, 23, 28). Derivatives with the 4-hydroxy group showed potent agonist activities for the δ receptor in the [(35)S]GTPγS binding assay. Although the 17-cyclopropylmethyl derivative (SN-11) with a 3-hydroxy group showed the lowest selectivity for the δ receptor among the morphinan derivatives, the agonist activity toward the δ receptor was the most potent for candidates with the 3-hydroxy group.

  2. 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

    2007-10-04

    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.

  3. New 1,4-dihydropyridines endowed with NO-donor and calcium channel agonist properties.

    PubMed

    Visentin, Sonja; Rolando, Barbara; Di Stilo, Antonella; Fruttero, Roberta; Novara, Monica; Carbone, Emilio; Roussel, Christian; Vanthuyne, Nicolas; Gasco, Alberto

    2004-05-06

    A new series of calcium channel agonists structurally related to Bay K8644, containing NO donor furoxans and the related furazans unable to release NO, is described. The racemic mixtures were studied for their action on L-type Ca(2+) channels expressed in cultured rat insulinoma RINm5F cells. All the products proved to be potent calcium channel agonists. All the racemic mixtures, with the only exception of the carbamoyl derivatives 9, 12 endowed with scanty solubility, were separated by chiral chromatography into the corresponding enantiomers; the (+) enantiomers were found to be potent agonists while the (-) ones were feeble antagonists. The racemic mixtures were also assessed for their positive inotropic activity on electrically stimulated rat papillary muscle and for their ability to increase Ca(2+) entry into the vascular smooth muscle of rat aorta strips. The cyanofuroxan 8 proved to be an interesting product with dual Ca(2+)-dependent positive inotropic and NO-dependent vasodilating activity.

  4. Nicotinamide is an endogenous agonist for a C. elegans TRPV OSM-9 and OCR-4 channel.

    PubMed

    Upadhyay, Awani; Pisupati, Aditya; Jegla, Timothy; Crook, Matt; Mickolajczyk, Keith J; Shorey, Matthew; Rohan, Laura E; Billings, Katherine A; Rolls, Melissa M; Hancock, William O; Hanna-Rose, Wendy

    2016-10-12

    TRPV ion channels are directly activated by sensory stimuli and participate in thermo-, mechano- and chemo-sensation. They are also hypothesized to respond to endogenous agonists that would modulate sensory responses. Here, we show that the nicotinamide (NAM) form of vitamin B3 is an agonist of a Caenorhabditis elegans TRPV channel. Using heterologous expression in Xenopus oocytes, we demonstrate that NAM is a soluble agonist for a channel consisting of the well-studied OSM-9 TRPV subunit and relatively uncharacterized OCR-4 TRPV subunit as well as the orthologous Drosophila Nan-Iav TRPV channel, and we examine stoichiometry of subunit assembly. Finally, we show that behaviours mediated by these C. elegans and Drosophila channels are responsive to NAM, suggesting conservation of activity of this soluble endogenous metabolite on TRPV activity. Our results in combination with the role of NAM in NAD+ metabolism suggest an intriguing link between metabolic regulation and TRPV channel activity.

  5. [Protective effect of adenosine receptor agonists in a model of spinal cord injury in rats].

    PubMed

    Sufianova, G Z; Usov, L A; Sufianov, A A; Perelomov, Iu P; Raevskaia, L Iu; Shapkin, A G

    2002-01-01

    Possibilities of the neuroprotector therapy using adenosine and cyclopentyladenosine (CPA), an adenosine receptor agonist, were studied on a model of spinal cord injury by compression in rats (most closely reproducing the analogous clinical pathological process in humans). The model was induced by slow, graded compression of the spinal cord at the thoracic level. Adenosine and CPA were introduced 60 min before injury by subcutaneous injections in a dose of 300 and 2.5 micrograms/kg, respectively. The protective effect was judged by comparing the neurological, electromyographic, and histopathological changes in animals with the model injury and in the control group (adenosine and CPA background). The A1-agonist CPA injections produced a pronounced, statistically significant neuroprotector effect on the given spinal cord injury model in rats. The neuroprotective effect of adenosine was significant but not as strong. It is concluded that it is expedient to use A-agonists in clinics.

  6. 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.

  7. 2-Thiazolylethylamine, a selective histamine H1 agonist, decreases seizure susceptibility in mice.

    PubMed

    Yokoyama, H; Onodera, K; Iinuma, K; Watanabe, T

    1994-03-01

    The effects of intracerebroventricular (ICV) administration of histamine and its selective agonists on electrically and pentylenetetrazole-induced convulsions in mice were studied. The ICV administration of histamine decreased seizure susceptibility on electrically and pentylenetetrazole-induced convulsions significantly and dose-dependently. The inhibitory effects of histamine were well antagonized by centrally acting histamine H1 antagonists such as pyrilamine (or mepyramine) and ketotifen, but not by a peripherally acting histamine H1 antagonist, astemizole, or a centrally acting H2 antagonist, zolantidine. The ICV administration of 2-thiazolylethylamine, a selective histamine H1 agonist, also decreased seizure susceptibility, which could be antagonized by centrally acting histamine H1 antagonists, whereas dimaprit, a selective histamine H2 agonist, did not affect seizure susceptibility. These findings strengthened the idea that the central histaminergic neuron system plays an inhibitory role in convulsions.

  8. A uniform molecular model of δ opioid agonist and antagonist pharmacophore conformations

    NASA Astrophysics Data System (ADS)

    Brandt, Wolfgang

    1998-11-01

    On the basis of a model of the pharmacophore conformations of agonist of the δ-opioid receptor the corresponding δ-antagonist conformations were determined by means of force field calculations. The results explain the unusual behavior of several cyclic β-casomorphin analogues on the molecular level. Thus, for instance, the model helps to understand why Tyr-c[D-Orn-2-Nal-D-Pro-Gly] is a mixed μ-agonist and δ-antagonist. Furthermore, the model is consistent with low energy conformations of other δ-antagonists such as Tyr-Tic-Phe, Tyr-Tic-Phe-Phe, naltrindole and BNTX. The occupation of a special spatial area by bulky groups close to the protonated N-terminus of opioid peptides is assumed to be highly critical for the switch from agonist to antagonist behavior.

  9. 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.

  10. 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).

  11. Inhibitory effects of peroxisome proliferator-activated receptor γ agonists on collagen IV production in podocytes.

    PubMed

    Li, Yanjiao; Shen, Yachen; Li, Min; Su, Dongming; Xu, Weifeng; Liang, Xiubin; Li, Rongshan

    2015-07-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-γ agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-γ was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-γ agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-β. In contrast, adding PPAR-γ antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-β in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-β-induced SBE4-luciferase activity. In conclusion, PPAR-γ activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-β-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-γ agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-γ agonists as podocyte protective agents.

  12. Identification of an extracellular segment of the oxytocin receptor providing agonist-specific binding epitopes.

    PubMed

    Hawtin, S R; Howard, H C; Wheatley, M

    2001-03-01

    The effects of the peptide hormone oxytocin are mediated by oxytocin receptors (OTRs) expressed by the target tissue. The OTR is a member of the large family of G-protein-coupled receptors. Defining differences between the interaction of agonists and antagonists with the OTR at the molecular level is of fundamental importance, and is addressed in this study. Using truncated and chimaeric receptor constructs, we establish that a small 12-residue segment in the distal portion of the N-terminus of the human OTR provides important epitopes which are required for agonist binding. In contrast, this segment does not contribute to the binding site for antagonists, whether peptide or non-peptide. It does, however, have a role in agonist-induced OTR signalling. Oxytocin is also an agonist at the vasopressin V(1a) receptor (V(1a)R). A chimaeric receptor (V(1a)R(N)-OTR) was engineered in which the N-terminus of the OTR was substituted by the corresponding, but unrelated, sequence from the N-terminus of the V(1a)R. We show that the V(1a)R N-terminus present in V(1a)R(N)-OTR fully restored both agonist binding and intracellular signalling to a dysfunctional truncated OTR construct. The N-terminal segment does not, however, contribute to receptor-selective agonism between the OTR and the V(1a)R. Our data establish a key role for the distal N-terminus of the OTR in providing agonist-specific binding epitopes.

  13. Adenosine-A1 receptor agonist induced hyperalgesic priming type II.

    PubMed

    Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D

    2016-03-01

    We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin acetate salt) induces a model of transition to chronic pain that we have termed type II hyperalgesic priming. Similar to type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, type II hyperalgesic priming differs from type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent. We report that, as with the repeated injection of a MOR agonist, the repeated administration of an agonist at the A1-adenosine receptor, also a Gi-protein coupled receptor, N-cyclopentyladenosine (CPA), also produces priming similar to DAMGO-induced type II hyperalgesic priming. In this study, we demonstrate that priming induced by repeated exposure to this A1-adenosine receptor agonist shares the same mechanisms, as MOR-agonist induced priming. However, the prolongation of PGE2 hyperalgesia induced by repeated administration of CPA depends on G-protein αi subunit activation, differently from DAMGO-induced type II priming, in which it depends on the β/γ subunit. These data implicate a novel form of Gi-protein signaling pathway in the type II hyperalgesic priming induced by repeated administration of an agonist at A1-adenosine receptor to the peripheral terminal of the nociceptor.

  14. Adenosine-A1 Receptor Agonist Induced Hyperalgesic Priming Type II

    PubMed Central

    Araldi, Dioneia; Ferrari, Luiz F.; Levine, Jon D.

    2016-01-01

    We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate salt) induces a model of the transition to chronic pain that we have termed Type II hyperalgesic priming. Similar to Type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, Type II hyperalgesic priming differs from Type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent. We report that as with the repeated injection of a MOR agonist, the repeated administration of an agonist at the A1-adenosine receptor, also a Gi-protein coupled receptor, N6-Cyclopentyladenosine (CPA), also produces priming similar to DAMGO-induced Type II hyperalgesic priming. In this study we demonstrate that priming induced by repeated exposure to this A1-adenosine receptor agonist shares the same mechanisms as MOR-agonist induced priming. However, the prolongation of PGE2 hyperalgesia induced by repeated administration of CPA depends on G-protein αi subunit activation, differently from DAMGO-induced Type II priming, in which it depends on the β/γ subunit. These data implicate a novel form of Gi-protein signaling pathway in the Type II hyperalgesic priming induced by repeated administration of an agonist at A1-adenosine receptor to the peripheral terminal of the nociceptor. PMID:26588695

  15. Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists

    PubMed Central

    Jaszberenyi, Miklos; Rick, Ferenc G.; Popovics, Petra; Block, Norman L.; Zarandi, Marta; Cai, Ren-Zhi; Vidaurre, Irving; Szalontay, Luca; Jayakumar, Arumugam R.; Schally, Andrew V.

    2014-01-01

    The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of growth hormone-releasing hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial growth, such as FGF basic and TGFβ. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells. PMID:24379381

  16. Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.

    PubMed

    Codd, Ellen E; Baker, Judith; Brandt, Michael R; Bryant, Stewart; Cai, Chaozhong; Carson, John R; Chevalier, Kristen M; Colburn, Raymond W; Coogan, Timothy P; Dax, Scott L; Decorte, Bart; Kemmerer, Michael; Legrand, Edmund K; Lenhard, James M; Leone, Angelique M; Lin, Ling; Mabus, John R; McDonnell, Mark E; McMillian, Michael K; McNally, James J; Stone, Dennis J; Wang, Charles Y; Zhang, Sui-Po; Flores, Christopher M

    2010-10-01

    The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic β-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.

  17. 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.

  18. Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity.

    PubMed

    Ursu, Daniel; Knopp, Kelly; Beattie, Ruth E; Liu, Bin; Sher, Emanuele

    2010-09-01

    TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency.

  19. Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor.

    PubMed

    Lin, Wenwei; Yang, Lei; Chai, Sergio C; Lu, Yan; Chen, Taosheng

    2016-01-27

    Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer cells to chemotherapeutic drugs. We recently reported a novel CAR inhibitor/inverse agonist CINPA1 (11). Here, we have obtained or designed 54 analogs of CINPA1 and used a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to evaluate their CAR inhibition potency. Many of the 54 analogs showed CAR inverse agonistic activities higher than those of CINPA1, which has an IC50 value of 687 nM. Among them, 72 has an IC50 value of 11.7 nM, which is about 59-fold more potent than CINPA1 and over 10-fold more potent than clotrimazole (an IC50 value of 126.9 nM), the most potent CAR inverse agonist in a biochemical assay previously reported by others. Docking studies provide a molecular explanation of the structure-activity relationship (SAR) observed experimentally. To our knowledge, this effort is the first chemistry endeavor in designing and identifying potent CAR inverse agonists based on a novel chemical scaffold, leading to 72 as the most potent CAR inverse agonist so far. The 54 chemicals presented are novel and unique tools for characterizing CAR's function, and the SAR information gained from these 54 analogs could guide future efforts to develop improved CAR inverse agonists.

  20. The dopamine D(1) receptor agonist SKF-82958 serves as a discriminative stimulus in the rat.

    PubMed

    Haile, C N; Carey, G; Varty, G B; Coffin, V L

    2000-01-28

    We examined the discriminative stimulus effects of the high-efficacy dopamine D(1) receptor agonist (+/-)6-chloro-7, 8-dihydroxy-3-ally1-phenyl-2,3,4,5-tetrahydro-1H-3benzazepine++ + hydrobromide (SKF-82958) in rats trained to discriminate SKF-82958 (0.03 mg/kg) from vehicle in a two-lever food-reinforced drug discrimination task. SKF-82958 produced dose-related increases in responding to the SKF-82958 appropriate lever with full substitution occurring at the training dose. Pretreatment with the dopamine D(1)/D(5) receptor antagonist (-)-trans-6,7,7a,8,9, 13b-hexahydro-3-chloro-2hydroxy-N-methyl-5H-benzo-[d]naphtho -¿2, 1-b¿azepine (SCH-39166) (0.01 mg/kg) attenuated the discriminative stimulus effects of SKF-82958. Pretreatment with the dopamine D(2) receptor antagonist raclopride (0.03 mg/kg) had no effect. The high-efficacy dopamine D(1) receptor agonist R(+)6chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) fully substituted for SKF-82958, whereas the low-efficacy dopamine D(1) receptor agonist (+/-)1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) produced only partial substitution. The dopamine D(2) receptor agonist trans-(+/-)-4,4a,5,6,7,8,8a, 9-octahydro-5-propyl-1H-propyl-1H-pyrazolo[3,4-g]quinoline dihydrochloride (quinpirole) and the indirect dopamine agonist cocaine did not substitute fully for the SKF-82958 discriminative stimulus cue. These results demonstrate that the high-efficacy dopamine D(1) receptor agonist SKF-82958 can serve as an effective discriminative stimulus in the rat, and that these effects are mediated by a dopamine D(1)-like receptor mechanism.

  1. STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus

    PubMed Central

    Guo, Fang; Zhao, Xuesen; Wang, Jianghua; Liu, Fei; Xu, Chunxiao; Wei, Lai; Jiang, Jian-Dong; Block, Timothy M.; Guo, Ju-Tao

    2014-01-01

    Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted. PMID:25512416

  2. Crystal Structures of the Nuclear Receptor, Liver Receptor Homolog 1, Bound to Synthetic Agonists.

    PubMed

    Mays, Suzanne G; Okafor, C Denise; Whitby, Richard J; Goswami, Devrishi; Stec, Józef; Flynn, Autumn R; Dugan, Michael C; Jui, Nathan T; Griffin, Patrick R; Ortlund, Eric A

    2016-12-02

    Liver receptor homolog 1 (NR5A2, LRH-1) is an orphan nuclear hormone receptor that regulates diverse biological processes, including metabolism, proliferation, and the resolution of endoplasmic reticulum stress. Although preclinical and cellular studies demonstrate that LRH-1 has great potential as a therapeutic target for metabolic diseases and cancer, development of LRH-1 modulators has been difficult. Recently, systematic modifications to one of the few known chemical scaffolds capable of activating LRH-1 failed to improve efficacy substantially. Moreover, mechanisms through which LRH-1 is activated by synthetic ligands are entirely unknown. Here, we use x-ray crystallography and other structural methods to explore conformational changes and receptor-ligand interactions associated with LRH-1 activation by a set of related agonists. Unlike phospholipid LRH-1 ligands, these agonists bind deep in the pocket and do not interact with residues near the mouth nor do they expand the pocket like phospholipids. Unexpectedly, two closely related agonists with similar efficacies (GSK8470 and RJW100) exhibit completely different binding modes. The dramatic repositioning is influenced by a differential ability to establish stable face-to-face π-π-stacking with the LRH-1 residue His-390, as well as by a novel polar interaction mediated by the RJW100 hydroxyl group. The differing binding modes result in distinct mechanisms of action for the two agonists. Finally, we identify a network of conserved water molecules near the ligand-binding site that are important for activation by both agonists. This work reveals a previously unappreciated complexity associated with LRH-1 agonist development and offers insights into rational design strategies.

  3. Molecular determinants of agonist selectivity in glutamate-gated chloride channels which likely explain the agonist selectivity of the vertebrate glycine and GABAA-ρ receptors.

    PubMed

    Blarre, Thomas; Bertrand, Hugues-Olivier; Acher, Francine C; Kehoe, JacSue

    2014-01-01

    Orthologous Cys-loop glutamate-gated chloride channels (GluClR's) have been cloned and described electrophysiologically and pharmacologically in arthropods and nematodes (both members of the invertebrate ecdysozoan superphylum). Recently, GluClR's from Aplysia californica (a mollusc from the lophotrochozoan superphylum) have been cloned and similarly studied. In spite of sharing a common function, the ecdysozoan and lophotrochozoan receptors have been shown by phylogenetic analyses to have evolved independently. The recent crystallization of the GluClR from C. elegans revealed the binding pocket of the nematode receptor. An alignment of the protein sequences of the nematode and molluscan GluClRs showed that the Aplysia receptor does not contain all of the residues defining the binding mode of the ecdysozoan receptor. That the two receptors have slightly different binding modes is not surprising since earlier electrophysiological and pharmacological experiments had suggested that they were differentially responsive to certain agonists. Knowledge of the structure of the C. elegans GluClR has permitted us to generate a homology model of the binding pocket of the Aplysia receptor. We have analyzed the differences between the two binding modes and evaluated the relative significance of their non-common residues. We have compared the GluClRs electrophysiologically and pharmacologically and we have used site-directed mutagenesis on both receptor types to test predictions made from the model. Finally, we propose an explanation derived from the model for why the nematode receptors are gated only by glutamate, whereas the molluscan receptors can also be activated by β-alanine, GABA and taurine. Like the Aplysia receptor, the vertebrate glycine and GABAA-ρ receptors also respond to these other agonists. An alignment of the sequences of the molluscan and vertebrate receptors shows that the reasons we have given for the ability of the other agonists to activate the Aplysia

  4. Comparison of the in vitro efficacy of mu, delta, kappa and ORL1 receptor agonists and non-selective opioid agonists in dog brain membranes.

    PubMed

    Lester, Patrick A; Traynor, John R

    2006-02-16

    Morphine and related opioid agonists are frequently used in dogs for their analgesic properties, their sedative effects and as adjuncts to anesthesia. Such compounds may be effective through a combined action at mu-, delta- and kappa-opioid receptors. In this work, the in vitro relative agonist efficacy of ligands selective for mu (DAMGO)-, delta (SNC80)- and kappa (U69593)-opioid receptors as well as the opioid receptor-like receptor ORL(1) (orphaninFQ/nociceptin) which may mediate nociceptive or antinociceptive actions was determined using the [35S]GTPgammaS binding assay in membrane homogenates from the frontal cortex, thalamus and spinal cord of beagle dogs. In addition, other analgesics commonly used in the dog were investigated. For the receptor-selective compounds, maximum stimulation of [35S]GTPgammaS binding decreased in the order kappa > ORL1 > delta > mu in cortical homogenates, compared with mu > ORL1 > kappa > delta in thalamic and spinal cord homogenates. For other opioids examined, efficacy decreased in the order etorphine > morphine > fentanyl = oxymorphine > butorphanol = oxycodone = nalbuphine. There was no significant difference in the potency of compounds to stimulate [35S]GTPgammaS binding between cortex and thalamus, with the exception of etorphine. Buprenorphine, the partial mu-opioid receptor agonist and kappa-, delta-opioid receptor antagonist, which does have analgesic efficacy in the dog, showed no agonism in any tissue but was an effective mu-opioid receptor > ORL1 receptor antagonist. The results show that the ability of agonists to stimulate [35S]GTPgammaS binding relates to the receptor distribution of opioid and ORL1 receptors in the dog.

  5. Effect of Light and Melatonin and Other Melatonin Receptor Agonists on Human Circadian Physiology.

    PubMed

    Emens, Jonathan S; Burgess, Helen J

    2015-12-01

    Circadian (body clock) timing has a profound influence on mental health, physical health, and health behaviors. This review focuses on how light, melatonin, and other melatonin receptor agonist drugs can be used to shift circadian timing in patients with misaligned circadian rhythms. A brief overview of the human circadian system is provided, followed by a discussion of patient characteristics and safety considerations that can influence the treatment of choice. The important features of light treatment, light avoidance, exogenous melatonin, and other melatonin receptor agonists are reviewed, along with some of the practical aspects of light and melatonin treatment.

  6. 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

  7. Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes

    PubMed Central

    2015-01-01

    We report herein the design and synthesis of a series of potent and selective GPR119 agonists. Our objective was to develop a GPR119 agonist with properties that were suitable for fixed-dose combination with a DPP4 inhibitor. Starting from a phenoxy analogue (1), medicinal chemistry efforts directed toward reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy analogues. Compound 28 was chosen for further profiling because of its favorable physicochemical properties and excellent GPR119 potency across species. This compound exhibited a clean off-target profile in counterscreens and good in vivo efficacy in mouse oGTT. PMID:26288697

  8. Effect of an α2 agonist (mivazerol) on limiting myocardial ischaemia in stable angina

    PubMed Central

    Fox, K; Dargie, H; de Bono, D P; Oliver, M; Wulfert, E; Kharkevitch, T

    1999-01-01

    A specific α2 agonist, mivazerol, known to be effective in reducing myocardial ischaemia when given intravenously immediately before an exercise tolerance test, produced a significant increase in exercise duration and time to the onset of angina when given orally over a two week period to 25 patients with stable angina. A non-significant trend to reduction in electrocardiographic signs of ischaemia was also noted. The clinical relevance of this improvement now needs to be tested in larger numbers.


Keywords: α2 agonist; sympathetic activity; myocardial ischaemia; stable angina; exercise tolerance test PMID:10455094

  9. Optimization of alpha-acylaminoketone ecdysone agonists for control of gene expression.

    PubMed

    Tice, Colin M; Hormann, Robert E; Thompson, Christine S; Friz, Jennifer L; Cavanaugh, Caitlin K; Saggers, Jessica A

    2003-06-02

    Fifteen new alpha-acylaminoketones were prepared by four different routes in an initial effort to optimize the potency of these compounds as ecdysone agonists. The compounds were assayed in mammalian cells expressing the ecdysone receptors from Bombyx mori (BmEcR) and Choristoneura fumiferana (CfEcR) for their ability to cause expression of a reporter gene downstream of an ecdysone response element. A new alpha-acylaminoketone was identified which had activity equal to that of the standard dibenzoylhydrazine ecdysone agonist GS()-E in the assay based on CfEcR.

  10. Potent complement C3a receptor agonists derived from oxazole amino acids: Structure-activity relationships.

    PubMed

    Singh, Ranee; Reed, Anthony N; Chu, Peifei; Scully, Conor C G; Yau, Mei-Kwan; Suen, Jacky Y; Durek, Thomas; Reid, Robert C; Fairlie, David P

    2015-12-01

    Potent ligands for the human complement C3a receptor (C3aR) were developed from the almost inactive tripeptide Leu-Ala-Arg corresponding to the three C-terminal residues of the endogenous peptide agonist C3a. The analogous Leu-Ser-Arg was modified by condensing the serine side chain with the leucine carbonyl with elimination of water to form leucine-oxazole-arginine. Subsequent elaboration with a variety of N-terminal amide capping groups produced agonists as potent as human C3a itself in stimulating Ca(2+) release from human macrophages. Structure-activity relationships are discussed.

  11. 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.

  12. Effect of Light and Melatonin and other Melatonin Receptor Agonists on Human Circadian Physiology

    PubMed Central

    Emens, Jonathan S.

    2015-01-01

    Synopsis Circadian (body clock) timing has a profound influence on mental health, physical health, and health behaviors. This review focuses on how light, melatonin and other melatonin receptor agonist drugs can be used to shift circadian timing in patients with misaligned circadian rhythms. A brief overview of the human circadian system is provided, followed by a discussion of patient characteristics and safety considerations that can influence the treatment of choice. The important features of light treatment, light avoidance, exogenous melatonin and other melatonin receptor agonists are reviewed, along with some of the practical aspects of light and melatonin treatment. PMID:26568121

  13. Dopamine Agonist Increases Risk Taking but Blunts Reward-Related Brain Activity

    PubMed Central

    Riba, Jordi; Krämer, Ulrike M.; Heldmann, Marcus; Richter, Sylvia; Münte, Thomas F.

    2008-01-01

    The use of D2/D3 dopaminergic agonists in Parkinson's disease (PD) may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of the reward system, following unexpected high gains and therefore propose that pathological gambling in PD results from the need to seek higher rewards to overcome the blunted response in this system. PMID:18575579

  14. 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

  15. The role of inhaled long-acting beta-2 agonists in the management of asthma.

    PubMed Central

    Kelly, H. William; Harkins, Michelle S.; Boushey, Homer

    2006-01-01

    The role of inhaled beta-2 agonists in the management of asthma has changed significantly over the last several years. This review outlines the most recent understanding of the pathophysiology of asthma and the studies that define the roles that both short- and long-acting beta-2 agonists play in therapy for this disease. A concentration on the clinical pharmacology and genetic implications for clinical use of this class of drugs in accordance with the national and international guidelines are described. PMID:16532973

  16. To kill a tumor cell: the potential of proapoptotic receptor agonists

    PubMed Central

    Ashkenazi, Avi; Herbst, Roy S.

    2008-01-01

    Disturbances in mechanisms that direct abnormal cells to undergo apoptosis frequently and critically contribute to tumorigenesis, yielding a logical target for potential therapeutic intervention. There is currently heightened interest in the extrinsic apoptosis pathway, with several proapoptotic receptor agonists (PARAs) in development. The PARAs include the ligand recombinant human Apo2L/TRAIL and agonistic mAbs. Mechanistic and preclinical data with Apo2L/TRAIL indicate exciting opportunities for synergy with conventional therapies and for combining PARAs with other molecularly targeted agents. Novel molecular biomarkers may help identify those patients most likely to benefit from PARA therapy. PMID:18523647

  17. The characterization of a novel rigid nicotine analog with alpha7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion.

    PubMed

    Papke, Roger L; Zheng, Guangrong; Horenstein, Nicole A; Dwoskin, Linda P; Crooks, Peter A

    2005-09-01

    The alpha7 nAChR subtype is of particular interest as a potential therapeutic target since it has been implicated as a mediator of both cognitive and neuroprotective activity. The rigid nicotine analog ACME and the N-cyanoborane conjugate ACME-B are selective partial agonists of rat alpha7 receptors expressed in Xenopus oocytes, with no significant activation of either alpha3beta4 or alpha4beta2 receptors. ACME-B is both more potent and efficacious than ACME. The efficacies of ACME-B and ACME are approximately 26% and 10% of the efficacy of ACh, respectively. Similar N-conjugation of S(-)nicotine with cyanoborane decreased efficacy for alpha3beta4 and alpha4beta2 receptors, as well as for alpha7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified alpha7-selective agonists, suggests that they share a similar structural motif that may be applicable to other alpha7-selective agonists.

  18. Biperiden enhances L-DOPA methyl ester and dopamine D(l) receptor agonist SKF-82958 but antagonizes D(2)/D(3) receptor agonist rotigotine antihemiparkinsonian actions.

    PubMed

    Domino, Edward F; Ni, Lisong

    2008-12-03

    The effects of biperiden (0, 100, and 320 microg/kg), a selective muscarinic M(1)/M(4) receptor cholinergic antagonist, were studied alone and in combination with those of L-DOPA methyl ester (16.7 mg/kg), a selective dopamine D(1) receptor agonist SKF-82958 (74.8 microg/kg), or a selective D(2)/D(3) receptor agonist rotigotine (32 microg/kg) on circling behavior in MPTP induced hemiparkinsonian monkeys. The doses selected were given i.m. in approximately equieffective doses to produce contraversive circling. Biperiden alone with 5% dextrose vehicle produced a slight increase in contraversive circling in a dose related manner. When combined with L-DOPA methyl ester, it enhanced contraversive circling and decreased ipsiversive circling. When biperiden was combined with SKF-82958, contraversive circling also was enhanced and ipsiversive circling decreased. Exactly the opposite was observed with the combination of biperiden and rotigotine. The results indicate a dramatic difference in effects of a prototypic muscarinic M(1)/M(4) receptor cholinergic antagonist in combination with prototypic full dopamine D(1) or D(2)/D(3) receptor agonists. Biperiden interactions with L-DOPA methyl ester were more predominantly D(l) than D(2)/D(3) receptor-like in this animal model of hemiparkinsonism.

  19. [Effects of agonists and antagonists of benzodiazepine, GABA and NMDA receptors, on caffeine-induced seizures in mice].

    PubMed

    Inano, S

    1992-08-01

    In mice, tonic convulsive seizure induced by intravenous administration of caffeine (adenosine A1, A2 receptors antagonist) was significantly potentiated by any one of L-PIA (adenosine A1 receptor agonist), NECA (adenosine A2 receptor agonist) and 2-ClAd (adenosine A1, A2 receptors agonist). The caffeine-induced seizure was unaffected by diazepam (benzodiazepine receptor agonist), but was inhibited by Ro 15-1788 (antagonist or partial agonist). beta-DMCM (antagonist or inverse agonist) increased the seizure. Muscimol (GABA-a receptor agonist), baclofen (GABA-b receptor agonist) and AOAA (GABA transaminase inhibitor) did not show significant effect on caffeine-induced convulsion. Bicuculline (GABA-a receptor antagonist) and picrotoxin (chloride channel blocker) significantly potentiated the convulsion at the doses which did not induce it. Caffeine-induced convulsion was potentiated by NMDA with its non-convulsive dose. CPP (competitive NMDA receptor antagonist) and MK-801 (non-competitive NMDA receptor antagonist) significantly inhibited the seizures. These results suggest that caffeine-induced seizure is not caused by blockade of adenosine receptors. Caffeine may act to beta-carboline sensitive benzodiazepine receptor (Type 1) which has no linkage with GABA-a receptor. Furthermore, it is implied that caffeine plays some role at NMDA receptor calcium ion channel complex.

  20. The Use of Anchored Agonists of Phagocytic Receptors for Cancer Immunotherapy: B16-F10 Murine Melanoma Model

    PubMed Central

    Janotová, Tereza; Jalovecká, Marie; Auerová, Marie; Švecová, Ivana; Bruzlová, Pavlína; Maierová, Veronika; Kumžáková, Zuzana; Čunátová, Štěpánka; Vlčková, Zuzana; Caisová, Veronika; Rozsypalová, Petra; Lukáčová, Katarína; Vácová, Nikol; Wachtlová, Markéta; Salát, Jiří; Lieskovská, Jaroslava; Kopecký, Jan; Ženka, Jan

    2014-01-01

    The application of the phagocytic receptor agonists in cancer immunotherapy was studied. Agonists (laminarin, molecules with terminal mannose, N-Formyl-methioninyl-leucyl-phenylalanine) were firmly anchored to the tumor cell surface. When particular agonists of phagocytic receptors were used together with LPS (Toll-like receptor agonist), high synergy causing tumour shrinkage and a temporary or permanent disappearance was observed. Methods of anchoring phagocytic receptor agonists (charge interactions, anchoring based on hydrophobic chains, covalent bonds) and various regimes of phagocytic agonist/LPS mixture applications were tested to achieve maximum therapeutic effect. Combinations of mannan/LPS and f-MLF/LPS (hydrophobic anchors) in appropriate (pulse) regimes resulted in an 80% and 60% recovery for mice, respectively. We propose that substantial synergy between agonists of phagocytic and Toll-like receptors (TLR) is based on two events. The TLR ligand induces early and massive inflammatory infiltration of tumors. The effect of this cell infiltrate is directed towards tumor cells, bearing agonists of phagocytic receptors on their surface. The result of these processes was effective killing of tumor cells. This novel approach represents exploitation of innate immunity mechanisms for treating cancer. PMID:24454822

  1. 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.

  2. Design driven HtL: The discovery and synthesis of new high efficacy β₂-agonists.

    PubMed

    Stocks, Michael J; Alcaraz, Lilian; Bailey, Andrew; Bonnert, Roger; Cadogan, Elaine; Christie, Jadeen; Connolly, Stephen; Cook, Anthony; Fisher, Adrian; Flaherty, Alice; Hill, Stephen; Humphries, Alexander; Ingall, Anthony; Jordan, Stephen; Lawson, Mandy; Mullen, Alex; Nicholls, David; Paine, Stuart; Pairaudeau, Garry; St-Gallay, Stephen; Young, Alan

    2011-07-01

    The design and synthesis of a new series of high efficacy β(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious β(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of β(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.

  3. 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).

  4. Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles.

    PubMed

    Goble, Stephen D; Wang, Liping; Howell, K Lulu; Bansal, Alka; Berger, Richard; Brockunier, Linda; DiSalvo, Jerry; Feighner, Scott; Harper, Bart; He, Jiafang; Hurley, Amanda; Hreniuk, Donna; Parmee, Emma; Robbins, Michael; Salituro, Gino; Sanfiz, Anthony; Streckfuss, Eric; Watkins, Eloisa; Weber, Ann E; Struthers, Mary; Edmondson, Scott D

    2010-03-15

    A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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 ...

  10. A Novel Method for Screening Adenosine Receptor Specific Agonists for Use in Adenosine Drug Development

    PubMed Central

    Jones, Karlie R.; Choi, Uimook; Gao, Ji-Liang; Thompson, Robert D.; Rodman, Larry E.; Malech, Harry L.; Kang, Elizabeth M.

    2017-01-01

    Agonists that target the A1, A2A, A2B and A3 adenosine receptors have potential to be potent treatment options for a number of diseases, including autoimmune diseases, cardiovascular disease and cancer. Because each of these adenosine receptors plays a distinct role throughout the body, obtaining highly specific receptor agonists is essential. Of these receptors, the adenosine A2AR and A2BR share many sequence and structural similarities but highly differ in their responses to inflammatory stimuli. Our laboratory, using a combination of specially developed cell lines and calcium release analysis hardware, has created a new and faster method for determining specificity of synthetic adenosine agonist compounds for the A2A and A2B receptors in human cells. A2A receptor expression was effectively removed from K562 cells, resulting in the development of a distinct null line. Using HIV-lentivector and plasmid DNA transfection, we also developed A2A and A2B receptor over-expressing lines. As adenosine is known to cause changes in intracellular calcium levels upon addition to cell culture, calcium release can be determined in these cell lines upon compound addition, providing a functional readout of receptor activation and allowing us to isolate the most specific adenosine agonist compounds. PMID:28317879

  11. The effect of adrenergic agonists and antagonists on cysteine-proteinase inhibitor (cystatin) in rat saliva.

    PubMed

    Bedi, G S

    1991-01-01

    The effect of a number of adrenergic agonists and antagonists on the induction of rat salivary cystatin was investigated. A highly sensitive and specific radioimmunoassay was used to determine cystatin in rat whole saliva. Treatment for 10 consecutive days with a non-specific beta-adrenergic agonist isoproterenol, or the beta 1-adrenergic agonists dobutamine or methoxyphenamine, resulted in the induction of the salivary cystatin. Induction was also found in rats treated for 10 days with arterenol. Only trace quantities of cystatin could be detected in saliva of rats treated with the beta 2-adrenergic agonists terbutaline or salbutamol. When isoproterenol was injected concomitantly with the mixed beta-antagonist propranolol or the beta 1-adrenergic antagonists metaprolol, proctocol or atenolol the production of cystatin was totally suppressed. However, the beta 2-antagonist, ICI 118551, produced only a partial reduction in salivary cystatin induction elicited by isoproterenol. The findings suggest that the induction of salivary cystatin is regulated, in part, by beta 1-adrenergic receptor stimulation.

  12. Automated Acoustic Dispensing for the Serial Dilution of Peptide Agonists in Potency Determination Assays.

    PubMed

    Naylor, Jacqueline; Rossi, Alessandra; Brankin, Christopher; Hornigold, David C

    2016-11-10

    As with small molecule drug discovery, screening for peptide agonists requires the serial dilution of peptides to produce concentration-response curves. Screening peptides affords an additional layer of complexity as conventional tip-based sample handling methods expose peptides to a large surface area of plasticware, providing an increased opportunity for peptide loss via adsorption. Preventing excessive exposure to plasticware reduces peptide loss via adherence to plastics and thus minimizes inaccuracies in potency prediction, and we have previously described the benefits of non-contact acoustic dispensing for in vitro high-throughput screening of peptide agonists(1). Here we discuss a fully integrated automation solution for non-contact acoustic preparation of peptide serial dilutions in microtiter plates utilizing the example of screening for peptide agonists at the mouse glucagon-like peptide-1 receptor (GLP-1R). Our methods allow for high-throughput cell-based assays to screen for agonists and are easily scalable to support increased sample throughput, or to allow for increased numbers of assay plate copies (e.g., for a panel of more target cell lines).

  13. 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

  14. The Glycine Transport Inhibitor Sarcosine Is an Inhibitory Glycine Receptor Agonist

    PubMed Central

    Zhang, Hai Xia; Lyons-Warren, Ariel; Thio, Liu Lin

    2009-01-01

    Summary Sarcosine is an endogenous amino acid that is a competitive inhibitor of the type I glycine transporter (GlyT1), an N-methyl-D-aspartate receptor (NMDAR) co-agonist, and an important intermediate in one-carbon metabolism. Its therapeutic potential for schizophrenia further underscores its clinical importance. The structural similarity between sarcosine and glycine and sarcosine's ability to serve as an NMDAR co-agonist led us to examine whether sarcosine is also an agonist at the inhibitory glycine receptor (GlyR). We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons and found that sarcosine evoked a dose-dependent, strychnine sensitive, Cl- current that cross-inhibited glycine currents. Sarcosine evoked this current with Li+ in the extracellular solution to block GlyT1, in neurons treated with the essentially irreversible GlyT1 inhibitor N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS), and in neurons plated in the absence of glia. These results indicate that the sarcosine currents did not result from GlyT1 inhibition or heteroexchange. We conclude that sarcosine is a GlyR agonist. PMID:19619564

  15. [Cardiovascular effects of GLP-1 receptor agonist treatment: focus on liraglutide].

    PubMed

    Haluzík, Martin; Trachta, Pavel; Mráz, Miloš

    2015-01-01

    Cardiovascular risk reduction is the major aim of type 2 diabetes mellitus treatment. The effects of various antidiabetics on the cardiovascular complications are currently under careful scrutiny. Incretin-based therapy that utilizes the effects of glucagon-like peptide 1 (GLP-1) or stimulation of its receptor by GLP-1 receptor agonists represents one of the most promising approaches from the potential cardiovascular risk reduction point of view. Experimental studies have shown that the GLP-1 and GLP-1 agonists treatment improves endothelial function, decrease blood pressure and protects myocardium during experimentally-induced ischemia. Clinical studies with GLP-1 receptor agonists consistently show that, in addition to good antidiabetic efficacy, its long-term administration decreases blood pressure, body weight and improves circulating lipid levels while slightly increasing heart rate. In this paper, we focus on the cardiovascular effects of GLP-1 receptor agonist liraglutide. Preliminary analyses of cardiovascular complications in phase III trials with liraglutide indicate its good cardiovascular safety. A possibility of cardioprotective effects of liraglutide remains still open and is currently studied within a prospective cardiovascular trial LEADER.

  16. The impact of improved glycaemic control with GLP-1 receptor agonist therapy on diabetic retinopathy.

    PubMed

    Varadhan, Lakshminarayanan; Humphreys, Tracy; Walker, Adrian B; Varughese, George I

    2014-03-01

    Rapid improvement in glycaemic control with GLP-1 receptor agonist (RA) therapy has been reported to be associated with significant progression of diabetic retinopathy. This deterioration is transient, and continuing GLP-1 RA treatment is associated with reversal of this phenomenon. Pre-existent maculopathy, higher grade of retinopathy and longer duration of diabetes may be risk factors for persistent deterioration.

  17. Toll-Like Receptor 7 Agonists: Chemical Feature Based Pharmacophore Identification and Molecular Docking Studies

    PubMed Central

    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

  18. Platelet-activating factor receptor agonists mediate xeroderma pigmentosum A photosensitivity.

    PubMed

    Yao, Yongxue; Harrison, Kathleen A; Al-Hassani, Mohammed; Murphy, Robert C; Rezania, Samin; Konger, Raymond L; Travers, Jeffrey B

    2012-03-16

    To date, oxidized glycerophosphocholines (Ox-GPCs) with platelet-activating factor (PAF) activity produced non-enzymatically have not been definitively demonstrated to mediate any known disease processes. Here we provide evidence that these Ox-GPCs play a pivotal role in the photosensitivity associated with the deficiency of the DNA repair protein xeroderma pigmentosum type A (XPA). It should be noted that XPA-deficient cells are known to have decreased antioxidant defenses. These studies demonstrate that treatment of human XPA-deficient fibroblasts with the pro-oxidative stressor ultraviolet B (UVB) radiation resulted in increased reactive oxygen species and PAF receptor (PAF-R) agonistic activity in comparison with gene-corrected cells. The UVB irradiation-generated PAF-R agonists were inhibited by antioxidants. UVB irradiation of XPA-deficient (Xpa-/-) mice also resulted in increased PAF-R agonistic activity and skin inflammation in comparison with control mice. The increased UVB irradiation-mediated skin inflammation and TNF-α production in Xpa-/- mice were blocked by systemic antioxidants and by PAF-R antagonists. Structural characterization of PAF-R-stimulating activity in UVB-irradiated XPA-deficient fibroblasts using mass spectrometry revealed increased levels of sn-2 short-chain Ox-GPCs along with native PAF. These studies support a critical role for PAF-R agonistic Ox-GPCs in the pathophysiology of XPA photosensitivity.

  19. Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity

    PubMed Central

    2016-01-01

    Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by “designing in” functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization. PMID:26351878

  20. 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...

  1. 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.…

  2. 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

  3. 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.

  4. Induction of rotational behaviour by intranigral baclofen suggests possible GABA-agonist activity.

    PubMed

    Waddington, J L

    1977-10-15

    In rats, unilateral injections of the GABA-derivative baclofen into the zona reticulata of the substantia nigra produced a contralateral rotation that was translated to ipsilateral rotation under the influence of amphetamine. These results mimic those following unilateral elevation of GABA levels in the substantia nigra and suggest that baclofen may have some GABA agonist activity following intracerebral injection.

  5. Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.

    PubMed

    Cheng, Jianjun; McCorvy, John D; Giguere, Patrick M; Zhu, Hu; Kenakin, Terry; Roth, Bryan L; Kozikowski, Alan P

    2016-11-10

    On the basis of the structural similarity of our previous 5-HT2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5-HT2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.

  6. 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...

  7. Effects of salvinorin A on locomotor sensitization to D2/D3 dopamine agonist quinpirole.

    PubMed

    Beerepoot, Pieter; Lam, Vincent; Luu, Alice; Tsoi, Bernice; Siebert, Daniel; Szechtman, Henry

    2008-12-03

    Locomotor sensitization induced by the dopamine agonist quinpirole can be potentiated by co-treatment with the synthetic kappa opioid agonist U69593. The identification of salvinorin A, an active component of the psychotropic sage Salvia divinorum, as a structurally different agonist of kappa-opioid receptors raised the question of whether this compound would similarly potentiate sensitization to quinpirole. Rats were co-treated with 0.5 mg/kg quinpirole and either salvinorin A (0.04, 0.4 or 2.0 mg/kg) or U69593 (0.3 mg/kg). Control groups were co-treated with vehicle and saline, vehicle and quinpirole (0.5 mg/kg), or saline and salvinorin A (0.4 mg/kg). Rats were injected biweekly for a total of 10 injections and locomotor activity measured after each treatment. Results showed that the highest dose of salvinorin A potentiated sensitization to quinpirole as did U69593, the middle salvinorin A dose had no effect on quinpirole sensitization, and the lowest dose of salvinorin A attenuated sensitization to quinpirole. These findings indicate that structural differences between salvinorin A and U69593 do not affect the potentiation of quinpirole sensitization. Moreover, the opposite effects of high and low salvinorin A doses suggest that salvinorin A can produce bidirectional modulation of sensitization to dopamine agonists.

  8. 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...

  9. RELATIONSHIPS BETWEEN RESIDUES OF AHR AGONISTS IN FISH AND CONCENTRATIONS IN WATER AND SEDIMENTS

    EPA Science Inventory

    Relationships between Residues of AhR Agonists in Fish and Concentrations in Water and Sediment. Cook, PM*, Burkhard, LP, Mount, DR, US-EPA, NHEERL, MED, Duluth, MN. The bioaccumulation visualization approach of Burkhard et al. (2002) can be effectively used to describe the bioa...

  10. Dopamine D1 receptor-agonist interactions: A mutagenesis and homology modeling study.

    PubMed

    Mente, Scot; Guilmette, Edward; Salafia, Michelle; Gray, David

    2015-01-01

    The dopamine D1 receptor is a G protein-coupled receptor that regulates intracellular signaling via agonist activation. Although the number of solved GPCR X-ray structures has been steadily increasing, still no structure of the D1 receptor exists. We have used site-directed mutagenesis of 12 orthosteric vicinity residues of possible importance to G protein-coupled activation to examine the function of prototypical orthosteric D1 agonists and partial agonists. We find that residues from four different regions of the D1 receptor make significant contributions to agonist function. All compounds studied, which are catechol-amines, are found to interact with the previously identified residues: the conserved D103(3.32), as well as the trans-membrane V serine residues. Additional key interactions are found for trans-membrane VI residues F288(6.51), F289(6.52) and N292(6.55), as well as the extra-cellular loop residue L190(ECL2). Molecular dynamics simulations of a D1 homology model have been used to help put the ligand-residue interactions into context. Finally, we considered the rescaling of fold-shift data as a method to account for the change in the size of the mutated side-chain and found that this rescaling helps to relate the calculated ligand-residue energies with observed experimental fold-shifts.

  11. Antihyperalgesic effects of δ opioid agonists in a rat model of chronic inflammation

    PubMed Central

    Fraser, Graeme L; Gaudreau, Geneviève-Anne; Clarke, Paul B S; Ménard, Daniel P; Perkins, Martin N

    2000-01-01

    Opioid receptors in the brain activate descending pain pathways to inhibit the nociceptive response to acute noxious stimuli. The aim of the present study was to clarify the role of supraspinal opioid receptors in modulating the nociceptive response to persistent inflammation in rats.Subcutaneous administration of 50 μl of complete Freund's Adjuvant (CFA) into the plantar surface of the hindpaw induced a significant decrease in paw withdrawal latency to thermal stimuli (P<0.01) at 24 h post-injection.Intracerebroventricular (i.c.v.) administration of the μ opioid receptor agonists, DAMGO and morphine, and the δ opioid receptor agonists, deltorphin II and SNC80, significantly reversed the hyperalgesic response associated with peripheral inflammation in a dose-dependent manner (P<0.0001).The μ and δ agonists also significantly attenuated the antinociceptive response to acute thermal stimulation in rats (P<0.001). However, deltorphin II and SNC80 were less potent, and in the case of SNC80 less efficacious, in modulating the response to acute thermal nociception in comparison to hyperalgesia associated with persistent inflammation.These results indicate that μ and δ opioid receptors in the brain modulate descending pain pathways to attenuate the nociceptive response to acute thermal stimuli in both normal and inflamed tissues. The heightened response to δ agonists in the hyperalgesia model suggests that δ opioid receptors in the brain are promising targets for the treatment of pain arising from chronic inflammation. PMID:10780972

  12. Studies on the adrenomedullary dependence of kappa-opioid agonist-induced diuresis in conscious rats.

    PubMed Central

    Borkowski, K. R.

    1989-01-01

    1. The dependence of kappa-opioid agonist-induced diuresis, upon an intact and functional adrenal medulla in conscious rats, was investigated in order to test the hypothesis that the diuresis is mediated by a blood-borne 'diuretic factor', of adrenomedullary origin, released by kappa-opioid receptor stimulation. 2. Confirming previous observations, adrenal demedullation significantly attenuated diuretic responses to the kappa-opioid agonists U50488H, ethylketocyclazocine (EKC) and tifluadom, but did not affect basal urine output, furosemide-induced diuresis or the antidiuretic response to the mu-opioid agonist, buprenorphine. Naloxone abolished U50488H-induced diuresis, confirming an involvement of opioid receptors. 3. Transfusion studies established that blood, from intact rats treated with U50488H, induced diuresis in intact and demedullated recipient rats, whether or not the recipients had been pretreated with naloxone. However, blood from demedullated rats treated with U50448H was unable to induce diuresis when administered to intact or demedullated recipients. 4. It is concluded that kappa-opioid agonist-induced diuresis is dependent upon an intact and functional adrenal medulla and appears to be mediated by a blood-borne 'diuretic factor' of adrenomedullary origin. PMID:2558758

  13. 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...

  14. Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor.

    PubMed

    Taylor, Lewis; Christou, Ivy; Kapellos, Theodore S; Buchan, Alice; Brodermann, Maximillian H; Gianella-Borradori, Matteo; Russell, Angela; Iqbal, Asif J; Greaves, David R

    2015-06-02

    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.

  15. Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist.

    PubMed

    Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

    2015-08-01

    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.

  16. Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists.

    PubMed

    Farzin, Davood; Asghari, Ladan; Nowrouzi, Mahvash

    2002-06-01

    The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.

  17. 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.

  18. A robotic BG1Luc reporter assay to detect estrogen receptor agonists.

    PubMed

    Stoner, Matthew A; Yang, Chun Z; Bittner, George D

    2014-08-01

    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).

  19. 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

  20. 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

  1. 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.

  2. 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...

  3. Design, synthesis and evaluation of novel zwitterionic compounds as PPARα/γ dual agonists (1).

    PubMed

    Shibata, Yoshihiro; Kagechika, Katsuji; Yamaguchi, Mitsuhiro; Kubo, Hideo; Usui, Hiroyuki

    2012-12-01

    We describe here the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR α/γ dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR α/γ dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR α/γ dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model.

  4. Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?

    PubMed Central

    Freitag, Caroline M.; Miller, Richard J.

    2014-01-01

    Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1α, fractalkine, SDF-1 among others) have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between the pain ameliorating effects of PPAR agonists and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide (PEA), shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain. PMID:25191225

  5. 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

  6. Neurotransmitter agonists inhibit inositol phosphate formation in the brain of bupropione-treated rats

    SciTech Connect

    Butler, P.D.; Hungund, B.; Suckow, R.; Barkai, A.I.

    1986-03-05

    Bupropione is a chemically unique antidepressant whose mechanism of action is not known. In this study they have evaluated the effect of chronic treatment with bupropione on the receptor-mediated release of inositol phosphates (IP) from brain slices in rats. Animals were implanted with Alzet osmotic pumps that delivered bupropione at a constant rate (40mg/kg/day) for 2 weeks. Cross-chopped slices of cerebral cortex from control and drug-treated rats were prelabelled with myo-/sup 3/H-inositol in HEPES buffer containing 11 mM LiCl. Accumulation of IP was measured in the presence and absence of the following agonists: Carbamylcholine (100..mu..m); norepinephrine (5..mu..M) and serotonin (10..mu..M). All agonists stimulated release of IP from slices of control animals but appeared to inhibit IP release in bupropione-treated rats. These results indicate that a phospholipase C inhibitor may appear following the activation of this enzyme by the agonist, and that the agonist-induced formation of the apparent inhibitor may be markedly enhanced after treatment with bupropione.

  7. Development of agonistic encounters in dominance hierarchy formation in juvenile crayfish.

    PubMed

    Sato, Daisuke; Nagayama, Toshiki

    2012-04-01

    We have characterized the behavioural patterns of crayfish during agonistic bouts between groups of crayfish of four different body lengths (9-19, 20-32, 41-48 and 69-75 mm) to characterize changes in the patterns of agonistic encounter during development. The behaviour of both dominant and subordinate animals was analysed by single frame measurement of video recordings. Behavioural acts that occurred during agonistic bouts were categorized as one of seven types: capture, fight, contact, approach, retreat, tailflip and neutral. Dominant-subordinate relationships were formed between juvenile crayfish as early as the third stage of development. Patterns of agonistic bouts to determine social hierarchy became more aggressive during development. The dominant-subordinate relationship was usually determined after contact in crayfish of less than 20 mm and 20-32 mm in length, while several bouts of fights were necessary for crayfish of 41-48 and 69-75 mm in length. Furthermore, social hierarchy was formed more rapidly in small crayfish. In larger animals, the number of approaches by dominant animals that promoted retreat in subordinate animals increased after the establishment of the winner-loser relationship. In smaller crayfish, in contrast, no measurable changes in these behaviour patterns were observed before and after the establishment of the winner-loser relationship. With increasing body size, the probability of tailflips decreased while that of retreats increased as the submissive behavioural act of subordinate animals.

  8. 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

  9. Effect of mu Agonists on Long-Term Survival and Recurrence in Nonsmall Cell Lung Cancer Patients.

    PubMed

    Wang, Kai; Qu, Xiao; Wang, Ying; Shen, Hongchang; Liu, Qi; Du, Jiajun

    2015-08-01

    Opioids are widely used for postoperative analgesia. Morphine may have an effect on cell replication, migration, and cancer recurrence. However, the association of postoperative mu agonists with outcome of nonsmall cell lung cancer (NSCLC) patients has not been fully investigated.We retrospectively evaluated the impact of postoperative mu agonists on overall survival (OS) and disease-free survival (DFS) in early stage NSCLC patients. Patients and relevant medical information were selected from the Bio-Bank of Shandong Provincial Hospital. Difference of clinicopathologic information in postoperative mu agonists group and no mu agonists group was analyzed by χ test. Univariate and multivariate Cox regression analysis were conducted and represented as hazards ratio and 95% confidence interval form. The primary endpoint was OS and secondary endpoint was DFS.This retrospective study included 984 consecutive NSCLC patients who underwent surgery between January 2006 and December 2011. No significant difference existed between postoperative mu agonists usage group and no mu agonists usage group in clinicopathologic information except operation type (P = 0.041). Postoperative mu agonists usage was related to shorter OS (HR 1.514, 95% CI 1.197-1.916, P = 0.001) and shorter DFS (HR 1.415, 95% CI 1.123-1.781, P = 0.003) in the multivariate Cox regression model. For the patients who received postoperative chemotherapy or radiotherapy postoperative mu agonists also predict shorter survival (HR 1.437, 95% CI 1.041-1.982, P = 0.027). Subgroup analysis showed that administration of postoperative mu agonists was related to shorter OS, especially in males, more smoking, poor differential degree, bilobectomy or pneumonectomy, and stage III subgroup, respectively.Administration of postoperative mu agonists was related to shorter OS and DFS for the NSCLC patients who underwent surgery.

  10. Comparative gene expression profiles induced by PPAR{gamma} and PPAR{alpha}/{gamma} agonists in rat hepatocytes

    SciTech Connect

    Rogue, Alexandra; Renaud, Marie Pierre; Claude, Nancy; Guillouzo, Andre; Spire, Catherine

    2011-07-01

    Species-differential toxic effects have been described with PPAR{alpha} and PPAR{gamma} agonists between rodent and human liver. PPAR{alpha} agonists (fibrates) are potent hypocholesterolemic agents in humans while they induce peroxisome proliferation and tumors in rodent liver. By contrast, PPAR{gamma} agonists (glitazones) and even dual PPAR{alpha}/{gamma} agonists (glitazars) have caused idiosyncratic hepatic and nonhepatic toxicities in human without evidence of any damage in rodent during preclinical studies. The mechanisms involved in such differences remain largely unknown. Several studies have identified the major target genes of PPAR{alpha} agonists in rodent liver while no comprehensive analysis has been performed on gene expression changes induced by PPAR{gamma} and dual PPAR{alpha}/{gamma} agonists. Here, we investigated transcriptomes of rat hepatocytes after 24 h treatment with two PPAR{gamma} (troglitazone and rosiglitazone) and two PPAR{alpha}/{gamma} (muraglitazar and tesaglitazar) agonists. Although, hierarchical clustering revealed a gene expression profile characteristic of each PPAR agonist class, only a limited number of genes was specifically deregulated by glitazars. Functional analyses showed that many genes known as PPAR{alpha} targets were also modulated by both PPAR{gamma} and PPAR{alpha}/{gamma} agonists and quantitative differences in gene expression profiles were observed between these two classes. Moreover, most major genes modulated in rat hepatocytes were also found to be deregulated in rat liver after tesaglitazar treatment. Taken altogether, these results support the conclusion that differential toxic effects of PPAR{alpha} and PPAR{gamma} agonists in rodent liver do not result from transcriptional deregulation of major PPAR target genes but rather from qualitative and/or quantitative differential responses of a small subset of genes.

  11. Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

    PubMed Central

    O'Connell, Robert; Morrissey, Ember; Cheng, Kejun; Rice, Kenner C.

    2012-01-01

    κ Opioid receptor agonists that do not readily cross the blood-brain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted κ agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral κ receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central κ receptors. The present study used assays of pain-related stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted κ agonists [the tetrapeptide d-Phe-d-Phe-d-Ile-d-Arg-NH2 (ffir) and the nonpeptidic compound ((R,S)-N-[2-(N-methyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride (ICI204448)], 2) a centrally penetrating κ agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal anti-inflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted κ agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted κ agonists had little effect, and salvinorin A exacerbated acid-induced depression of ICSS. These results suggest that peripherally restricted κ agonists may be safer than centrally penetrating κ agonists but less efficacious than NSAIDS or μ opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with κ agonists capable of greater peripheral selectivity are warranted. PMID:22128346

  12. Gonadotropin-releasing Hormone Agonist Overuse: Urologists’ Response to Reimbursement and Characteristics Associated with Persistent Overuse

    PubMed Central

    Ellis, Shellie D.; Nielsen, Matthew E.; Carpenter, William R.; Jackson, George L.; Wheeler, Stephanie B.; Liu, Huan; Weinberger, Morris

    2015-01-01

    BACKGROUND Medicare reimbursement cuts have been associated with declining Gonadotropin-releasing Hormone (GnRH) agonist overuse in localized prostate cancer. Medical school affiliation and foreign training have been associated with persistent overuse. However, physician-level prescribing changes and the practice type of persistent overusers have not been examined. We sought to describe physician-level changes in GnRH agonist overuse and test the association of time in practice and solo practice type with GnRH agonist overuse. METHODS We matched American Medical Association physician data for 2,138 urologists to SEER–Medicare data for 12,943 men diagnosed with early stage and lower grade adenocarcinoma of the prostate between 2000 and 2007. We conducted a population-based, retrospective study using multi-level modeling to control for patient and provider characteristics. RESULTS Three distinct patterns of GnRH agonist overuse were observed. Urologists’ time in practice was not associated with GnRH agonist overuse (OR 0.89; 95% CI 0.75–1.05).However, solo practice type (OR 1.65; 95% CI 1.34–2.02), medical school affiliation (OR 0.65; 95% CI 0.55–0.77), and patient race were. Compared to non-Hispanic whites, non-Hispanic blacks (OR 1.76; 95% CI 1.37–2.27), Hispanics (OR 1.41; 95% CI 1.12–1.79) and men of “other” race (OR 1.44; 95% CI 1.04–1.99) had greater odds of receiving unnecessary GnRH agonists. CONCLUSIONS GnRH agonist overuse remains high among some urologists who may be professionally isolated and difficult to reach. These urologists treat more vulnerable populations, which may contribute to health disparities in prostate cancer treatment quality. Nonetheless, these findings provide guidance to develop interventions to address overuse in prostate cancer. PMID:25849354

  13. Stimulants as Specific Inducers of Dopamine-Independent σ Agonist Self-Administration in Rats

    PubMed Central

    Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi; Kopajtic, Theresa A.

    2013-01-01

    A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of σ agonists mediated by their selective actions at σ1 receptors (σ1Rs), which are intracellularly mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were tr