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Derivatives of Diethylstilbestrol (DES), Mass Spectral Properties and Their Use in Biological Analysis  

Microsoft Academic Search

A series of perfluoroester and chloroacetate derivatives of diethylstilbestrol (DES) were prepared from the corresponding anhydride using trimethylamine as a catalyst. In all cases, accurate mass measurements by high resolution electron impact (EI) mass spectrometry of ?g or less quantities showed a strong base peak which corresponded to the disubstituted product. Gas chromatography-mass spectrometric (GC-MS) analysis of the DES derivatives

John Joseph Ryan; Walter F. Miles



Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy  

Microsoft Academic Search

From 1940 through the 1960s, diethylstilbestrol (DES), a synthetic oestrogen, was given to pregnant women to prevent pregnancy complications and losses. Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and

L Titus-Ernstoff; E E Hatch; R N Hoover; J Palmer; E R Greenberg; W Ricker; R Kaufman; K Noller; A L Herbst; T Colton; P Hartge



Prenatal exposure to diethylstilbestrol (DES): Childhood play behavior and adult gender-role behavior in women  

Microsoft Academic Search

Data from lower mammals suggest a masculinizing or defeminizing influence of pre- or perinatal diethylstilbestrol (DES) exposure on various aspects of the sex-dimorphic behavior (including juvenile rough-and-tumble play) of genetic females. However, three previous studies on childhood play and adult gender-role behavior in human females have led to ambiguous results. In a follow-up study of 60 women with prenatal exposure

Jennifer D. Lish; Heino F. L. Meyer-Bahlburg; Anke A. Ehrhardt; Bayla G. Travis; Norma P. Veridiano



In Utero Exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) Increases EZH2 Expression in the Mammary Gland: An Epigenetic Mechanism Linking Endocrine Disruptors to Breast Cancer  

Microsoft Academic Search

Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic\\u000a changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer\\u000a in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that\\u000a epigenetic alterations would precede the increased risk of

Leo F. Doherty; Jason G. Bromer; Yuping Zhou; Tamir S. Aldad; Hugh S. Taylor



In Utero Exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) Increases EZH2 Expression in the Mammary Gland: An Epigenetic Mechanism Linking Endocrine Disruptors to Breast Cancer  

PubMed Central

Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that epigenetic alterations would precede the increased risk of breast neoplasia after in utero exposure to endocrine disruptors. Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that has been linked to breast cancer risk and epigenetic regulation of tumorigenesis. We examined the effect of BPA and DES on EZH2 expression and function in MCF-7 cells and in mammary glands of mice exposed in utero. DES and BPA treatment approximated human exposure. EZH2 functional activity was assessed by measuring histone H3 trimethylation. Treatment of MCF-7 cells with DES or BPA led to a 3- and 2-fold increase in EZH2 mRNA expression, respectively (p<0.05) as well as increased EZH2 protein expression. Mice exposed to DES in utero showed a >2-fold increase in EZH2 expression in adult mammary tissue compared with controls (p<0.05). EZH2 protein was elevated in mammary tissue of mice exposed to DES or BPA. Histone H3 trimethylation was increased in MCF-7 cells treated with BPA or DES. Similarly, mice exposed to BPA or DES in utero showed increased mammary histone H3 trimethylation. Developmental programming of EZH2 is a novel mechanism by which in utero exposure to endocrine disruptors leads to epigenetic regulation of the mammary gland. PMID:21761357

Doherty, Leo F.; Bromer, Jason G.; Zhou, Yuping; Aldad, Tamir S.



Time to Pregnancy and Secondary Sex Ratio in Men Exposed Prenatally to Diethylstilbestrol  

Microsoft Academic Search

Little is known about the influence of prenatal diethylstilbestrol (DES) exposure on time to pregnancy or sec- ondary sex ratio in men. The authors evaluated these associations among men participating in the DES Combined Cohort Follow-up Study for whom exposure status was confirmed by medical record. In 2001, men provided data on their reproductive histories. Demographic, behavioral, and medical data

Lauren A. Wise; Linda Titus-Ernstoff; Julie R. Palmer; Robert N. Hoover; Elizabeth E. Hatch; Kimberly M. Perez; William C. Strohsnitter; Raymond Kaufman; Diane Anderson; Rebecca Troisi



Sexually disrupting effects of nonylphenol and diethylstilbestrol on male silver carp ( Carassius auratus) in aquatic microcosms  

Microsoft Academic Search

Based on detected nonylphenol (NP) levels in aquaculture water, this study investigated sexually disrupting effects in mature male silver carp (Carassius auratus) exposed to NP and a positive control diethylstilbestrol (DES). The combined evidences of steroid hormone (17?-estradiol, estrone and testosterone) levels and hispathological pictures showed that NP (?10?g\\/L) and DES could exert estrogenic effects through indirect mechanisms [i.e. increased

Lihua Yang; Li Lina; Shaoping Weng; Zhiqin Feng; Tiangang Luan



The DES Story: Lessons Learned

Dr. Robert Hoover discusses the DES followup study, which follows diethylstilbestrol (DES) exposed and unexposed mothers, daughters and sons, and granddaughters for adverse health effects resulting from this exposure.


Diethylstilbestrol exposure in utero and depression in women.  


Diethylstilbestrol (DES) is an estrogenic endocrine disruptor with long-term health effects, possibly including depression, following exposure in utero. Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of bisphenol A, a functionally similar and ubiquitous endocrine disruptor. The association between in utero DES exposure and depression was assessed among participants in the Nurses' Health Study II who first reported their history of antidepressant use in 1993 and lifetime history of depressive symptoms in 2001. DES exposure was reported by 1,612 (2.2%) women. A history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed (age-adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.26, 1.72) (P < 0.001). Incident depression (first use of antidepressants among women who also reported depressive symptoms) during follow-up (1995-2005) was reported by 19.7% of women exposed to DES and 15.9% unexposed (age-adjusted OR = 1.41, 95% CI: 1.22, 1.63) (P < 0.001). Adjustment for risk factors of depression and correlates of DES exposure moderately attenuated the association (multivariable-adjusted OR = 1.30, 95% CI: 1.13, 1.51) (P = 0.0004). These results suggest that the neurophysiologic effects of in utero exposure to DES could lead to an increased risk of depression in adult life. Further research should assess whether in utero exposure to bisphenol A has similar adverse effects. PMID:20332145

O'Reilly, Eilis J; Mirzaei, Fariba; Forman, Michele R; Ascherio, Alberto



Diethylstilbestrol Exposure in Utero and Depression in Women  

PubMed Central

Diethylstilbestrol (DES) is an estrogenic endocrine disruptor with long-term health effects, possibly including depression, following exposure in utero. Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of bisphenol A, a functionally similar and ubiquitous endocrine disruptor. The association between in utero DES exposure and depression was assessed among participants in the Nurses’ Health Study II who first reported their history of antidepressant use in 1993 and lifetime history of depressive symptoms in 2001. DES exposure was reported by 1,612 (2.2%) women. A history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed (age-adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.26, 1.72) (P < 0.001). Incident depression (first use of antidepressants among women who also reported depressive symptoms) during follow-up (1995–2005) was reported by 19.7% of women exposed to DES and 15.9% unexposed (age-adjusted OR = 1.41, 95% CI: 1.22, 1.63) (P < 0.001). Adjustment for risk factors of depression and correlates of DES exposure moderately attenuated the association (multivariable-adjusted OR = 1.30, 95% CI: 1.13, 1.51) (P = 0.0004). These results suggest that the neurophysiologic effects of in utero exposure to DES could lead to an increased risk of depression in adult life. Further research should assess whether in utero exposure to bisphenol A has similar adverse effects. PMID:20332145

O'Reilly, Eilis J.; Mirzaei, Fariba; Forman, Michele R.; Ascherio, Alberto



Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects  

PubMed Central

Diethylstilbestrol (DES) is a potent estrogen mimic that was predominantly used from the 1940s to 1970s in hopes of preventing miscarriage in pregnant women. Decades later, DES is known to enhance breast cancer risk in exposed women, and cause a variety of birth related adverse outcomes in their daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death. Additionally, children exposed to DES in utero suffer from sub/infertility and cancer of reproductive tissues. DES is a pinnacle compound which demonstrates the fetal basis of adult disease. The mechanisms of cancer and endocrine disruption induced by DES are not fully understood. Future studies should focus on common target tissue pathways affected and the health of the DES grandchildren. PMID:23897597

Reed, Casey E.; Fenton, Suzanne E.



New approaches for estimating risk from exposure to diethylstilbestrol.  

PubMed Central

A subgroup from a National Institute of Environmental Health Sciences, workshop concerned with characterizing the effects of endocrine disruptors on human health at environmental exposure levels considered the question, If diethylstilbestrol (DES) were introduced into the market for human use today and likely to result in low-dose exposure of the human fetus, what would be required to assess risk? On the basis of an analysis of the quality of data on human DES exposure, the critical times and doses for inducing genital tract malformations and cancer must be determined. This would be facilitated through analysis of the ontogeny of estrogen receptor expression in the developing human genital tract. Models of low-dose estrogenic effects will have to be developed for human and rodent genital tract development. Mouse models offer many advantages over other potential animal models because of the wealth of the earlier literature, the availability of sensitive end points, the availability of mutant lines, and the possibility of generating genetically engineered model systems. Through multidisciplinary approaches, it should be possible to elucidate the cellular and molecular mechanisms of endocrine disruption elicited by estrogens during development and facilitate an assessment of risk to humans. PMID:10421773

Cunha, G R; Forsberg, J G; Golden, R; Haney, A; Iguchi, T; Newbold, R; Swan, S; Welshons, W



Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer  

Microsoft Academic Search

Diethylstilbestrol (DES) is a synthetic oestrogen, and its anticancer effects are exerted in androgen-dependent prostate cancer. The administration of DES decreases serum testosterone to castration levels. However, in androgen-independent prostate cancer patients, who are already orchiectomised, the administration of DES improves symptoms and decreases prostate-specific antigen (PSA). The mechanisms responsible for these direct inhibitory effects have been explained as biological

H Koike; K Ito; Y Takezawa; T Oyama; H Yamanaka; K Suzuki



Developmental effects of perinatal exposure to bisphenol-A and diethylstilbestrol on reproductive organs in female mice  

Microsoft Academic Search

Reproductive tract development is influenced by estrogen. The aim of this study was to determine the effects of an environmental estrogenic chemical bisphenol-A (BPA) on prenatal and postnatal development of female mouse reproductive organs. In the prenatal treatment group, BPA or the synthetic estrogen diethylstilbestrol (DES) were given by subcutaneous (s.c.) injections to pregnant mice during gestational days 10–18. Some

Atsuko Suzuki; Akika Sugihara; Kaoru Uchida; Tomomi Sato; Yasuhiko Ohta; Yoshinao Katsu; Hajime Watanabe; Taisen Iguchi



Neonatal diethylstilbestrol exposure alters the metabolic profile of uterine epithelial cells  

PubMed Central

SUMMARY Developmental exposure to diethylstilbestrol (DES) causes reproductive tract malformations, affects fertility and increases the risk of clear cell carcinoma of the vagina and cervix in humans. Previous studies on a well-established mouse DES model demonstrated that it recapitulates many features of the human syndrome, yet the underlying molecular mechanism is far from clear. Using the neonatal DES mouse model, the present study uses global transcript profiling to systematically explore early gene expression changes in individual epithelial and mesenchymal compartments of the neonatal uterus. Over 900 genes show differential expression upon DES treatment in either one or both tissue layers. Interestingly, multiple components of peroxisome proliferator-activated receptor-? (PPAR?)-mediated adipogenesis and lipid metabolism, including PPAR? itself, are targets of DES in the neonatal uterus. Transmission electron microscopy and Oil-Red O staining further demonstrate a dramatic increase in lipid deposition in uterine epithelial cells upon DES exposure. Neonatal DES exposure also perturbs glucose homeostasis in the uterine epithelium. Some of these neonatal DES-induced metabolic changes appear to last into adulthood, suggesting a permanent effect of DES on energy metabolism in uterine epithelial cells. This study extends the list of biological processes that can be regulated by estrogen or DES, and provides a novel perspective for endocrine disruptor-induced reproductive abnormalities. PMID:22679223

Yin, Yan; Lin, Congxing; Veith, G. Michael; Chen, Hong; Dhandha, Maulik; Ma, Liang



[Isolation, identification and characterization of a diethylstilbestrol-degrading bacterial strain Serratia sp].  


Utilizing the diethylstilbestrol (DES)-degrading bacteria to biodegrade DES is a most reliable technique for cleanup of DES pollutants from the environment. However, little information is available heretofore on the isolation of DES-degrading bacteria and their DES removal performance in the environment. A novel bacterium capable of degrading DES was isolated from the activated sludge of a wastewater treatment plant. According to its morphology, physiochemical characteristics, and 16S rDNA sequence analysis, this strain was identified as Serratia sp.. The strain was an aerobic bacterium, and it could degrade 68.3% of DES (50 mg x L(-1)) after culturing for 7 days at 30 degrees C, 150 r x min(-1) in shaking flasks. The optimal conditions for DES biodegradation by the obtained strain were 30 degrees C, 40-60 mg x L(-1) DES, pH 7.0, 5% of inoculation volume, 0 g x L(-1) of added NaCl, and 10 mL of liquid medium volume in 100 mL flask. PMID:25338395

Xu, Ran-Fang; Sun, Min-Xia; Liu, Juan; Wang, Hong; Li, Xin; Zhu, Xue-Zhu; Ling, Wan-Ting



PROGINS polymorphism of progesterone receptor is increased in female offspring with maternal exposure to diethylstilbestrol.  


DES (Diethylstilbestrol) was used for the treatment of corpus luteum insufficiences in early pregnancy. Prenatal exposure to DES leads to an increased frequency of vaginal cancer in female offspring. DES causes persistent alterations of steroid hormone binding in the vaginal tissue. The frequency of a polymorphism (PROGINS) of human progesterone receptor (hPR) gene which is associated with an increased risk of sporadic ovarian cancer was tested in DES-exposed offspring with vaginal dysplasia. Genomic DNA was isolated from the serum of 15 US Caucasian DES-offspring. PROGINS analysis was performed using sequencing, gel-electrophoresis and SSCP-PCR. The results demonstrated that the frequency of PROGINS is increased in DES-offspring (DES: 6.7% homozygous, 26.7% heterozygous, normal US Caucasians: 3.3% homozygous, 15% heterozygous). Mutation screening of PROGINS is an important advantage for the clinical management of screening and can give additional information to prevent or find vaginal cancer in early stages in DES-offspring. PMID:11326686

Engehausen, D G; Schrott, K M



Induction of mammary neoplasms in the ACI rat by 430-keV neutrons, X-rays, and diethylstilbestrol.  


Mammary tumorigenesis was studied in female ACi rats after treatment with X-irradiation or neutron-irradiation, with or without diethylstilbestrol (DES) treatment. The mortality-corrected cumulative tumor rate based on all mammary neoplasms and the mortality-corrected incidence based on the first neoplasms only have been derived. In non-DES-treated animals, at the relatively high radiation doses studied, all dose-effect relationships were consistent with relative biological effectiveness (RBE) values slightly in excess of 10. In DES-treated rats definite findings were observed at neutron doses as low as 0.01 Gy (1 rad). The dose-effect relationship in DES-treated rats showed a strong sublinearly (dose exponent less than 1) at low neutron doses. RBE values in DES-treated rats increased in inverse proportion to the square root of the neutron dose, and exceeded 100 at a neutron dose of 0.01 Gy (1 rad). PMID:6957658

Shellabarger, C J; Chmelevsky, D; Kellerer, A M; Stone, J P; Holtzman, S



Carcinogenicity of diethylstilbestrol in the Wistar rat: effect of postnatal oral contraceptive steroids.  


Diethylstilbestrol (DES) has been associated with vaginal neoplasia and malformations in humans. We have studied a test population of 504 female Wistar rats given diethylstilbestrol at from 0.0 to 0.5 mg/kg maternal body weight on days 18, 19, and 20 of gestation. Animals were euthanized in extremis, or at 2 years of age. The incidence of vaginal epithelial tumors was dose related. The types of epithelial tumors of the vagina were adenocarcinoma, squamous cell carcinoma, and mixed carcinoma, containing discrete adenomatous and squamous components. The incidence of vaginal epithelial tumors was determined to be dose related: rats exposed to 0 mg DES/kg maternal weight had an incidence of 0.6% (1 of 167 rats); 0.1 mg/kg, 4.1%; and 0.5 mg/kg, 4.3% (6 of 140); 25 mg/kg, 1.6% (1 of 63); and 50 mg/kg, 11.5% (3 of 26). Tumors of other reproductive tissues (mammary gland, ovary, oviduct, cervix, or uterus) demonstrated no discernible DES dose-response relationship. There was no oncogenic effect of postnatal administration of oral contraceptives (0 oral contraceptives, 31.25 micrograms/kg diet ethynylestradiol, and 31.25 micrograms/kg diet norethindrone or 104 micrograms/kg diet ethynylestradiol and 31.25 micrograms/kg diet norethindrone). Thus, vaginal tumors can be induced in a dose-related manner in the rat following in utero DES exposure. Oral contraceptive treatment did not increase the risk of neoplasia. PMID:2040004

Baggs, R B; Miller, R K; Odoroff, C L



Perinatal exposure to diethylstilbestrol alters the functional differentiation of the adult rat uterus.  


The exposure to endocrine disrupters and female reproductive tract disorders has not been totally clarified. The present study assessed the long-term effect of perinatal (gestation+lactation) exposure to diethylstilbestrol (DES) on the rat uterus and the effect of estrogen replacement therapy. DES (5?g/kg bw/day) was administered in the drinking water from gestational day 9 until weaning and we studied the uterus of young adult (PND90) and adult (PND360) females. To investigate whether perinatal exposure to DES modified the uterine response to a long-lasting estrogen treatment, 12-month-old rats exposed to DES were ovariectomized and treated with 17?-estradiol for 3 months (PND460). In young adult rats (PND90), the DES treatment decreased both the proliferation of glandular epithelial cells and the percentage of glandular perimeter occupied by ?-smooth muscle actin-positive cells. The other tissue compartments remained unchanged. Cell apoptosis was not altered in DES-exposed females. In control adult rats (PND360), there were some morphologically abnormal uterine glands. In adult rats exposed to DES, the incidence of glands with cellular anomalies increased. In response to estrogens (PND460), the incidence of cystic glands increased in the DES group. We observed glands with daughter glands and conglomerates of glands only on PND460 and in response to estrogen replacement therapy, independently of DES exposure. The p63 isoforms were expressed without changes on PND460. Estrogen receptors ? and ? showed no changes, while the progesterone receptor decreased in the subepithelial stroma of DES-exposed animals with estrogen treatment. The long-lasting effects of perinatal exposure to DES included the induction of abnormalities in uterine tissues of aged female rats and an altered response of the adult uterus to estradiol. PMID:23454116

Bosquiazzo, Verónica L; Vigezzi, Lucía; Muñoz-de-Toro, Mónica; Luque, Enrique H



Synergism of diethylstilbestrol and radiation in mammary carcinogenesis in female F344 rats.  


One compressed 20-mg pellet containing cholesterol only or cholesterol mixed with 0.98, 1.6, 2.6, or 3.9 mg of diethylstilbestrol (DES) was implanted into each of 203 female F344 rats. Two days later, half the animals in each group were exposed to 150 R of X-rays, and the other half were sham irradiated. The rats were maintained until 350 days post implantation. Mortality increased with the higher doses of DES, with or without X-rays. DES at all dose levels, with or without X-rays, produced pituitary tumors and pyometritis. Only rats that received both DES and X-rays had mammary adenocarcinomas (AC). A synergistic AC response was found in the group that received 2.6 mg DES plus X-rays. Synergism was defined as a significantly greater incidence of rats with mammary neoplasia resulting from DES plus X-ray treatment when compared to the summed incidence from comparable individual treatments. For all other groups of rats that received both treatments, synergism was detected only when their data were combined. Synergism was not detected among rats that had fibroadenomas (FA). Both types of neoplasms were independent phenomena because no significant relationship was found between the incidences of FA and AC. PMID:480380

Holtzman, S; Stone, J P; Shellabarger, C J



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


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. PMID:22165080

Altarac, Silvio



Experimental electron density studies of non-steroidal synthetic estrogens: Diethylstilbestrol and dienestrol  

NASA Astrophysics Data System (ADS)

An experimental charge density analysis has been carried out on two synthetic estrogens, diethylstilbestrol (DES) and dienestrol (DNS), to further investigate the alignment and binding of estrogenic compounds to the estrogen receptor, and to also establish a relationship between the biological function and the electronic properties of steroidal and non-steroidal estrogens by analysis of their electron density distribution. X-ray diffraction data for DES and DNS were obtained using a Rigaku R-Axis Rapid high-power rotating anode diffractometer with a curved image plate detector at 20(1) K. The total electron density was modeled using the Hansen-Coppens multipole model. Relatively strong O···H sbnd O hydrogen bonds, weak O···H sbnd C hydrogen bonds, and a number of intermolecular H···H interactions were characterized from the topological analyses of the total electron density of DES and DNS. Mapping of the electrostatic potential onto the molecular surface revealed negative regions around all the hydroxyl oxygens, above and below the aromatic rings as expected from previous studies. A proposed alignment and binding of DES and DNS to the estrogen receptor is discussed in terms of the atomic charges and electrostatic potential derived from the electron density distribution.

Yearley, Eric J.; Zhurova, Elizabeth A.; Zhurov, Vladimir V.; Alan Pinkerton, A.



Effect of in utero exposure to diethylstilbestrol on lumbar and femoral bone, articular cartilage, and the intervertebral disc in male and female adult mice progeny with and without swimming exercise  

PubMed Central

Introduction Developmental exposure to estrogens has been shown to affect the musculoskeletal system. Furthermore, recent studies have shown that environmental exposure to estrogen-like compounds is much higher than originally anticipated. The aim of this study was to determine the effects of diethylstilbestrol (DES), a well-known estrogen agonist, on articular cartilage, intervertebral disc (IVD), and bone phenotype. Methods C57Bl/6 pregnant mice were dosed orally with vehicle (peanut oil) or 0.1, 1.0, and 10 ?g/kg/day of DES on gestational days 11 to 14. Male and female pups were allowed to mature without further treatment until 3 months of age, when swim and sedentary groups were formed. After euthanasia, bone mineral density (BMD), bone mineral content (BMC), bone area (BA), and trabecular bone area (TBA) of the lumbar vertebrae and femur were measured by using a PIXImus Bone Densitometer System. Intervertebral disc proteoglycan was measured with the DMMB assay. Histologic analysis of proteoglycan for IVD and articular cartilage was performed with safranin O staining, and degeneration parameters were scored. Results The lumbar BMC was significantly increased in female swimmers at both the highest and lowest dose of DES, whereas the femoral BMC was increased only at the highest. The males, conversely, showed a decreased BMC at the highest dose of DES for both lumbar and femoral bone. The female swim group had an increased BA at the highest dose of DES, whereas the male counterpart showed a decreased BA for femoral bone. The TBA showed a similar pattern. Proteoglycan analysis of lumbar IVDs showed a decrease at the lowest doses but a significant increase at the highest doses for both males and females. Histologic examination showed morphologic changes of the IVD and articular cartilage for all doses of DES. Conclusions DES significantly affected the musculoskeletal system of adult mice. Results suggest that environmental estrogen contaminants can have a detrimental effect on the developmental lumbar bone growth and mineralization in mice. Further studies measuring the impact of environmental estrogen mimics, such as bisphenol A, are then warranted. PMID:22269139



A time-resolved fluorescence immunoassay for the ultrasensitive determination of diethylstilbestrol based on the double-codified gold nanoparticles.  


An ultrasensitive and selective method is presented for the determination of diethylstilbestrol (DES) using time-resolved fluorescence immunoassay (TRFIA) based on double-codified gold nanoparticles (DC-AuNPs). In this system, the DC-AuNPs, that are gold nanoparticles (AuNPs) modified with anti-DES antibody and SH-dsDNA-biotin, was regarded as signal amplifier. A competitive immunoreaction was performed on polystyrene microtitration plates, where the DES compete with the immobilized DES-ovalbumin on polystyrene microtitration plates to bind to anti-DES antibodies on DC-AuNPs, and the europium(III)-labeled streptavidin was added to link to the SH-dsDNA-biotin as a tracer. Fluorescence signal was amplified via the AuNPs and the biotin-streptavidin double amplification systems. Under the optimized condition, DES can be quantified by TRFIA. The linear range and the limit of detection of DES were 1.0×10(-6)-10ngmL(-1) and 0.4fgmL(-1), respectively. This method was applied to determine DES in beef sample, with the recoveries ranging from 88% to 105%. PMID:25091151

Wang, Longjun; Zhang, Yuanfu; Liu, Guofu; Zhang, Chunyan; Wang, Shuhao



Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters  

PubMed Central

The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression. Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible. PMID:25032259



Prenatal exposure to diethylstilbestrol: ovarian-independent growth of mammary tumors induced by 7,12-dimethylbenz[a]anthracene.  


The effects of ovariectomy on the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were investigated after rats ahd been exposed prenatally to diethylstilbestrol (DES). Pregnant rats were inoculated with either DES (total dose: 1.2 micrograms) in sesame oil or with the vehicle alone on days 10 and 13 of gestation. Female offspring were given 2 gastric intubations of DMBA (10 mg each) 1 week apart beginning at 50 plus or minus 1 days of age. When the average diameter of a mammary tumor exceeded 2 cm, the animal was ovariectomized. The initial response of most tumors in both the DES-exposed and control groups to ovariectomy was size regression. The growth of 7 tumors that arose soon after DMBA treatment in each group was studied for 12-20 weeks after ovariectomy. Whereas only 1 tumor from the control group resumed active growth after the initial regression period, 6 tumors in the DES-exposed group overcame the initial effects of ovariectomy and began to grow again. Thus ovariectomy appeared to be less effective in producing sustained control growth in DMBA-induced mammary tumors in rats exposed prenatally to DES. PMID:6785506

Boylan, E S; Calhoon, R E



Downregulation of cytochrome P450scc as an initial adverse effect of adult exposure to diethylstilbestrol on testicular steroidogenesis.  


Reproductive toxicities and endocrine disruptions caused by chemicals in adult males are still poorly understood. It is our objectives to understand further details of the initial adverse effects leading severe testicular toxicities of a pharmaceutical endocrine disruptor, diethylstilbestrol (DES). Downregulations of both testicular regulatory proteins, such as the steroidogenic acute regulatory protein (StAR) and the peripheral benzodiazepine receptor (PBR), which play important roles in the transport of cholesterol into the mitochondria, and cytochrome P450 mediating the cholesterol side chain cleavage reaction (P450scc), were observed in the rat orally administered DES (340??g/kg/2 days) for 2 weeks. We found that after only 1 week treatment with DES, the blood and testicular testosterone (TS) levels were drastically decreased without abnormalities of the StAR and PBR; however, the protein and mRNA levels of P450scc were diminished. Decrease in the conversion rate of cholesterol to pregnenolone was delayed in the in vitro assay using the testicular mitochondrial fraction from the rat treated with DES for 1 week. When the precursors in TS biosynthesis containing the testis were identified and determined by liquid chromatography-mass spectrometry analysis, decreased levels of all precursors except cholesterol were observed. In conclusion, suppressed cytochrome P450scc expression in adult male rat was identified as an initial target of DES in testicular steroidogenesis disorder leading reproductive toxicities. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1452-1459, 2014. PMID:23873838

Maeda, Naoyuki; Okumura, Kanako; Tanaka, Emi; Suzuki, Tomokazu; Miyasho, Taku; Haeno, Satoko; Ueda, Hiromi; Hoshi, Nobuhiko; Yokota, Hiroshi



Mechanisms of hormonal carcinogenesis in the p53+/- hemizygous knockout mouse: studies with diethylstilbestrol.  


The 2-year rodent bioassay has long had a central role in determining whether a compound is carcinogenic. It has recently been suggested that the use of 6-month studies in transgenic mice could reduce costs and animal numbers, without impairing the validity of cancer risk assessment. The p53+/- hemizygous knockout mouse model is phenotypically stable and develops tumors during the 6-month study period only in response to chemical and physical stimuli, showing a high concordance with genotoxic rodent carcinogens. We treated p53+/- mice and wild-type parent strain (C57BL/6J) animals with diethylstilbestrol (DES). 500 micromol/kg i.p. for 4 days. Following sacrifice, DNA was extracted from various tissues and adducts measured by a modified monophosphate version of the 32P-postlabelling assay. Major DES adducts were detected in the liver DNA of DES-treated wild-type mice at a level of 118.7+/-17.0 (mean +/- SD relative adduct level [RAL]/10(10) nucleotides) compared with 207.7+/-36.4 in p53+/- mice. No such adducts were detected in vehicle-treated animals. Total adduct levels, including endogenous I-compound adducts, in wild-type mice were 192.4+/-17.5 and 311.5+/-58.6 in p53+/- animals. These data support the hypothesis that deficient p53-dependent global genomic repair of DES adducts in p53+/- mice may result in the persistence of exogenous and endogenous DNA adducts that could contribute to earlier carcinogenicity in this model. We also prepared hepatic microsomes from male and female p53+/- and wild-type mice exposed to DES or vehicle. Western blot analysis demonstrated modestly higher basal levels of various cytochrome P450 (CYP) enzymes in the untreated p53+/- mice compared to the wild-type mice. Furthermore, P450 levels were higher in female DES-treated p53+/- mice compared to treated wild-type mice. For the p53+/- knockout mice to be used with contidence in drug safety studies, a further understanding of the metabolic capacity of these animals is needed. PMID:11695552

Carmichael, P L; Mills, J J; Campbell, M; Basu, M; Caldwell, J



Subchronic exposure to phytoestrogens alone and in combination with diethylstilbestrol - pituitary tumor induction in Fischer 344 rats  

PubMed Central

Background Subchronic administration of the potent pharmaceutical estrogen diethylstilbestrol (DES) to female Fischer 344 (F344) rats induces growth of large, hemorrhagic pituitaries that progress to tumors. Phytoestrogens (dietary plant estrogens) are hypothesized to be potential tumor inhibitors in tissues prone to estrogen-induced cancers, and have been suggested as "safer" estrogen replacements. However, it is unknown if they might themselves establish or exacerbate the growth of estrogen-responsive cancers, such as in pituitary. Methods We implanted rats with silastic capsules containing 5 mg of four different phytoestrogens - either coumestrol, daidzein, genistein, or trans-resveratrol, in the presence or absence of DES. We examined pituitary and other organ weights, blood levels of prolactin (PRL) and growth hormone (GH), body weights, and pituitary tissue histology. Results Blood level measurements of the administered phytoestrogens confirmed successful exposure of the animals to high levels of these compounds. By themselves, no phytoestrogen increased pituitary weights or serum PRL levels after 10 weeks of treatment. DES, genistein, and resveratrol increased GH levels during this time. Phytoestrogens neither changed any wet organ weight (uterus, ovary, cervix, liver, and kidney) after 10 weeks of treatment, nor reversed the adverse effects of DES on pituitaries, GH and PRL levels, or body weight gain after 8 weeks of co-treatment. However, they did reverse the DES-induced weight increase on the ovary and cervix. Morphometric examination of pituitaries revealed that treatment with DES, either alone or in combination with phytoestrogens, caused gross structural changes that included decreases in tissue cell density, increases in vascularity, and multiple hemorrhagic areas. DES, especially in combination with phytoestrogens, caused the development of larger and more heterogeneous nuclear sizes in pituitary. Conclusions High levels of phytoestrogens by themselves did not cause pituitary precancerous growth or change weights of other estrogen-sensitive organs, though when combined with DES, they counteracted the growth effects of DES on reproductive organs. In the pituitary, phytoestrogens did not reverse the effects of DES, but they did increase the sizes and size heterogeneity of nuclei. Therefore, phytoestrogens may oppose some but not all estrogen-responsive tissue abnormalities caused by DES overstimulation, and appear to exacerbate DES-induced nuclear changes. PMID:20459739



Synergism of diethylstilbestrol and other carcinogens in concurrent development of hepatic, mammary, and pituitary tumors in castrated male rats  

SciTech Connect

Castrated male WF rats, given implants of pellets containing 5.0 mg diethylstilbestrol (DES), were given N-butyl-N-nitrosourea (NBU) in small amounts, which alone produced no mammary tumors in intact female rats. Treatment resulted in the high yield of hepatic tumors (HT), mammary tumors (MT), and pituitary tumors (PT) concurrently in each rat. If animals were further tested with prolactin, the development of HT and MT was accelerated, whereas that of PT was suppressed. None of the intact or castrated rats receiving NBU and/or prolactin developed tumors in any tissues if DES treatment was omitted. Exposure of male rats, preconditioned similarly to NBU treatment, to 200 rads of 14.1-MeV fast-neutron radiation also elicited HT, MT, and PT with an efficiency comparable to that of NBU-treated rats. These findings indicate that DES played an essential role in the whole carcinogenic process in each tissue and that castrated male rats, if conditioned properly with estrogens, are useful for the study of the carcinogenesis mechanism in these tissues.

Sumi, C.; Yokoro, K.; Kajitani, T.; Ito, A.



Enhancement of blood-tumor barrier permeability by Sar-[D-Phe8]des-Arg9BK, a metabolically resistant bradykinin B1 agonist, in a rat C6 glioma model  

PubMed Central

Background While it is well known that bradykinin B2 agonists increase plasma protein extravasation (PPE) in brain tumors, the bradykinin B1 agonists tested thus far are unable to produce this effect. Here we examine the effect of the selective B1 agonist bradykinin (BK) Sar-[D-Phe8]des-Arg9BK (SAR), a compound resistant to enzymatic degradation with prolonged activity on PPE in the blood circulation in the C6 rat glioma model. Results SAR administration significantly enhanced PPE in C6 rat brain glioma compared to saline or BK (p < 0.01). Pre-administration of the bradykinin B1 antagonist [Leu8]-des-Arg (100 nmol/Kg) blocked the SAR-induced PPE in the tumor area. Conclusions Our data suggest that the B1 receptor modulates PPE in the blood tumor barrier of C6 glioma. A possible role for the use of SAR in the chemotherapy of gliomas deserves further study. PMID:15458573

Cardoso, Ronie Cleverson; Lobao-Soares, Bruno; Bianchin, Marino Muxfeldt; Carlotti, Carlos Gilberto; Walz, Roger; Alvarez-Silva, Marcio; Trentin, Andrea Goncalves; Nicolau, Mauro



Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer  

PubMed Central

Diethylstilbestrol (DES) is a synthetic oestrogen, and its anticancer effects are exerted in androgen-dependent prostate cancer. The administration of DES decreases serum testosterone to castration levels. However, in androgen-independent prostate cancer patients, who are already orchiectomised, the administration of DES improves symptoms and decreases prostate-specific antigen (PSA). The mechanisms responsible for these direct inhibitory effects have been explained as biological actions not mediated by oestrogen receptors. We assessed the gene expression profiles of prostate cancer cells treated with DES, and investigated direct inhibitory effects of DES. DES inhibited the proliferation of LNCaP and PC-3 cells. cDNA microarray analysis showed that expression of many genes was downregulated by DES. However, insulin-like growth factor binding protein 6 (IGFBP-6) gene expression levels were upregulated in PC-3 cells. IGFBP-6 gene expression and protein levels significantly increased after DES treatment. Recombinant IGFBP-6 inhibited cell proliferation, and the inhibitory effect of DES was neutralised by anti-IGFBP-6 antibody. From the immunohistochemical analysis of IGFBP-6 using biopsy samples from androgen-independent prostate cancer, we found IGFBP-6 expression in androgen independent prostate cancer, and that DES treatment increased the IGFBP-6 staining intensity of the cancer cells in one sample. These findings suggested that DES induces IGFBP-6, which inhibits cell proliferation in an androgen-independent prostate cancer cell line, PC-3. IGFBP-6 therefore might be involved in the direct effects of DES in androgen-independent prostate cancer. PMID:15846301

Koike, H; Ito, K; Takezawa, Y; Oyama, T; Yamanaka, H; Suzuki, K



GLP-1 Receptor Agonists  


... GLP-1 Receptor Agonists Share: Fact Sheet GLP-1 Receptor Agonists May, 2012 Download PDFs English Espanol ... too high or too low. What are GLP-1 receptor agonist medicines? GLP-1 receptor agonist medicines, ...


Metal ions-based immunosensor for simultaneous determination of estradiol and diethylstilbestrol.  


Environmental estrogens (EEs) can cause various endocrine diseases. Herein, we designed an ultrasensitive electrochemical immunosensor for simultaneous detection of two typical EEs, estradiol and diethylstilbestrol. These two analytes were immobilized on graphene sheet (GS) modified glassy carbon electrode (GCE). Amino-group functionalized mesoporous Fe3O4 (Fe3O4-NH2) was loaded with Pb(2+) or Cd(2+), and then incubated with estradiol and diethylstilbestrol antibodies, respectively. Using an electrochemical analysis technique, two well-separated peaks were generated by the redox reaction of Pb(2+) or Cd(2+), making the simultaneous detection of two analytes on the electrode possible. Subsequently, square wave anodic stripping voltammetry (SWASV) and electrochemical impedance spectroscopy (EIS) were used to investigate the electrochemical behaviors of the immunosensor. Under optimized conditions, the SWASV peak currents were proportional to the concentrations of estradiol and diethylstilbestrol in the range from 0.050 pg mL(-1) to 100 ng mL(-1) and 1.0 pg mL(-1) to 100 ng mL(-1), respectively. The immunosensor exhibited highly sensitive response to estradiol with a detection limit of 0.015 pg mL(-1) and diethylstilbestrol with a detection limit of 0.38 pg mL(-1). Furthermore, the immunosensor was satisfactorily employed to detect estradiol and diethylstilbestrol simultaneously in water samples. PMID:24055936

Zhang, Sen; Du, Bin; Li, He; Xin, Xiaodong; Ma, Hongmin; Wu, Dan; Yan, Liangguo; Wei, Qin



Histone Methyltransferase EZH2 Is Transcriptionally Induced by Estradiol as Well as Estrogenic Endocrine Disruptors Bisphenol-A and Diethylstilbestrol.  


Enhancer of Zeste homolog 2 (EZH2), a methyltransferase specific to histone 3 lysine 27, is a critical player in gene silencing and is overexpressed in breast cancer. Our studies demonstrate that EZH2 is transcriptionally induced by estradiol in cultured breast cancer cells and in the mammary glands of ovariectomized rats. EZH2 promoter contains multiple functional estrogen-response elements. Estrogen receptors (ERs) and ER coregulators such as mixed lineage leukemia (MLL) histone methylases (MLL2 and MLL3) and histone acetyltransferase CBP/P300 bind to the EZH2 promoter in the presence of estradiol and regulate estradiol-induced EZH2 expression. EZH2 expression is also increased upon exposure to estrogenic endocrine disrupting chemicals (EDCs) such as bisphenol-A (BPA) and diethylstilbestrol (DES). Similar to estradiol, BPA and DES-induced EZH2 expression is coordinated by ERs, MLLs and CBP/P300. In summary, we demonstrate that EZH2 is transcriptionally regulated by estradiol in vitro and in vivo, and its expression is potentially dysregulated upon exposure to estrogenic EDCs. PMID:25088689

Bhan, Arunoday; Hussain, Imran; Ansari, Khairul I; Bobzean, Samara A M; Perrotti, Linda I; Mandal, Subhrangsu S



Analysis of the Effect of Estrogen/Androgen Perturbation on Penile Development in Transgenic and Diethylstilbestrol-Treated Mice  

PubMed Central

Because both androgens and estrogens have been implicated in penile morphogenesis, we evaluated penile morphology in transgenic mice with known imbalance of androgen and estrogen signaling using scanning electron microscopy (SEM), histology, and immunohistochemistry of androgen and estrogen receptors ?/?. Penises of adult wild-type, estrogen receptor-? knockout (?ERKO), estrogen receptor-? knockout (?ERKO), aromatase knockout (Arom-KO), and aromatase overexpression (Arom+) mice were evaluated, as well as adult mice treated with diethylstilbestrol (DES) from birth to day 10. Adult penises were examined because the adult pattern is the endpoint of development. The urethral orifice is formed by fusion of the MUMP (male urogenital mating protuberance) with the MUMP ridge, which consists of several processes fused to each other and to the MUMP. Similarly, the internal prepuce is completed ventrally by fusion of a ventral cleft. In adult murine penises the stromal processes that form the MUMP ridge are separated from their neighbors by clefts. ?ERKO, ?ERKO, and Arom-KO mice have penises with a MUMP ridge clefting pattern similar to that of wild-type mice. In contrast, Arom+ mice and neonatally DES-treated mice exhibit profound malformations of the MUMP, MUMP ridge clefting pattern, and internal prepuce. Abnormalities observed in Arom+ and neonatally DES-treated mice correlate with the expression of estrogen receptor-beta (ER?) in the affected structures. This study demonstrates that formation of the urethal orifice and internal prepuce is due to fusion of separate epithelial-surfaced mesenchymal elements, a process dependent upon both androgen and estrogen signaling, in which ER? signaling is strongly implicated. PMID:23653160




Effects of non-steroidal estrogen diethylstilbestrol on pH and ion transport in the mantle epithelium of a bivalve Anodonta cygnea.  


Freshwater bivalves are used as sentinel organisms to detect pollutants effects in the aquatic environment due to their sedentary nature, filter-feeding behaviour. We aimed to determine the in vivo, ex vivo and in vitro influence of Diethylstilbestrol (DES), a widely used synthetic non-steroidal estrogen and endocrine disruptor, in Anodonta cygnea shell growth mechanisms. For that, in vivo exposure to DES (0.75?M) during 15 days, in vitro and ex vivo exposure of outer mantle epithelium (OME) cells to DES (0.75?M), were performed followed by study of short-circuit current (Isc), transepithelial potential (Vt) and transepithelial conductance (Gt) as well as identification of membrane transport systems and intracellular pH (pHi). Our results show that in vivo exposure to DES decreases in 30% the OME Isc and ex vivo addition of DES to the basolateral side of OME also induced Isc decrease. Several membrane transporters such as V-type ATPases, Na(+)/H(+) exchangers, Na(+)-K(+) pump, Na(+)-driven and Na(+)-independent HCO3(-)/Cl(-) transporters and Na(+)/HCO3(-) co-transporter were identified as responsible for pHi maintenance in OME and noteworthy, DES caused a pHi decrease in OME cells similar to the effect observed when OME cells were exposed to 4,4'-diisothiocyanostilbene disulfonic acid (DIDS), an inhibitor of several bicarbonate membrane transporters. The addition of DIDS after OME cells exposure to DES did not cause any alteration. We concluded that DES is able to modulate membrane ion transport and pHi in the OME of A. cygnea and that this effect seems to be due to inhibition of HCO3(-)/Cl(-) co-transporters present on the basolateral membrane. PMID:23953926

Alves, Marco G; Oliveira, Pedro F



Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery  

SciTech Connect

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effects of DES on T-cell differentiation in the thymus using the HY-TCR transgenic (Tg) mouse model in which the female mice exhibit positive selection of T cells bearing the Tg TCR, while the male mice show negative selection of such T cells. In female HY-TCR-Tg mice, exposure to DES showed more pronounced decrease in thymic cellularity when compared to male mice. Additionally, female mice also showed a significant decrease in the proportion of double-positive (DP) T cells in the thymus and HY-TCR-specific CD8{sup +} T cells in the periphery. Male mice exhibiting negative selection also showed decreased thymic cellularity following DES exposure. Moreover, the male mice showed increased proportion of double-negative (DN) T cells in the thymus and decreased proportion of CD8{sup +} T cells. The density of expression of HY-TCR on CD8{sup +} cells was increased following DES exposure in both females and males. Finally, the proliferative response of thymocytes to mitogens and peripheral lymph node T cells to male H-Y antigen was significantly altered in female and male mice following DES treatment. Taken together, these data suggest that DES alters T-cell differentiation in the thymus by interfering with positive and negative selection processes, which in turn modulates the T-cell repertoire in the periphery.

Brown, Nicole [Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 (United States); Nagarkatti, Mitzi [Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 (United States); Nagarkatti, Prakash S. [Department of Pharmacology and Toxicology, PO Box 980613, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0613 (United States)]. E-mail:



DES Education and Research Amendments of 1992. Report to accompany H.R. 4178. House of Representatives, 102D Congress, 2d Session.  

ERIC Educational Resources Information Center

This document is a Congressional report about a proposed amendment to the Public Health Service Act to provide for a program to carry out research on the drug diethylstilbestrol (DES), to educate health professionals and the public on the drug, and to provide for certain longitudinal studies regarding DES. The amendment itself is presented in the…

Congress of the U.S., Washington, DC. House Committee on Energy and Commerce.


Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen  

SciTech Connect

Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 {mu}g/pup/day) or tamoxifen (TAM; 10 {mu}g/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-{alpha}, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.

Waalkes, Michael P. [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709 (United States)]. E-mail:; Liu Jie [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709 (United States); Ward, Jerrold M. [National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892 (United States); Diwan, Bhalchandra A. [Basic Research Program, Science Applications International Corporation, National Cancer Institute at Frederick, Frederick, MD 21702-1201 (United States)



Response of Steers to Implantation of Diethylstilbestrol During Suckling, Wintering and Finishing Periods.  

E-print Network

in planning and conducting this work in its earlier phases is gratefully acknowl- . edged. The stilbestrol implants used in this work were provided by Charles Pfizer Inc., Terre Haute, Indiana and Discan Cor- poration, Los Angeles, California.... Implanting 3-month-old suckling steer calves with I? milligrams (mg.) of diethylstilbestrol increased weaning weight under West Texas range conditions by approximately 15 pounds, an average for 4 years. The weight advantage of tlie implanted calves ranged...

Melton, A. A.; Riggs, J. K.



In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles  

SciTech Connect

Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10{sup -6} M) caused the strongest decline in estradiol and testosterone levels but did not have detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals.

Myllymaeki, Sari [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland) and Departments of Physiology and Pediatrics, University of Turku, Turku (Finland)]. E-mail:; Haavisto, Tapio [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland); Vainio, Minna [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland); Toppari, Jorma [Departments of Physiology and Pediatrics, University of Turku, Turku (Finland); Paranko, Jorma [Department of Biology, Laboratory of Animal Physiology, 20014 University of Turku, Turku (Finland)



Expression of a Dominant Negative Estrogen Receptor Alpha Variant in Transgenic Mice Accelerates Uterine Cancer Induced by the Potent Estrogen Diethylstilbestrol  

PubMed Central

ER?3 transgenic mice expressing a dominant negative estrogen receptor ? (ER?) variant lacking the second zinc finger in the DNA binding domain were developed to examine its potential to inhibit estrogen action in vivo. To investigate if ER?3 expression influences uterine carcinogenesis, ER?3 transgenic mice were exposed to diethylstilbestrol (DES) on post-natal days 1–5. Neonatal DES treatment induced uterine adenocarcinomas in 81% of 8-month-old ER?3 mice compared to 49% of wild-type females (p<0.016). ER?3 did not inhibit the expression of the estrogen-responsive progesterone receptor and lactoferrin genes in the presence of ER? or modify their expression in ER? knockout (?ERKO) mice. Higher circulating 17?-estradiol levels and non-classical signaling by ER?3 may be related to the earlier incidence of uterine cancer. These findings indicate that expression of this ER? variant can influence determining events in uterine cancer development and its natural occurrence in the human uterus would unlikely be protective. PMID:22989549

Davis, Vicki L.; Newbold, Retha R.; Couse, John F.; Rea, Sheri L.; Gallagher, Katie M.; Hamilton, Katherine J.; Goulding, Eugenia H.; Jefferson, Wendy; Eddy, E. M.; Bullock, Bill C.; Korach, Kenneth S.



Metabolism of diethylstilbestrol by horseradish peroxidase and prostaglandin-H synthase. Generation of a free radical intermediate and its interaction with glutathione  

SciTech Connect

Diethylstilbestrol is carcinogenic in rodents and in humans and its peroxidatic oxidation in utero has been associated with its carcinogenic activity. Horseradish peroxidase-catalyzed oxidation of (14C)diethylstilbestrol and (14C)diethylstilbestrol analogs induced binding of radiolabel to DNA only when the compound contained a free hydroxy group (Metzler, M., and Epe, B. (1984) Chem. Biol. Interact. 50, 351-360). We have found that horseradish peroxidase or prostaglandin-H synthase-catalyzed oxidation of diethylstilbestrol in the presence of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide caused the generation of an ESR signal indicative of a free radical intermediate (aN = 14.9 G, aH = 18.3 G). The identity of the trapped radical could not be identified on the basis of published hyperfine coupling constants, but the observation that horseradish peroxidase-catalyzed oxidation of 1-naphthol produced an identical ESR signal suggests that the radical was either a phenoxy or phenoxy-derived radical. During horseradish peroxidase-catalyzed oxidation of diethylstilbestrol in the presence of glutathione the thiol reduced the diethylstilbestrol radical to generate a thiyl radical. This was shown by a thiol-dependent oxygen uptake during horseradish peroxidase-catalyzed oxidation of diethylstilbestrol and the observation of an ESR signal consistent with 5,5-dimethylpyrroline-N-oxide-glutathionyl radical adduct formation. A diethylstilbestrol analog devoid of free hydroxy groups, namely diethylstilbestrol dipropionate, did not produce an ESR signal above control levels during horseradish peroxidase-catalyzed metabolism in the presence of 5,5-dimethylpyrroline-N-oxide. Thus, free radicals are formed during peroxidatic oxidation of diethylstilbestrol and must be considered as possible determinants of the genotoxic activity of this compound.

Ross, D.; Mehlhorn, R.J.; Moldeus, P.; Smith, M.T.



Effect of PCB and DES on rat monoamine oxidase, acetylcholinesterase, testosterone, and estradiol ontogeny  

Microsoft Academic Search

Diethylstilbestrol (DES) and polychlorinated biphenyl (PCB) have been documented as potentially hazardous environmental agents. In utero exposure to DES produces human vaginal adenocarcinoma, male reproductive tract lesions in mice, and has been correlated with personality changes in human males. PCB (Kanechlor) was found to be the major toxin in the {open_quotes}Yusho{close_quotes} rice oil poisoning in Japan in 1968. Other investigators

D. R. Vincent; W. S. Bradshaw; G. M. Booth; R. E. Seegmiller; S. D. Allen



Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring  

PubMed Central

Maternal exposure to estrogenic xenobiotics or phthalates has been implicated in the distortion of early male reproductive development, referred to in humans as the testicular dysgenesis syndrome. It is not known, however, whether such early gestational and/or lactational exposure can influence the later adult-type Leydig cell phenotype. In this study, Sprague–Dawley rats were exposed to dibutyl phthalate (DBP; from gestational day (GD) 14.5 to postnatal day (PND) 6) or diethylstilbestrol (DES; from GD14.5 to GD16.5) during a short gestational/lactational window, and male offspring subsequently analysed for various postnatal testicular parameters. All offspring remained in good health throughout the study. Maternal xenobiotic treatment appeared to modify specific Leydig cell gene expression in male offspring, particularly during the dynamic phase of mid-puberty, with serum INSL3 concentrations showing that these compounds led to a faster attainment of peak values, and a modest acceleration of the pubertal trajectory. Part of this effect appeared to be due to a treatment-specific impact on Leydig cell proliferation during puberty for both xenobiotics. Taken together, these results support the notion that maternal exposure to certain xenobiotics can also influence the development of the adult-type Leydig cell population, possibly through an effect on the Leydig stem cell population. PMID:23314658

Ivell, Richard; Heng, Kee; Nicholson, Helen; Anand-Ivell, Ravinder



Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring.  


Maternal exposure to estrogenic xenobiotics or phthalates has been implicated in the distortion of early male reproductive development, referred to in humans as the testicular dysgenesis syndrome. It is not known, however, whether such early gestational and/or lactational exposure can influence the later adult-type Leydig cell phenotype. In this study, Sprague-Dawley rats were exposed to dibutyl phthalate (DBP; from gestational day (GD) 14.5 to postnatal day (PND) 6) or diethylstilbestrol (DES; from GD14.5 to GD16.5) during a short gestational/lactational window, and male offspring subsequently analysed for various postnatal testicular parameters. All offspring remained in good health throughout the study. Maternal xenobiotic treatment appeared to modify specific Leydig cell gene expression in male offspring, particularly during the dynamic phase of mid-puberty, with serum INSL3 concentrations showing that these compounds led to a faster attainment of peak values, and a modest acceleration of the pubertal trajectory. Part of this effect appeared to be due to a treatment-specific impact on Leydig cell proliferation during puberty for both xenobiotics. Taken together, these results support the notion that maternal exposure to certain xenobiotics can also influence the development of the adult-type Leydig cell population, possibly through an effect on the Leydig stem cell population. PMID:23314658

Ivell, Richard; Heng, Kee; Nicholson, Helen; Anand-Ivell, Ravinder



GnRH agonists.  


The development of GnRH agonists has had a major impact on the practice of gynecology and reproductive endocrinology. The clinical usefulness of GnRH agonists will increase as modes of administration are improved and indications become better defined. GnRH agonists and, potentially, antagonists will provide a prompt, effective, and reversible method of suppressing ovarian function. GnRH agonists may soon become a treatment of choice for many of the noncontraceptive uses of oral contraceptives. Current indications for GnRH agonist administration are best divided into two groups: short-term (less than 6 months) and long-term (greater than 6 months) suppression. Short-term administration of GnRH agonist include most of the current usage of GnRH agonists. Short-term administration avoids most of the side effects of GnRH agonist and offers the most potential for development of GnRH antagonists. Short-term therapy has been shown to be particularly effective in the preoperative treatment of fibroids, suppression of ovarian function before ovulation induction, for short-term suppression of endometriosis, and for diagnostic purposes to determine whether a medical illness is related to ovarian function. Chronic administration of GnRH agonist has produced varying degrees of success. The treatment of precocious puberty is probably the perfect indication for GnRH agonist suppression. The disease is completely reversed with a remarkable absence of side effects. Long-term administration for metastatic breast or prostatic cancer has been shown to be as efficacious as other forms of gonadal suppression and the potential benefits of suppression outweigh the potential side effects of long-term suppression. The risk-benefit ratio must be carefully analyzed for the other indications for long-term suppression. Long-term suppression could be used for medical illnesses exacerbated by the menstrual cycle, painful symptoms related to endometriosis, contraception, and suppression of hyperandrogynism. Although initial studies show the agonist to be quite effective in treating all of these disorders, long-term suppression also may result in potential serious side effects related to hypoestrogenism including hot flashes and osteoporosis. Long-term administration of GnRH agonist may become feasible by lowering the dose and degree of suppression or by combining GnRH agonist with estrogen or progestin replacement, or both. PMID:2673600

Schriock, E D



No Increased Risk for Most Cancers Yet Observed in Daughters of Women Exposed to DES in the 1940s and 1950s

The first systematic follow-up study of a large group of women, whose mothers were given the synthetic estrogen diethylstilbestrol (DES) during pregnancy in the 1940s and 1950s, found no increase in any type of cancer except for clear cell adenocarcinoma of the vagina and cervix in women under age 30.


Trace analysis of diethylstilbestrol, dienestrol and hexestrol in environmental water by Nylon 6 nanofibers mat-based solid-phase extraction coupled with liquid chromatography-mass spectrometry.  


A simple, rapid and sensitive method for the determination of diethylstilbestrol (DES), dienestrol (DE) and hexestrol (HEX) was developed by using the Nylon 6 nanofibers mat-based solid-phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS). These estrogens were separated within 8 min by LC using an ODS column and methanol/water (80/20, v/v) at a flow rate of 1.0 mL min(-1). Electrospray ionization conditions in the negative ion mode were optimized for MS detection of the estrogens. Under the optimum SPE conditions, all target analytes in 50 mL environmental water samples can be completely extracted by 1.5 mg Nylon 6 nanofibers mat at flow rate of 3.0 mL min(-1) and easily eluted by passage of 500 ?L mobile phase. By using the novel SPE-LC/MS method, good linearity of the calibration curve (r(2) ? 0.9992) was obtained in the concentration range from 0.10 ng L(-1) to 1.0 mg L(-1) (except for DE which was 0.20 ng L(-1) to 1.0 mg L(-1)) for all analytes examined. The limits of detection (S/N = 3) of the three estrogens ranged from 0.05 ng L(-1) to 0.10 ng L(-1). This method was applied successfully to the analysis of environmental water samples without any other pretreatment and interference peaks. Several water samples were collected from Jinchuan River and Xuanwu Lake, and in Jinchuan River water DES was detected at 0.13 ng L(-1). The recoveries of estrogens spiked into tap water were above 98.2%, and the relative standard deviations were below 4.78%. PMID:21994916

Xu, Qian; Wang, Min; Yu, ShuQin; Tao, Qing; Tang, Meng



Mal-Development of the Penis and Loss of Fertility in Male Rats Treated Neonatally with Female Contraceptive 17?-Ethinyl Estradiol: A Dose-Response Study and a Comparative Study with a Known Estrogenic Teratogen Diethylstilbestrol  

PubMed Central

The objectives of this study were to find a minimal dose of 17?-ethinyl estradiol (EE) that is detrimental to the developing penis and fertility and to compare estrogenic effects between EE and diethylstilbestrol (DES). Neonatal rats received EE at 10 ng (1 ?g/kg), 100 ng, 1 ?g, or 10 ?g per pup on alternate days from postnatal days 1 to 11 (dose-response study) or received EE or DES at 100 ng per pup daily from postnatal days 1 to 6 (comparative study). Effects of EE were dose dependent, with ? 100-ng dose inducing significant (p < 0.05) reductions in penile length, weight, and diameter. Additionally, the penis was malformed, characterized by underdeveloped os penis and accumulation of fat cells. Fertility was 0% in the ? 1-?g groups, in contrast to 60% in the 100-ng group and 100% in the 10-ng and control groups. Animals treated with ? 10 ng had significant reductions in the weight of bulbospongious muscle, testis, seminal vesicle, epididymal fat pad, and in epididymal sperm numbers. A comparison of EE and DES effects showed similar reductions in penile weight and length and the weight of bulbospongiosus muscle, testis, seminal vesicle, epididymis, and epididymal fat pad in both adolescent and adult rats. While 5/6 control males sired, only 1/6 in the EE group and 0/6 in the DES group sired. Hence, neonatal exposure to EE at 10 ng (environmentally relevant dose) adversely affects male reproductive organs. A dose ten times higher than this leads to permanently mal-developed penis and infertility. Furthermore, EE and DES exposures show similar level of toxicity to male reproductive organs. PMID:19729556

Mathews, Ensa; Braden, Tim D.; Williams, Carol S.; Williams, John W.; Bolden-Tiller, Olga; Goyal, Hari O.



Nonsteroidal ecdysone agonists.  


Nonsteroidal ecdysone agonists are novel compounds that have become attractive candidates not only as pest control agents in agriculture but also as tools for research. Their narrow spectrum of activity makes them relatively safe as pesticides, and their mode of action as ligands for gene expression has found application in gene therapy and inducing transgenic gene expression in plants. These diacylhydrazines (DAHs) are potent nonsteroidal ecdysone agonists, and four of them, tebufenozide, methoxyfenozide, chromafenozide, and halofenozide, have been developed as insecticides. Although these compounds are very toxic to insects, they are safe for mammals and are environmentally benign. Their action on insects is also selective, the first three are effective against Lepidoptera but weakly active or inactive on Diptera and Coleoptera. On the other hand, halofenozide is effective on Coleoptera but mildly active on Lepidoptera. Previous reviews on ecdysone agonists have concentrated on the biological response of some DAHs and their effects on pests. In this review, the chemistry, biological effects and their modes of action at the molecular level will be covered. In addition, a few studies on other nonsteroidal ecdysone agonists, such as 3,5-di-tert-butyl-4-hydroxy-N-iso-butylbenzamide, acylaminoketones, and benzoyl-1,2,3,4-tetrahydroquinolines, will be briefly reviewed. PMID:16399410

Nakagawa, Yoshiaki




Microsoft Academic Search

ABSTRCT.--Agonistic behavior of Gila Woodpeckers, including vocalizations, visual displays, and other related behaviors, is described. Interactions with both con- and heterospecifics were analyzed by stochastic processes, and it is shown that the timing of aggression toward a species coincided with the time during which that species was searching for nest sites or cavities. The behavior shown toward Flickers and Starlings



Effects of diethylstilbestrol and ethinylestradiol on gene transcription of very low-density apolipoprotein II in the liver of Japanese quail, Coturnix japonica.  


Very low-density apolipoprotein II (apoVLDL) is one of the constituents of yolk in avian eggs. The expression of the apoVLDL gene is highly specific to the liver in mature female birds during the egg-laying period but is stimulated by exogenous estrogens in immature male birds. In the present study, we compared the effects of two estrogenic compounds, diethylstilbestrol and ethinylestradiol, on the expression of apoVLDL mRNA in the liver of Japanese quail (Coturnix japonica). Three-week-old, immature male quail were treated with a single intraperitoneal injection of the estrogenic compounds, and the level of apoVLDL mRNA in the liver was measured by gene-specific real-time polymerase chain reaction. Diethylstilbestrol and ethinylestradiol had a similar effect on the level of mRNA, increasing it in a dose-dependent manner. Next, the levels of apoVLDL mRNA in the liver of male embryos, which were developed in fertile eggs laid by quail injected with the estrogenic compounds during yolk formation, were measured. Maternal exposure to ethinylestradiol caused an increase in the mRNA in embryos, whereas exposure to diethylstilbestrol had no effect. These results point out the importance of the route of administration to the evaluation of the estrogenic effects of endocrine disruptors in oviparous species. PMID:16704069

Hanafy, Ahmed M; Sasanami, Tomohiro; Mori, Makoto



Dopamine agonists and Othello's syndrome  

PubMed Central

Background Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists. Methods We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities. Results Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions. Conclusions OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option. PMID:20829092

Graff-Radford, Jonathan; Ahlskog, J Eric.; Bower, James H.; Josephs, Keith A.



Women exposed to DES in the womb face increased cancer risk:

A large study of the daughters of women who had been given DES, the first synthetic form of estrogen, during pregnancy has found that exposure to the drug while in the womb (in utero) is associated with many reproductive problems and an increased risk of certain cancers and pre-cancerous conditions. Beginning in 1940, diethylstilbestrol, known as DES, was used clinically to prevent certain complications of pregnancy. In the 1950s, clinical studies showed DES was ineffective for this purpose. In the late 1960s, an unusual occurrence of a rare cancer of the vagina among young women, called clear cell adenocarcinoma (CCA), was observed and subsequently linked to their exposure to DES while in the womb.


Parallel changes in agonistic and non-agonistic behaviors during dominance hierarchy formation in crayfish  

Microsoft Academic Search

Agonistic and non-agonistic behaviors were studied before, during, and after the formation of social status in crayfish. Differences in the expression of a non-agonistic behavior by dominant and subordinate crayfish developed in parallel with the differences in agonistic behaviors that indicate the animals' social status. An increase in burrowing behavior marked the ascendancy of the dominant animal, while an immediate

J. Herberholz; M. M. Sen; D. H. Edwards



PPAR Agonists and Cardiovascular Disease in Diabetes  

PubMed Central

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, PPAR? 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 PPAR? agonists, and more recently dual PPAR?/? coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPAR? 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

Calkin, Anna C.; Thomas, Merlin C.



Novel Human Interleukin-15 Agonists  

PubMed Central

IL-15 is an immunostimulatory cytokine trans-presented with the IL-15 receptor ? chain to the shared IL-2/IL-15R? and common ? chains displayed on the surface of T cells and NK cells. To further define the functionally important regions of this cytokine, activity and binding studies were conducted on human IL-15 muteins generated by site-directed mutagenesis. Amino acid substitutions of the asparagine residue at position 72, which is located at the end of helix C, were found to provide both partial agonist and superagonist activity, with various non-conservative substitutions providing enhanced activity. Particularly, the N72D substitution provided a 4–5 fold increased in biological activity of the IL-15 mutein compared to the native molecule based on proliferations assays with cells bearing human IL-15R? and common ? chains. The IL-15N72D mutein exhibited superagonist activity through improved binding ability to the human IL-15R? chain. However, the enhanced potency of IL-15N72D was not observed with cells expressing the mouse IL-15R?-IL-15R?-?c complex suggesting that this effect is specific to human IL-15 receptor. The enhanced biological activity of IL-15N72D was associated with more intense phosphorylation of Jak1 and Stat5 and better anti-apoptotic activity compared to the wild-type IL-15. IL-15N72D superagonist activity was also preserved when linked to a single-chain T cell receptor domain to generate a tumor-specific fusion protein. Thus, the human IL-15 superagonist muteins and fusions may create opportunities to construct more efficacious immunotherapeutic agents with clinical utility. PMID:19710453

Zhu, Xiaoyun; Marcus, Warren D.; Xu, Wenxin; Lee, Hyung-Il; Han, Kaiping; Egan, Jack O.; Yovandich, Jason L.; Rhode, Peter R.; Wong, Hing C.



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


?-adrenergic receptors (?ARs) 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 ?ARs 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) ?(1)-adrenergic receptor (?(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. PMID:21228877

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



Gonadotropin releasing hormone agonists: Expanding vistas  

PubMed Central

Gonadotropin-releasing hormone (GnRH) agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as “pseudomenopause” or “medical oophorectomy,” which are both misnomers. GnRH analogues (GnRH-a) work by temporarily “switching off” the ovaries. Ovaries can be “switched off” for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of “add-back” therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women's healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential. PMID:22028996

Magon, Navneet



Harnessing the benefits of PPAR?/? agonists.  


Lipid mediators have complex effects on the cell; one of the key transcriptional factors that moderate proliferation and inflammatory effects is PPAR?/?. Following highly successful clinical trials using the PPAR?/? agonists GW501516 for treatment of diabetes, GSK announced that any further research would be discontinued due to preclinical trials in rodents which linked this drug to wide spread tumour development. In this review we outline the dual molecular functions of PPAR?/? and connect these to the diverse results from in vitro studies, and draw parallels with the outcomes of animal and human studies. The PPAR?/? agonists have a great potential in terms of therapy, and we hope to provide some insight into the reasons why such contrasting results have been published. The discussion presented here is important to the future development of PPAR?/? agonists for the clinic, and for a fuller understanding for their complex regulatory roles in the cell. PMID:24184294

Mackenzie, Louise S; Lione, Lisa



Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure  

PubMed Central

Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor. PMID:23447620

Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.



Muscimol as an ionotropic GABA receptor agonist.  


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. PMID:24473816

Johnston, Graham A R



A covalently bound photoisomerizable agonist. Comparison with reversibly bound agonists at electrophorus electroplaques  

PubMed Central

After disulphide bonds are reduced with dithiothreitol, trans-3- (?-bromomethyl)-3’-[?- (trimethylammonium)methyl]azobenzene (trans-QBr) alkylates a sulfhydryl group on receptors. The membrane conductance induced by this “tethered agonist” shares many properties with that induced by reversible agonists. Equilibrium conductance increases as the membrane potential is made more negative; the voltage sensitivity resembles that seen with 50 [mu]M carbachol. Voltage- jump relaxations follow an exponential time-course; the rate constants are about twice as large as those seen with 50 ?M carbachol and have the same voltage and temperature sensitivity. With reversible agonists, the rate of channel opening increases with the frequency of agonist-receptor collisions: with tethered trans-Qbr, this rate depends only on intramolecular events. In comparison to the conductance induced by reversible agonists, the QBr-induced conductance is at least 10-fold less sensitive to competitive blockade by tubocurarine and roughly as sensitive to “open-channel blockade” bu QX-222. Light-flash experiments with tethered QBr resemble those with the reversible photoisomerizable agonist, 3,3’,bis-[?-(trimethylammonium)methyl]azobenzene (Bis-Q): the conductance is increased by cis {arrow} trans photoisomerizations and decreased by trans {arrow} cis photoisomerizations. As with Bis-Q, ligh-flash relaxations have the same rate constant as voltage-jump relaxations. Receptors with tethered trans isomer. By comparing the agonist-induced conductance with the cis/tans ratio, we conclude that each channel’s activation is determined by the configuration of a single tethered QBr molecule. The QBr-induced conductance shows slow decreases (time constant, several hundred milliseconds), which can be partially reversed by flashes. The similarities suggest that the same rate-limiting step governs the opening and closing of channels for both reversible and tethered agonists. Therefore, this step is probably not the initial encounter between agonist and receptor molecules. PMID:6246192

Lester, HA; Krouse, ME; Nass, MM; Wassermann, NH; Erlanger, BF



Predictors of Impulsivity and Reward Seeking Behavior With Dopamine Agonists  

E-print Network

Predictors of Impulsivity and Reward Seeking Behavior With Dopamine Agonists William Ondo, M.D1, sexuality) in subjects taking dopamine agonists for Parkinson's disease and restless legs syndrome. Methods

Lichtarge, Olivier


?2-adrenoceptor agonists: current and future direction  

PubMed Central

Despite the passionate debate over the use of ?2-adrenoceptor agonists in the treatment of airway disorders, these agents are still central in the symptomatic management of asthma and COPD. A variety of ?2-adrenoceptor agonists with long half-lives, also called ultra long-acting ?2-adrenoceptor agonists (ultra-LABAs; indacaterol, olodaterol, vilanterol, carmoterol, LAS100977 and PF-610355) are currently under development with the hopes of achieving once-daily dosing. It is likely that the once-daily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is important for treating patients suffering from asthma, and a combination with an inhaled long-acting antimuscarinic agent (LAMA) is important for treating COPD patients whose conditions are not sufficiently controlled by monotherapy with a ?2-adrenoceptor agonist, some novel once-daily combinations of LABAs and ICSs or LAMAs are under development. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit PMID:21232045

Cazzola, Mario; Calzetta, Luigino; Matera, Maria Gabriella



Lead Exposure Alters the Development of Agonistic  

E-print Network

Lead Exposure Alters the Development of Agonistic Behavior in Golden Hamsters M. Catalina ABSTRACT: We tested the effects of exposure to different doses of lead acetate (either 0, 25, 100, or 400-specific effect of lead exposure on the development of aggression during puberty at doses resulting in blood

Delville, Yvon


NMR Solution Structure of the Glucagon Antagonist [desHis1 ]Glucagon Amide in the Presence of Perdeuterated Dodecylphosphocholine  

E-print Network

NMR Solution Structure of the Glucagon Antagonist [desHis1 , desPhe6 , Glu9 ]Glucagon Amide 85721 ReceiVed August 14, 2002; ReVised Manuscript ReceiVed December 2, 2002 ABSTRACT: Glucagon, a 29 glucagon antagonists and agonists have been developed, but limited structural information is available

Brown, Michael F.


AMPK and PPAR? agonists are exercise mimetics  

PubMed Central

SUMMARY The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPAR?/? agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1?, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPAR? pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise. PMID:18674809

Narkar, Vihang A.; Downes, Michael; Yu, Ruth T.; Embler, Emi; Wang, Yong-Xu; Banayo, Ester; Mihaylova, Maria M.; Nelson, Michael C.; Zou, Yuhua; Juguilon, Henry; Kang, Heonjoong; Shaw, Reuben; Evans, Ronald M.



Agonistic and reproductive interactions in Betta splendens.  


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. PMID:6542479

Bronstein, P M



Novel endogenous peptide agonists of cannabinoid receptors  

PubMed Central

Hemopressin (Hp), a 9-residue ?-hemoglobin-derived peptide, was previously reported to function as a CB1 cannabinoid receptor antagonist (1). In this study, we report that mass spectrometry (MS) data from peptidomics analyses of mouse brain extracts identified N-terminally extended forms of Hp containing either three (RVD-Hp?) or two (VD-Hp?) additional amino acids, as well as a ?-hemoglobin-derived peptide with sequence similarity to that of hemopressin (VD-Hp?). Characterization of the ?-hemoglobin-derived peptides using binding and functional assays shows that in contrast to Hp, which functions as a CB1 cannabinoid receptor antagonist, both RVD-Hp? and VD-Hp? function as agonists. Studies examining the increase in the phosphorylation of ERK1/2 levels or release of intracellular Ca2+ indicate that these peptides activate a signal transduction pathway distinct from that activated by the endocannabinoid, 2-arachidonoylglycerol, or the classic CB1 agonist, Hu-210. This finding suggests an additional mode of regulation of endogenous cannabinoid receptor activity. Taken together, these results suggest that the CB1 receptor is involved in the integration of signals from both lipid- and peptide-derived signaling molecules.—Gomes, I., Grushko, J. S., Golebiewska, U., Hoogendoorn, S., Gupta, A., Heimann, A. S., Ferro, E. S., Scarlata, S., Fricker, L. D., Devi, L. A. Novel endogenous peptide agonists of cannabinoid receptors. PMID:19380512

Gomes, Ivone; Grushko, Julia S.; Golebiewska, Urszula; Hoogendoorn, Sascha; Gupta, Achla; Heimann, Andrea S.; Ferro, Emer S.; Scarlata, Suzanne; Fricker, Lloyd D.; Devi, Lakshmi A.



Melanocortin 1 Receptor Agonists Reduce Proteinuria  

PubMed Central

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

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



Melanocortin 1 receptor agonists reduce proteinuria.  


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

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



Pentapeptides displaying mu opioid receptor agonist and delta opioid receptor partial agonist/antagonist properties  

PubMed Central

Chronic use of mu-opioid agonists has been shown to cause neurochemical adaptations resulting in tolerance and dependence. While the analgesic effects of these drugs are mediated by mu-opioid receptors (MOR), several studies have shown that antagonism or knockdown of delta-opioid receptors (DOR) can lessen or prevent development of tolerance and dependence. Based on computational modeling of putative active and inactive conformations of MOR and DOR, we have synthesized a series of pentapeptides with the goal of developing a MOR agonist/DOR antagonist peptide with similar affinity at both receptors as a tool to probe functional opioid receptor interaction(s). The eight resulting naphthylalanine-substituted cyclic pentapeptides displayed variable mixed-efficacy profiles. The most promising peptide (9; Tyr-c(S-CH2-S)[D-Cys-Phe-2-Nal-Cys]NH2) displayed a MOR agonist and DOR partial agonist/antagonist profile and bound with equipotent affinity (Ki ~ 0.5 nM) to both receptors, but also showed kappa opioid receptor (KOR) agonist activity. PMID:19788201

Purington, Lauren C.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.



AMPK-Dependent Metabolic Regulation by PPAR Agonists  

PubMed Central

Comprehensive studies support the notion that the peroxisome proliferator-activated receptors, (PPARs), PPAR?, PPAR?/?, and PPAR?, regulate cell growth, morphogenesis, differentiation, and homeostasis. Agonists of each PPAR subtype exert their effects similarly or distinctly in different tissues such as liver, muscle, fat, and vessels. It is noteworthy that PPAR? or PPAR? agonists have pharmacological effects by modulating the activity of AMPK, which is a key cellular energy sensor. However, the role of AMPK in the metabolic effects of PPAR agonists has not been thoroughly focused. Moreover, AMPK activation by PPAR agonists seems to be independent of the receptor activation. This intriguing action of PPAR agonists may account in part for the mechanistic basis of the therapeutics in the treatment of metabolic disease. In this paper, the effects of PPAR agonists on metabolic functions were summarized with particular reference to their AMPK activity regulation. PMID:20814441

Lee, Woo Hyung; Kim, Sang Geon



ORIGINAL PAPER The glutamate agonist NMDA blocks gonadal regression  

E-print Network

ORIGINAL PAPER The glutamate agonist NMDA blocks gonadal regression and enhances antibody response through actions on peripheral glutamate receptors. These results support a previous finding that NMDA

Demas, Greg


Discovery of novel orally bioavailable GPR40 agonists.  


The GPR40 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. A series of novel orally bioavailable GPR40 agonists was discovered. SAR study and structural optimization led to identification of compounds 28a and 30a as potent GPR40 agonists with superior physiochemical properties and robust in vivo efficacy in rhesus monkeys. PMID:23582779

Lu, Hejun; Fei, Hongbo; Yang, Fanglong; Zheng, Suxin; Hu, Qiyue; Zhang, Lei; Yuan, Jijun; Feng, Jun; Sun, Piaoyang; Dong, Qing



Agonistic profile and metabolism in alevins of the Nile tilapia  

Microsoft Academic Search

Metabolic differences derived from social stress usually show data with high variance that may hinder the finding of important differences. Since such high variance may be caused by agonistic variability occurring during social interactions, this work tested whether metabolism is associated with agonistic profile in the cichlid fish Nile tilapia, Oreochromis niloticus (L.). Metabolism was inferred from oxygen consumption, resistance

Cláudia Maria Domingues Alvarenga; Gilson Luiz Volpato



Substituted acyclic sulfonamides as human cannabinoid-1 receptor inverse agonists  

Microsoft Academic Search

Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia.

Helen E. Armstrong; Amy Galka; Linus S. Lin; Thomas J. Lanza Jr.; James P. Jewell; Shrenik K. Shah; Ravi Guthikonda; Quang Truong; Linda L. Chang; Grace Quaker; Vincent J. Colandrea; Xinchun Tong; Junying Wang; Sherry Xu; Tung M. Fong; Chun-Pyn Shen; Julie Lao; Jing Chen; Lauren P. Shearman; D. Sloan Stribling; Kimberly Rosko; Alison Strack; Sookhee Ha; Lex Van der Ploeg; Mark T. Goulet; William K. Hagmann



Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists  

ERIC Educational Resources Information Center

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…

King, Angela G.



Agonistic behavior of the crayfish Euastacus armatus and Cherax destructor  

Microsoft Academic Search

The intra- and interspecific agonistic behavior of Euastacus armatus and Cherax destructor from northeastern Victoria were examined. While the agonistic patterns of E. armatus appeared similar to those shown by most crayfish, individuals of C. destructor execute an unusual, highly stylized cheliped “punch” behavior during strong interactions, along with the other behaviors seen in many species. Juvenile C. destructor exhibited

Brian A. Hazlett; Susan Lawler; Geoffrey Edney



Agonistic profile and metabolism in alevins of the Nile tilapia.  


Metabolic differences derived from social stress usually show data with high variance that may hinder the finding of important differences. Since such high variance may be caused by agonistic variability occurring during social interactions, this work tested whether metabolism is associated with agonistic profile in the cichlid fish Nile tilapia, Oreochromis niloticus (L.). Metabolism was inferred from oxygen consumption, resistance to progressive hypoxia and ventilatory rate. Fifteen pairs of alevins were used for each metabolic and behavioral series. An ethogram based on 8 types of agonistic interactions was employed. Agonistic profiles were determined and associated with the physiological parameters later on. The test of canonical correlation showed significant association between some agonistic profiles and metabolism. Ventral nipping and lateral fight appeared as the two most important in promoting association with metabolism. PMID:7878128

Alvarenga, C M; Volpato, G L



GnRH agonist triggering: recent developments.  


The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin(HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages, including virtually complete prevention of ovarian hyperstimulation syndrome(OHSS), the introduction of a surge of FSH in addition to the LH surge and finally the possibility to individualize luteal-phase supplementation based on ovarian response to stimulation. We maintain that the automatic HCG triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. PMID:23337420

Kol, Shahar; Humaidan, Peter



The mangement of DES-exposed patients at the Medical College of Pennsylvania.  


Since diethylstilbestrol (DES)-exposed offspring are mostly asymptomatic the 1st problem is finding these patients. Maternity charts have been examined to determine if DES was taken when the patient was pregnant. New patients in the range of possible DES mothers are questioned regarding DES history. Referring physicians are sent a history of any DES exposure. Where a doubt exists colposcopic examination is made. At the 1st visit Papanicolaou (Pap) smears are taken from the cervix and vaginal walls and colposcopy is done to rule out carcinoma. Intensive colposcopy is done after admission to the hospital. General anesthesia is then used. Areas for excisional biopsies are determined and 8 or 10 excisional biopsies may be taken. Biopsy wounds may be sutured. or Monsel's solution applied to stop bleeding of lesser lesions. Schiller's iodine is applied to determine the extent of cauterization. All abnormal areas are cauterized. After intensive colposcopy a dilatation and curettage may be done. A 2-inch pack is placed in the vagina after application of Sultrin cream. Each piece of removed tissue is put in a separate jar and a sketch is drawn to inform the pathologist of its original site. Glandular tissue from the vagina means adenosis but from the cervix it may be a common finding. The next morning the vaginal pack is removed and the patient is discharged. 2-4 weeks later, a colposcopic examination is made to ensure healing. A repeat Pap smear is made after 6 months. After 12 months the patient is reevaluated, Vaginal tampons are advised at menstruation to prevent vaginal adhesions. If a carcinoma is found colposcopy is needed to determine the extent of indicated surgery or irradiation therapy. Others report doing colposcopy at shorter intervals with no therapy until changes are found. This method is advised only when follow-up is complete. PMID:957353

Schmitt, A W



Structure and Function of an Irreversible Agonist-?2 Adrenoceptor complex  

PubMed Central

G protein-coupled receptors (GPCRs) are eukaryotic integral membrane proteins that modulate biological function by initiating cellular signaling in response to chemically diverse agonists. Despite recent progress in the structural biology of GPCRs1, the molecular basis for agonist binding and allosteric modulation of these proteins is poorly understood. Structural knowledge of agonist-bound states is essential for deciphering the mechanism of receptor activation, and for structure-guided design and optimization of ligands. However, the crystallization of agonist-bound GPCRs has been hampered by modest affinities and rapid off-rates of available agonists. Using the inactive structure of the human ?2 adrenergic receptor (?2AR) as a guide, we designed a ?2AR agonist that can be covalently tethered to a specific site on the receptor through a disulfide bond. The covalent ?2AR-agonist complex forms efficiently, and is capable of activating a heterotrimeric G protein. We crystallized a covalent agonist-bound ?2AR-T4L fusion protein in lipid bilayers through the use of the lipidic mesophase method2, and determined its structure at 3.5 Å resolution. A comparison to the inactive structure and an antibody-stabilized active structure (companion paper3) shows how binding events at both the extracellular and intracellular surfaces are required to stabilize an active conformation of the receptor. The structures are in agreement with long-timescale (up to 30 ?s) molecular dynamics simulations showing that an agonist-bound active conformation spontaneously relaxes to an inactive-like conformation in the absence of a G protein or stabilizing antibody. PMID:21228876

Rosenbaum, Daniel M.; Zhang, Cheng; Lyons, Joseph; Holl, Ralph; Aragao, David; Arlow, Daniel H.; Rasmussen, S?ren G. F.; Choi, Hee-Jung; DeVree, Brian T.; Sunahara, Roger K.; Chae, Pil Seok; Gellman, Samuel H.; Dror, Ron O.; Shaw, David E.; Weis, William I.; Caffrey, Martin; Gmeiner, Peter; Kobilka, Brian K.



GPR119 agonists 2009-2011.  


The increasing incidence of Type II diabetes mellitus worldwide continues to attract the attention and resources of the pharmaceutical industry in the pursuit of more effective therapies for blood glucose control. New approaches that compare favorably with classical medicaments while avoiding hypoglycemic episodes or waning effectiveness are paramount. Recent advances toward this end have been realized based on the biology of the glucagon like peptide-1 receptor (GLP1R). This ?-cell-expressed GPCR has the ability to promote insulin release in a glucose-dependent fashion, and has been shown to elicit improved glycemic control and preservation of ?-cell mass. Direct activation of GLP1R utilizing peptide mimetics has been achieved; however, attempts to access the biology of this receptor via small-molecule approaches have thus far been elusive. In this context, GPR119 has emerged as a tractable new alternative to GLP1R. GPR119 is another GPCR expressed on the ?-cell, which, like GLP1R, signals in a glucose-dependent manner. Moreover, GPR119-mediated increases in GLP-1 and other incretins upon activation in the intestine further increase the insulinotropic activity of the ?-cell. The early success in identifying small-molecule agonists of the GPR119 has prompted a rapid increase in the number of patent applications filed in the last few years. In this review we provide a comprehensive summary of all patent activity in this field that has appeared within the 2009-2011 timeframe. PMID:24236842

Buzard, Daniel J; Lehmann, Juerg; Han, Sangdon; Jones, Robert M



Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer  

E-print Network

Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly...

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




Microsoft Academic Search

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

John J. McGlone



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


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

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



Identification of M-CSF agonists and antagonists  


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.

Pandit, Jayvardhan (Mystic, CT); Jancarik, Jarmila (Walnut Creek, CA); Kim, Sung-Hou (Moraga, CA); Koths, Kirston (El Cerrito, CA); Halenbeck, Robert (San Rafael, CA); Fear, Anna Lisa (Oakland, CA); Taylor, Eric (Oakland, CA); Yamamoto, Ralph (Martinez, CA); Bohm, Andrew (Armonk, NY)



Alteration of Lymphocyte Trafficking by Sphingosine 1Phosphate Receptor Agonists  

Microsoft Academic Search

Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in

Suzanne Mandala; Richard Hajdu; James Bergstrom; Elizabeth Quackenbush; Jenny Xie; James Milligan; Rosemary Thornton; Gan-Ju Shei; Deborah Card; CarolAnn Keohane; Mark Rosenbach; Jeffrey Hale; Christopher L. Lynch; Kathleen Rupprecht; William Parsons; Hugh Rosen



5-HT4 receptor agonists: similar but not the same.  


5-Hydroxytryptamine(4) (5-HT(4)) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT(4) receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT(4) receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K(+) channel and tegaserod: 5-HT(1) and 5-HT(2) receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT(4) receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT(4) receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT(4) receptor-related differences between agonists. Based on drug- and tissue-related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5-HT(4) receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT(4) receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders. PMID:18199093

De Maeyer, J H; Lefebvre, R A; Schuurkes, J A J



Inhibition of platelet aggregation by adenosine receptor agonists  

Microsoft Academic Search

2-(Ar)alkoxyadenosines, which are agonists selective for the A2AAR in PC 12 cell and rat striatum membranes, are also agonists at the A2AR coupled to adenylate cyclase (AC) that mediates the inhibition of platelet aggregation. A panel of twelve well-characterized\\u000a adenosine analogues stimulated human platelet AC and inhibited ADP-induced platelet aggregation at sub- to low-micromolar\\u000a concentrations with a potency ranking CGS

Gloria Cristalli; Sauro Vittori; Robert D. Thompson; William L. Padgett; Dan Shi; John W. Daly; Ray A. Olsson



Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management.  


Beta2 (?2) adrenergic receptor agonists (beta agonists) are a commonly prescribed treatment for asthma despite the small increase in risk for life-threatening adverse responses associated with long-acting beta agonist (LABA). The concern for life-threatening adverse effects associated with LABA and the inter-individual variability of therapeutic responsiveness to LABA-containing combination therapies provide the rationale for pharmacogenetic studies of beta agonists. These studies primarily evaluated genes within the ?2-adrenergic receptor and related pathways; however, recent genome-wide studies have identified novel loci for beta agonist response. Recent studies have identified a role for rare genetic variants in determining beta agonist response and, potentially, the risk for rare, adverse responses to LABA. Before genomics research can be applied to the development of genetic profiles for personalized medicine, it will be necessary to continue adapting to the analysis of an increasing volume of genetic data in larger cohorts with a combination of analytical methods and in vitro studies. PMID:24641588

Ortega, V E



Glucagon Receptor Agonists and Antagonists Affect the Growth of the Chick Eye: A Role for Glucagonergic Regulation of Emmetropization?  

PubMed Central

Purpose In chicks, plus defocus retards eye growth, thickens the choroid, and activates glucagonergic amacrine cells, probably releasing glucagon. Glucagon receptor antagonists (expected to inhibit compensation to plus defocus) and agonists (expected to block myopia induction by form deprivation) were administered to eyes of chicks, to test the hypothesis that glucagon mediates the induction of changes in eye growth by plus defocus. Methods Seven-day-old (P7) chick eyes were injected intravitreally with peptides at concentrations of ~10?9 to 10?5 M in 20 ?L (injection volume). The glucagon-receptor antagonists [des-His1,des- Phe6,Glu9]-glucagon-NH2 (des- Phe6-antagonist) and [des-His1,Glu9]-glucagon-NH2 (Phe6-antagonist) were administered daily for 4 to 5 days to plus-defocused eyes. Agonists (porcine glucagon-[1–29] and [Lys17,18,Glu21]-glucagon-NH2) were monocularly administered daily for 5 days to form-deprived eyes. The contralateral eye remained open and received saline. After treatment, eyes were refracted, measured, and examined for histologic changes. Results The Phe6-antagonist at 10?5 M (in the syringe) inhibited changes in both refractive error and axial length compensation induced by +7-D lens wear; however, des-Phe6-antagonist (10?5 M) had weak, inconsistent effects and did not antagonize the action of exogenous glucagon. Glucagon prevented ocular elongation and myopia and induced choroidal thickening in form-deprived eyes. [Lys17,18,Glu21]-glucagon-NH2 had little effect at 1037 M, but at 10?6 to 10?5 M altered rod structure and inhibited eye growth. Conclusions Exogenous glucagon inhibited the growth of form-deprived eyes, whereas Phe6-antagonist inhibited compensation to plus defocus, as might be expected if glucagon is an endogenous mediator of emmetropization. The reason for the failure of des-Phe6-antagonist to counteract the effects of exogenous glucagon requires further investigation. PMID:16249465

Vessey, Kirstan A.; Lencses, Kathy A.; Rushforth, David A.; Hruby, Victor J.; Stell, William K.



Evidence for postsynaptic dopamine agonist effects of BHT 920 in the presence of the dopamine D-1 agonist SKF 38393  

Microsoft Academic Search

The ability of B-HT 920, a selective dopamine (DA) D-2 agonist, to stimulate postsynaptic DA receptors in brain was evaluated by assessing its ability to induce stereotypy and to increase locomotor activity in rats. When administered alone, B-HT 920 (0.03–3.0 mg\\/kg) did not induce stereotypy and produced only inhibition of locomotor activity, suggesting a lack of postsynaptic DA agonist actions.

Leonard T. Meltzer; James N. Wiley; Ann E. Williams; Thomas G. Heffner



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


Cannabinoid receptor agonists, such as ?(9)-tetrahydrocannabinol (?(9)-THC), enhance the antinociceptive effects of ?-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 ?-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, ?(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 ?(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. ?(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 ?(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. PMID:25194020

Maguire, David R; France, Charles P



Dihydrocodeine/Agonists for Alcohol Dependents  

PubMed Central

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 optimizations are possible. PMID:22470353

Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard



Methamphetamine-like discriminative-stimulus effects of nicotinic agonists.  


Nicotine was recently shown to engender d-methamphetamine (MA)-like discriminative-stimulus effects in rats, which may be indicative of shared psychomotor stimulant properties. To further investigate such overlapping discriminative-stimulus effects, nicotinic agonists varying in efficacy and selectivity were studied in squirrel monkeys that discriminated a moderate intramuscular dose of MA (0.1 mg/kg) from vehicle. These included ?4?2-selective ligands that may vary in efficacy from relatively high [nicotine, (+)- and (-)-epibatidine] to relatively low [isoarecolone, varenicline, (-)-cytisine, (-)-lobeline] and the ?7-selective ligands anabaseine and anabasine. Results show that nicotine, (+)-epibatidine, and (-)-epibatidine substituted fully for MA, whereas the highest doses of other nicotinic agonists produced intermediate levels of MA-like effects (isoarecolone, anabaseine, anabasine, and varenicline) or did not substitute for MA [(-)-cytisine and (-)-lobeline]. The relative potencies of nicotinic agonists, based on effective dose50 (ED50) values, corresponded more closely with their relative affinities at ?4?2 than at ?7 receptors. Regardless of selectivity or efficacy, nicotinic agonists also were observed to produce untoward effects, including salivation and emesis during or after experimental sessions. In pretreatment studies, the ?4?2-selective antagonist dihydro-?-erythroidine hydrobromide (DH?E) (0.032 and 0.1 mg/kg) and the partial agonists varenicline (0.0032-0.1 mg/kg) and (-)-cytisine (0.032 and 0.1 mg/kg) surmountably antagonized (>10-fold rightward shift) nicotine's MA-like effects but were ineffective in blocking nicotine's emetic effects. Overall, our results show that 1) MA-like discriminative-stimulus effects of nicotinic agonists likely are mediated through ?4?2 nicotinic acetylcholine receptor actions, and 2) nicotinic ?4?2 partial agonists, like the nicotinic antagonist DH?E, can reduce MA-like behavioral effects of nicotine. PMID:24389640

Desai, Rajeev I; Bergman, Jack



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

SciTech Connect

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.

Buck, K.J.; Harris, R.A. (Univ. of Colorado Health Sciences Center, Denver (USA))



Honokiol: A non-adipogenic PPAR? agonist from nature?  

PubMed Central

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

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



Modification of opiate agonist binding by pertussis toxin  

SciTech Connect

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.

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



Opioid agonist and antagonist activities of morphindoles related to naltrindole.  


A series of naltrindole-related ligands (4-10) with an N-methyl,N-phenethyl,N-cinnamyl, or an unsubstituted basic nitrogen were synthesized and tested for opioid agonist and antagonist activity in smooth muscle preparations and in mice. The nor compounds (4 and 6) and the phenethyl derivatives (5 and 8) displayed full agonist activity (IC50 = 85-179 nM) in the mouse vas deferens preparation (MVD) while the other members of the series exhibited partial agonist or weak antagonist activity. In the guinea pig ileum preparation (GPI), all compounds except 8 were partial agonists. The ligands that were evaluated in mice were found to produce antinociception that was not selectively mediated via delta opioid receptors. However, two of these ligands (4 and 5) appeared to be delta-selective opioid receptor antagonists at subthreshold doses for antinociception. The finding that all of the compounds bind selectively to delta opioid receptors in guinea pig brain membranes together with the in vitro pharmacology and in vivo antagonist studies suggests that the lack of delta agonist selectivity in vivo may be due to a number of factors, including a basic difference between the delta receptor system in the MVD and in the mouse brain. Further, it is suggested that the constellation of message and address components in the morphindole nucleus may tend to stabilize delta receptors in the brain in antagonist state. PMID:1333013

Portoghese, P S; Larson, D L; Sultana, M; Takemori, A E



Species variability in platelet aggregation response to different agonists.  


Conflicting data on platelet function in animal species are reported in the literature. In this study, the response of buffalo, horse, pig and sheep platelets to different agonists was assessed. Blood samples were collected from the jugular vein of six healthy subjects of each species and platelet-rich plasma was obtained by centrifugation. Platelet aggregation responses to increasing doses of adenosine 5'-diphosphate (ADP), arachidonic acid, collagen, platelet activating factor (PAF) and ristocetin were measured by a turbidimetric method. Horse platelets were the most responsive to ADP, collagen and PAF, whereas sheep platelets were the most responsive to ristocetin. The response to arachidonic acid varied least between species. PAF was the most effective agonist, inducing a maximum aggregation response at a concentration of 1 micro M for platelets of each species. Conversely, concentrations of ristocetin higher than 1mg/ml induced a maximum aggregation response only with sheep and horse platelets. The different responses of platelets from the four animal species to various agonists may reflect either (1). structural differences (including composition of the platelet membrane and presence of specific agonist receptors), or (2). activation of distinct signalling pathways by the agonist. PMID:12354523

Pelagalli, A; Lombardi, P; d'Angelo, D; Della Morte, R; Avallone, L; Staiano, N



Channel blocking properties of a series of nicotinic cholinergic agonists.  

PubMed Central

Inhibition of the nicotinic acetylcholine receptor (nAChR) by channel blockade has been demonstrated with a variety of large organic cations, including several nicotinic agonists. We have studied the kinetics of channel blocking of a series of agonists which vary systematically in size and hydrophobicity due to a hydrocarbon chain from one to six carbons in length, as well as one agonist with a tertiary isomer of one hydrocarbon chain. Single-channel recording was used in combination with three different analysis techniques for determining the kinetic and equilibrium parameters of channel blockade. With an increasing number of methylenes, the blocking rates were essentially constant and the unblocking rates decreased exponentially. This is consistent with studies of the blocking properties of alcohols at the nAChR channel. Also, a linear decrease in the depth to which the larger agonists penetrate the membrane spanning region of the channel was observed. The three smaller agonists, however, all traverse approximately 75% of the membrane field, in agreement with previous measurements of the location of the narrowest region of the channel, the selectivity filter. Images FIGURE 9 PMID:7693004

Carter, A A; Oswald, R E



Novel nonsecosteroidal VDR agonists with phenyl-pyrrolyl pentane skeleton.  


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 (EC??: 1.06 nM) exhibited stronger VDR agonistic activity than tacalcitol (EC??: 7.05 nM), inhibited the proliferations of HaCaT and MCF-7 cells with IC?? of 2.06 ?M and 0.307 ?M (tacalcitol: 2.07 ?M and 0.057 ?M) and showed no significant effect on serum calcium. PMID:24099996

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



The atypical antidepressant mianserin exhibits agonist activity at ?-opioid receptors  

PubMed Central

BACKGROUND AND PURPOSE Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [35S]GTP?S binding and MAPK phosphorylation. KEY RESULTS Mianserin displayed 12- and 18-fold higher affinity for ?- than µ- and ?-opioid receptors respectively. In [35S]GTP?S assays, mianserin selectively activated ?-opioid receptors. The agonist activity was antagonized by the selective ?-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed ?-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing ?-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTP?S binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full ?-opioid agonists (–)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full ?-opioid receptor agonists in [35S]GTP?S assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS In different cell systems, mianserin directly activates ?-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. PMID:22708686

Olianas, Maria C; Dedoni, Simona; Onali, Pierluigi



Insect Nicotinic Receptor Agonists as Flea Adulticides in Small Animals  

PubMed Central

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

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




E-print Network

#12;#12;FEMININ, MASCULIN : ANTHROPOLOGIE DES CAT�GORIES ET DES PRATIQUES MEDICALES 2007 #12;AUX;FEMININ, MASCULIN. ANTHROPOLOGIE DES CAT�GORIES ET DES PRATIQUES MEDICALES Sous la direction de Virginie, en France, du paradoxe d'une surmortalité masculine et d'une surmor- bidité féminine. Cette apparente

Boyer, Edmond


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


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

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



Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease.  


The dopamine agonist medications, pramipexole and ropinirole, are commonly used to treat Parkinson's disease. These two drugs have a highly specific affinity for cerebral D3 receptors, known to be localized to the mesolimbic system. Herein is described a common side effect of these drugs, encountered in our routine clinical practice: pathological behaviors. This includes excessive gambling, hypersexuality, shopping, hyperphagia or obsessive hobbying, which may develop in up to 30% of people taking higher agonist doses. In contrast, treatment with the dopamine precursor, levodopa, in the absence of D3 agonist therapy very rarely provokes such behavioral syndromes. Although these agonist-induced behaviors have been called "impulse control disorders", the problem is not simply loss of impulse control, but rather a novel obsessive-compulsion directed at one or a few behaviors, often taking on pathological proportions. This experience points to the dopamine D3 receptor as a potential therapeutic target for gambling, sex or other addictions occurring spontaneously in the general population. PMID:21557955

Ahlskog, J Eric



Concepts of establishing clinical bioequivalence of chlorofluorocarbon and hydrofluoroalkane ?-agonists  

Microsoft Academic Search

There are no established guidelines for judging equivalence between inhaled medications. The principles of establishing bioequivalence on the basis of bioavailability and pharmacokinetics may not be applicable to inhaled medications with predominantly topical and minimal systemic effects. For inhaled ?2-agonists, the most practical method of showing in vivo therapeutic equivalence is by comparing relative potencies (RPs) of pharmacodynamic effects (bronchodilation

Krishnan Parameswaran



CLINICAL STUDIES Inhaled Beta-2 Adrenergic Receptor Agonists and  

E-print Network

CLINICAL STUDIES Inhaled Beta-2 Adrenergic Receptor Agonists and Primary Cardiac Arrest Rozenn N with higher risk of primary cardiac arrest in patients with asthma or chronic obstructive pulmonary disease primary cardiac arrest during 1980 to 1994. We randomly selected 586 controls from strata of en- rollees

Lin, Danyu


Effects of melanocortin 1 receptor agonists in experimental nephropathies.  


Nephrotic syndrome, characterized by massive proteinuria, is caused by a large group of diseases including membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS). Although the underlying mechanisms are beginning to unravel, therapy is unspecific and far from efficient. It has been suggested that adrenocorticotropic hormone (ACTH) has beneficial effects in patients with MN and possibly in other nephrotic diseases. We have previously reported that ACTH may act directly on podocytes through the melanocortin 1 receptor (MC1R). In the present study, we evaluate the effect of highly specific MC1R agonists in two different nephrotic disease models. Experimental MN: Passive Heymann nephritis (PHN) was induced in rats that were treated for four weeks with MS05, a selective MC1R agonist, or saline. The degree of albuminuria was significantly reduced over time and the effect was sustained one week after treatment withdrawal (p<0.05). Experimental FSGS: Based on a dose-response study, two doses of adriamycin were used for induction of nephropathy in Balb/c mice. Mice were treated with either a synthetic MC1R agonist (BMS-470539), with ?-melanocyte stimulating hormone (?-MSH) or with saline. There was no beneficial effect of treatment. In summary, MC1R agonists reduce albuminuria and improve morphology in experimentally induced MN whereas they have no effect in experimental FSGS. The results illustrate the differences in these podocytopathies in terms of signaling mechanisms underlying proteinuria, and progression of disease. PMID:24498203

Lindskog Jonsson, Annika; Granqvist, Anna; Elvin, Johannes; Johansson, Martin E; Haraldsson, Börje; Nyström, Jenny



PPAR? agonists inhibit TGF-?-PKA signaling in glomerulosclerosis  

PubMed Central

Aim: To study the probable mechanisms of the anti-glomerulosclerosis effects induced by peroxisome proliferator-activated receptor gamma (PPAR?) agonists in rat intraglomerular mesangial cells (MCs). Methods: Cells were transfected with the pTAL-PPRE-tk-Luc+ plasmid and then treated with different concentrations of PPAR? agonist, either troglitazone or telmisartan, for the indicated times. Promega luciferase assays were subsequently used for the detection of PPAR? activation. Protein expression levels were assessed by Western blot, and PepTag® assays were used for the non-radioactive detection of protein kinase A (PKA) activity. The deposition of ?-smooth muscle actin (?-SMA) and p-cyclic AMP responsive element binding protein (pCREB) were analyzed by confocal laser scanning. Results: Both troglitazone and telmisartan remarkably inhibit the PKA activation and pCREB expression that is stimulated by TGF-?. The PPAR? agonists also inhibited ?-SMA and collagen IV protein expression by blocking PKA activation. Conclusion: PPAR? ligands effectively suppress the activation of MCs and the accumulation of collagen IV stimulated by TGF-? in vitro. The renal protection provided by PPAR? agonists is partly mediated via their blockade of TGF-?/PKA signaling. PMID:20037602

Zou, Rong; Xu, Gang; Liu, Xiao-cheng; Han, Min; Jiang, Jing-jing; Huang, Qian; He, Yong; Yao, Ying



Synthetic LXR agonists increase LDL in CETP species  

Microsoft Academic Search

Liver X receptor (LXR) nuclear receptors regu- late the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and an- tidiabetic actions. Accordingly, LXR is considered an ap- pealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progres- sion in murine genetic models; however, these

Pieter H. E. Groot; Nigel J. Pearce; John W. Yates; Claire Stocker; Charles Sauermelch; Christopher P. Doe; Robert N. Willette; Alan Olzinski; Tambra Peters; Denise d'Epagnier; Kathleen O. Morasco; John A. Krawiec; Christine L. Webb; Karpagam Aravindhan; Beat Jucker; Mark Burgert; Chun Ma; Joseph P. Marino; Jon L. Collins; Colin H. Macphee; Scott K. Thompson; Michael Jaye



Estrogen receptor agonists and immune system in ovariectomized mice.  


Several data implicate the immune system in bone lost after estrogen deficiency, however, some of the effects on the immune system of estrogen deficiency or of estrogen receptor (ER) modulation are not well established. In this study, the effect of ER agonists on the immune system in ovariectomized mice is analyzed. Mice were ovariectomized and were administered 17beta-estradiol (E2), raloxifene (RAL) or genistein (GEN). The effect of a 4-week treatment on bone turnover and on several parameters that reflect the status of the immune system was studied. Results show that ovariectomy provoked both uterine atrophy and thymic hypertrophy. Although RAL corrected thymic hypertrophy, only E2 corrected both. Ovariectomized mice showed increased levels of serum calcium and cathepsin K gene expression and decreased levels of serum alkaline phosphatase (ALP) activity, which suggests that there is a persistent alteration in bone metabolism. Moreover, ovariectomy increased B-cells and CD25+ cells, and decreased the percentages of T-cells and Cbfa1 gene expression in bone marrow (BM). All ER agonists corrected, although to different degrees, changes induced by the ovariectomy. Furthermore, results showed that it is essential to adjust ER agonist doses to avoid immunosuppression, since all ER agonists decreased BM T-cell levels. PMID:17166402

García-Pérez, M A; Del Val, R; Noguera, I; Hermenegildo, C; Pineda, B; Martinez-Romero, A; Cano, A



Agonistic displays in the rock bass, Ambloplites rupestris  

Microsoft Academic Search

Agonistic encounters between pairs of adult rick bass, Ambloplites rupestris were observed and the behaviour and changes in coloration of the dominant and subordinate individuals analysed. Dominance coloration involved the establishment of a high degree of visual contrast, whereas subordinate coloration made the animals darker and their coloration less striking, thus perhaps serving a protective function.

Martha E. Casterlin; William W. Reynolds



Reversibly Caged Glutamate: A Photochromic Agonist of Ionotropic Glutamate Receptors  

E-print Network

Reversibly Caged Glutamate: A Photochromic Agonist of Ionotropic Glutamate Receptors Matthew of the central nervous system (CNS). In particular, caged glutamate has emerged as a tool for the dissection photochemical cleavage of a protecting group,2 released glutamate is free to bind ionotropic glutamate receptors

Trauner, Dirk


Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease  

Microsoft Academic Search

The dopamine agonist medications, pramipexole and ropinirole, are commonly used to treat Parkinson's disease. These two drugs have a highly specific affinity for cerebral D3 receptors, known to be localized to the mesolimbic system. Herein is described a common side effect of these drugs, encountered in our routine clinical practice: pathological behaviors. This includes excessive gambling, hypersexuality, shopping, hyperphagia or

J. Eric Ahlskog



Agonist-antagonist muscle activation during drop jumps.  


Pre-programmed and stretch-induced muscle activities of agonist muscles can play important roles during stretch-shortening cycle exercises. It is still not clear how the antagonist muscles function when the drop and rebound intensities are varied during drop jump (DJ) exercises. The purpose of the present study was to examine the regulation of agonist-antagonist muscle activation during DJ with different drop and rebound heights. The subjects performed DJs with two drop heights (0.2 and 0.4 m) and three different efforts (maximal rebound height, 50% effort of maximal rebound height and landing without rebound). Ankle and knee joint angles, and vertical ground reaction force together with an electromyogram of the lower leg muscles (medial gastrocnemius [MG], soleus [SOL] and tibialis anterior [TA]) were measured simultaneously during DJ. Our results clearly showed that the pre-activation of the antagonist TA was increased with increasing rebound height. Our results further showed that the coactivations of agonist and antagonist muscles during the post-impact 30-ms phase were increased with increasing rebound height. These results suggested that not only the pre-programmed agonist MG muscle activation, but also the pre-programmed antagonist TA activation and the coactivation of the post-impact 30-ms phase may play important roles in the control of rebound height. PMID:24050466

Arai, Aya; Ishikawa, Masaki; Ito, Akira



Effects of Melanocortin 1 Receptor Agonists in Experimental Nephropathies  

PubMed Central

Nephrotic syndrome, characterized by massive proteinuria, is caused by a large group of diseases including membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS). Although the underlying mechanisms are beginning to unravel, therapy is unspecific and far from efficient. It has been suggested that adrenocorticotropic hormone (ACTH) has beneficial effects in patients with MN and possibly in other nephrotic diseases. We have previously reported that ACTH may act directly on podocytes through the melanocortin 1 receptor (MC1R). In the present study, we evaluate the effect of highly specific MC1R agonists in two different nephrotic disease models. Experimental MN: Passive Heymann nephritis (PHN) was induced in rats that were treated for four weeks with MS05, a selective MC1R agonist, or saline. The degree of albuminuria was significantly reduced over time and the effect was sustained one week after treatment withdrawal (p<0.05). Experimental FSGS: Based on a dose-response study, two doses of adriamycin were used for induction of nephropathy in Balb/c mice. Mice were treated with either a synthetic MC1R agonist (BMS-470539), with ?-melanocyte stimulating hormone (?-MSH) or with saline. There was no beneficial effect of treatment. In summary, MC1R agonists reduce albuminuria and improve morphology in experimentally induced MN whereas they have no effect in experimental FSGS. The results illustrate the differences in these podocytopathies in terms of signaling mechanisms underlying proteinuria, and progression of disease. PMID:24498203

Elvin, Johannes; Johansson, Martin E.; Haraldsson, Borje; Nystrom, Jenny



The Agonistic Approach: Reframing Resistance in Qualitative Research  

ERIC Educational Resources Information Center

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…

Vitus, Kathrine



Characterization of aryl hydrocarbon receptor agonists in sediments of Wenyu River, Beijing, China  

Microsoft Academic Search

Aryl hydrocarbon receptor agonistic (Ah-agonistic) effects of 23 sediments from Wenyu River in Beijing, China were evaluated using the H4IIE cell bioassay. Five samples were selected for chemical analysis of most concerned Ah-agonists, i.e. polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs). All raw sediment extracts induced significant Ah-agonistic effects, and the bioassay-derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents

Jianping Luo; Mei Ma; Jinmiao Zha; Zijian Wang



Agonistic Displays and the Benefits of Fighting in the Field Cricket, Gryllus bimaculatus  

Microsoft Academic Search

Fighting is often composed of discrete agonistic displays. Few studies have partitioned fighting behavior into its component agonistic displays and evaluated the relationships between the frequency of the displays and the potential benefits of fighting, particularly mating success. In this study, we quantified the frequency of male field cricket, Gryllus bimaculatus, agonistic displays. The displays were quantified under three social

Gabrielle Tachon; Anne-Marie Murray; David A. Gray; William H. Cade



Synthesis and SAR of potent LXR agonists containing an indole pharmacophore  

SciTech Connect

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.

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.; (GSKNC); (GSKPA)



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

Microsoft Academic Search

Objectives: Three motivational profiles have been associated with recurring psychological stress in low-income youth and young adults: Striving to control others (agonistic striving), striving to control the self (transcendence striving), and not asserting control (dissipated striving). Agonistic striving has been associated with elevated ambulatory blood pressure during daily activities. Three studies tested the hypotheses that: (1) agonistic striving is associated

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



Dopamine agonists and risk: impulse control disorders in Parkinson's disease.  


Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals. PMID:21596771

Voon, Valerie; Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J; Hallett, Mark



Interactions between ?-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration  

PubMed Central

Cannabinoid receptor agonists enhance the antinociceptive effects of ?-opioid receptor agonists, which suggests that combinations of these drugs might enhance therapeutic effectiveness (e.g., analgesia). However, it is not clear whether combinations of these drugs also enhance abuse or dependence liability. This experiment examined whether combinations of cannabinoids and opioids that enhance antinociception also increase abuse-related effects by studying the effects of the cannabinoid receptor agonists 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212) on the antinociceptive, discriminative stimulus, and positive reinforcing effects of ?-opioid receptor agonists in rhesus monkeys. In one group of monkeys (n = 3), morphine (0.1–5.6 mg/kg s.c.), CP 55,940 (0.0032–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) dose-dependently increased tail withdrawal latency from 50°C water, and pretreatment with small, otherwise ineffective, doses of CP 55,940 and WIN 55,212 shifted the morphine dose-effect curve to the left. In monkeys (n = 3) discriminating 3.2 mg/kg morphine, CP 55,940 (0.01–0.032 mg/kg s.c.) and WIN 55,212 (0.1–1.78 mg/kg s.c.) attenuated the discriminative stimulus effects of morphine, shifting the dose-effect curve to the right. In monkeys (n = 4) self-administering heroin (0.32–32.0 µg/kg/infusion i.v.), CP 55,940 (0.001–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) shifted the heroin dose-effect curve rightward and downward. Cannabinoid receptor agonists CP 55,940 and WIN 55,212 enhanced the antinociceptive effects but not the discriminative stimulus or positive reinforcing effects of ?-opioid receptor agonists in rhesus monkeys, supporting the view that combining cannabinoid and opioid receptor agonists might result in enhanced treatment effectiveness for pain without similarly enhancing abuse and dependence liability. PMID:23536317

Maguire, David R.; Yang, Wenjuan



Pharmacological characterization of the cardiovascular responses elicited by kinin B1 and B2 receptor agonists in the spinal cord of streptozotocin-diabetic rats  

PubMed Central

Kinin receptor agonists and antagonists at the B1 and B2 receptors were injected intrathecally (i.t., at T-9 spinal cord level) to conscious unrestrained rats and their effects on mean arterial pressure (MAP) and heart rate (HR) were compared in streptozotocin (STZ)-diabetic rats (65?mg?kg?1 STZ, i.p. 3 weeks earlier) and aged-matched control rats. The B1 receptor agonist, des-Arg9-Bradykinin (BK) (3.2–32.5?nmol), evoked dose-dependent increases in MAP and tachycardia during the first 10?min post-injection in STZ-diabetic rats only. The cardiovascular response to 6.5?nmol des-Arg9-BK was reversibly blocked by the prior i.t. injection of antagonists for the B1 receptor ([des-Arg10]-Hoe 140, 650?pmol or [Leu8]-des-Arg9-BK, 65?nmol) and B2 receptor (Hoe 140, 81?pmol or FR173657, 81?pmol) or by indomethacin (5?mg?kg?1, i.a.). The i.t. injection of BK (8.1–810?pmol) induced dose-dependent increases in MAP which were accompanied either by tachycardiac (STZ-diabetic rats) or bradycardiac (control rats) responses. The pressor response to BK was significantly greater in STZ-diabetic rats. The cardiovascular response to 81?pmol BK was reversibly blocked by 81?pmol Hoe 140 or 81?pmol FR173657 but not by B1 receptor antagonists nor by indomethacin in STZ-diabetic rats. The data suggest that the activation of kinin B1 receptor in the spinal cord of STZ-diabetic rats leads to cardiovascular changes through a prostaglandin mediated mechanism. Thus, this study affords an accessible model for studying the expression, the pharmacology and physiopathology of the B1 receptor in the central nervous system. PMID:10807676

Cloutier, Frank; Couture, Rejean



PHARMA -Rglement des examens et des jurys 2013-2014 Rglement des examens -Pharma 2013  

E-print Network

PHARMA - Règlement des examens et des jurys 2013-2014 Règlement des examens - Pharma 2013 1 missions décrites dans ce règlement. #12;PHARMA - Règlement des examens et des jurys 2013-2014 Règlement des examens - Pharma 2013 2 UNIVERSITE LIBRE DE BRUXELLES DEPARTEMENT ENSEIGNEMENT SERVICE D

Cerf, Nicolas


Dopamine Agonists and the Suppression of Impulsive Motor Actions in Parkinson's Disease  

PubMed Central

The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-basal ganglia circuitry. Basal ganglia dysfunction caused by Parkinson’s 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 thirty-eight 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 to an off agonist state, patients on their agonist 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. PMID:22571461

Wylie, S.A.; Claassen, D.O.; Huizenga, H.M.; Schewel, K.D.; Ridderinkhof, K.R.; Bashore, T.R.; van den Wildenberg, W.P.M.



Des Programmes de recherche  

E-print Network

'aléa sismique. La cartographie du risque de tsunami obtenue - véritable photographie instantanée de l chercheurs expliquent certains modes de propagation du tsunami le long des côtes thaïlandaises. Ainsi, la'élaboration des plans d'urbanisation des zones côtières et le maintien ou la réimplan- tation des protections


Structure of an agonist-bound ionotropic glutamate receptor.  


Ionotropic glutamate receptors (iGluRs) mediate most excitatory neurotransmission in the central nervous system and function by opening their ion channel in response to binding of agonist glutamate. Here, we report a structure of a homotetrameric rat GluA2 receptor in complex with partial agonist (S)-5-nitrowillardiine. Comparison of this structure with the closed-state structure in complex with competitive antagonist ZK 200775 suggests conformational changes that occur during iGluR gating. Guided by the structures, we engineered disulfide cross-links to probe domain interactions that are important for iGluR gating events. The combination of structural information, kinetic modeling, and biochemical and electrophysiological experiments provides insight into the mechanism of iGluR gating. PMID:25103407

Yelshanskaya, Maria V; Li, Minfen; Sobolevsky, Alexander I



Imidazole-derived agonists for the neurotensin 1 receptor.  


A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 (1) and associated analogs, including its naphthyl analog (14) which exhibited similar properties. Compound 1 showed full agonist behavior (79-93%) with an EC50 of 2.0-4.1?M against NTR1. Compound 1 also showed good activity in a Ca mobilization FLIPR assay (93% efficacy at 298nM), consistent with it functioning via the Gq coupled pathway, and good selectivity relative to NTR2 and GPR35. In further profiling, 1 showed low potential for promiscuity and good overall pharmacological data. This report describes the discovery, synthesis, and SAR of 1 and associated analogs. Initial in vitro pharmacologic characterization is also presented. PMID:24332089

Hershberger, Paul M; Hedrick, Michael P; Peddibhotla, Satyamaheshwar; Mangravita-Novo, Arianna; Gosalia, Palak; Li, Yujie; Gray, Wilson; Vicchiarelli, Michael; Smith, Layton H; Chung, Thomas D Y; Thomas, James B; Caron, Marc G; Pinkerton, Anthony B; Barak, Lawrence S; Roth, Gregory P



?2-adrenoceptor agonists in the regulation of mitochondrial biogenesis  

PubMed Central

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 ?2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of ?2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB. PMID:23954364

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



Integrating costimulatory agonists to optimize immune-based cancer therapies  

PubMed Central

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

Pardee, Angela D; Wesa, Amy K



Theories of recovery for DES damage. Is tort liability the answer?  


An estimated 1000 individual or class action products liability lawsuits have been filed against the pharmaceutical manufacturers of diethylstilbestrol (DES). The field of potential plaintiffs is estimated at 500,000-6,000,000 and there are 150-300 potential defendant manufacturers. This article addresses the question of whether the current system of tort liability dispenses fair, timely, and uniform justice both to DES claimants and manufacturers and presents a historical perspective on the basis for liability. Traditional theories of tort recovery are based on negligence, breach of warranty, and strict liability. They place the burden of proof on the claimant to specifically identify the product manufacturer and establish proximate causation. Novel theories of recovery have had to be applied in DES lawsuits, including concert of action and alternative liability. Most of these theories have been unaccepted by trial and appellate courts because of the inability to identify the manufacturer. Even if DES manufacturers were to be held liable under a theory of industry-wide or market share liability, defendants would be called upon to allocate liability among themselves. Many believe that any departure from traditional tort principles should be accomplished by the legislature, not the judiciary. There is not currently a bill before the US Congress dealing specifically with compensation for damages to DES victims. Any model toxic tort legislation should aim to eliminate the benefit inequities as between claimants and the cost inequities in delivering benefits to qualified recipients by the responsible parties. The claimant's burden of establishing fault should be eliminated in exchange for a claimant's surrender of a right to sue a third party, and a standardization of compensatory damages. The requirements of specific product identification, duration of exposure, and degree of fault would be eliminated. Jurisdictional requirements and statues of limitation must be drafted to permit recovery for previously unknown injuries. Finally, there should be an overall goal of promptness in recovery. The most equitable solution to problems with the tort system is legislation which deals with the toxic tort problem as a whole and not just on a case-by-case basis. PMID:6604118

Downey, A H; Gulley, K G



Phenylacetic acid derivatives as hPPAR agonists.  


Beginning with the weakly active lead structure 1, a new series of hPPAR agonists was developed. In vivo glucose and triglyceride lowering activity was obtained by homologation and oxamination to 3, then conversion to substituted benzisoxazoles 4 and 5. Further manipulation afforded benzofurans 6 and 7. Compound 7 was of comparable potency as a glucose and triglyceride lowering agent in insulin resistant rodents to BRL 49653. PMID:12657263

Santini, Conrad; Berger, Gregory D; Han, Wei; Mosley, Ralph; MacNaul, Karen; Berger, Joel; Doebber, Thomas; Wu, Margaret; Moller, David E; Tolman, Richard L; Sahoo, Soumya P



Piperazinyl-oxadiazoles as selective sphingosine-1-phosphate receptor agonists.  


The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3mg/kg. PMID:25241927

Horan, Joshua C; Sanyal, Sulagna; Choi, Younggi; Hill-Drzewi, Melissa; Patnaude, Lori; Anderson, Shawn; Fogal, Steve; Mao, Can; Cook, Brian N; Gueneva-Boucheva, Kristina; Fisher, Michael B; Hickey, Eugene; Pack, Edward; Bannen, Lynne C; Chan, Diva S; Mac, Morrison B; Ng, Stephanie M; Wang, Yong; Xu, Wei; Modis, Louise K; Lemieux, René M



Adenosine: A Partial Agonist of the Growth Hormone Secretagogue Receptor  

Microsoft Academic Search

The growth hormone secretagogue receptor (GHS-R) is involved in the regulation of pulsatile GH release. However, until recently, natural endogenous ligands for the receptor were unknown. We fractionated porcine hypothalamic extracts and assayed fractions for activity on HEK293 cells expressing GHS-R and aequorin. A partial agonist was isolated and identified using microspray tandem mass spectrometry as adenosine. GHS-R activation by

Roy G. Smith; Patrick R. Griffin; Yuan Xu; Alexander G. A. Smith; Ken Liu; Jimmy Calacay; Scott D. Feighner; C.-S. Pong; Denis Leong; Anna Pomés; Kang Cheng; Andrew D. Howard; James Schaeffer; Reid J. Leonard



Excretion study of the ? 2-agonist reproterol in human urine  

Microsoft Academic Search

An excretion study of the ?2-agonist 7-[3-[(?-3,5-trihydroxyphenethyl)amino]-propyl]theophylline (reproterol) in human urine, which is reportedly misused by athletes and horses as a doping agent, is presented. The study was performed after an oral administration of 20 mg of reproterol hydrochloride. The collected urine samples were prepared using the standard anabolic steroid extraction procedure and analyzed by gas chromatography coupled with quadrupole

C. G Georgakopoulos; C Tsitsimpikou; M.-H. E Spyridaki



Antipruritic activity of the ?-opioid receptor agonist, TRK-820  

Microsoft Academic Search

The effects of the ?-opioid receptor agonist, TRK-820, (?)-17-(cyclopropylmethyl)-3, 14?-dihydroxy-4, 5?-epoxy-6?-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride, on the itch sensation were compared with those of histamine H1 receptor antagonists, using the mouse pruritogen-induced scratching model. Peroral administration of TRK-820 reduced the numbers of substance P- or histamine-induced scratches dose dependently. No obvious suppression of the spontaneous locomotor activity was observed at the

Yuko Togashi; Hideo Umeuchi; Kiyoshi Okano; Naoki Ando; Yoshitaka Yoshizawa; Toshiyuki Honda; Kuniaki Kawamura; Takashi Endoh; Jun Utsumi; Junzo Kamei; Toshiaki Tanaka; Hiroshi Nagase



Die Entwicklung des Universums  

E-print Network

/= =AbstandzwischenzweientferntenGalaxien Evolution des Universums (Einstein) Alter des Universums ~ 15 Milliarden Jahre Urknall Beobachtungen+ = Hintergrundstrahlung Rotverschiebung Alter ~ Jahre Chemie : 75% H, 25% He 10 1015 #12;T.Hebbeker Evolution des Universums (a la Einstein) == krit m 3 /3 mAtomeH - · Hubble-Konstante (kinetische Energie

Hebbeker, Thomas


TLR agonists: our best frenemy in cancer immunotherapy  

PubMed Central

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

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



Experience-based agonistic behavior in female crickets, Gryllus bimaculatus.  


Fighting behavior in male crickets is already well described, and some of the mechanisms underlying aggression and aggressive motivation have already been revealed. Much less is known about female/female interactions. Here, we report that adult female crickets that had been isolated for several days readily entered into agonistic interactions with conspecific individuals. Characteristic dyadic encounters between isolated females escalated in a stepwise manner and were concluded with the establishment of a dominant/subordinate relationship. For 15 to 30 minutes following an initial fight, former subordinate females showed a dramatic change in agonistic behavior. If they were paired with the former dominant opponent during this interval, a significant majority did not enter into any aggressive interaction but instead actively avoided the opponent. A similar experience-based and time-dependent increase in avoidance was observed when former subordinate females were paired with unfamiliar naïve opponents. However, when faced with an unfamiliar subordinate individual in the second encounter, no such increase in avoidance behavior was observed. We propose that the observed changes in the behavior of former subordinate females are the consequence of a change in the general state of arousal and of the recognition of dominance status, but not of individual recognition. The fact that former dominant individuals did not show similar experience-based changes in agonistic behavior suggests that dominant/subordinate relationships between pairs of female crickets are maintained mainly by the behavior of subordinate individuals. PMID:17043399

Delago, Antonia; Aonuma, Hitoshi



Covalent agonists for studying G protein-coupled receptor activation  

PubMed Central

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 ?2-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

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



Contact- and agonist-regulated microvesiculation of human platelets.  


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 ?IIb?3. 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. PMID:23784603

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



Science gone translational: the OX40 agonist story  

PubMed Central

Summary OX40 (CD134) is a tumor necrosis factor (TNF) receptor expressed primarily on activated CD4+ and CD8+ T cells and transmits a potent costimulatory signal when engaged. OX40 is transiently expressed after T-cell receptor engagement and is upregulated on the most recently antigen-activated T cells within inflammatory lesions (e.g. sites of autoimmune destruction and on tumor-infiltrating lymphocytes). Hence, it is an attractive target to modulate immune responses: OX40 blocking agents to inhibit undesirable inflammation or OX40 agonists to enhance immune responses. In regards to this review, OX40 agonists enhance anti-tumor immunity, which leads to therapeutic effects in mouse tumor models. A team of laboratory and clinical scientists at the Providence Cancer Center has collaborated to bring the preclinical observations in cancer models from the bench to the bedside. This review describes the journey from in vitro experiments through preclinical mouse models to the successful translation of the first OX40 agonist to the clinic for the treatment of patients with cancer. PMID:22017441

Weinberg, Andrew D.; Morris, Nicholas P.; Kovacsovics-Bankowski, Magdalena; Urba, Walter J.; Curti, Brendan D.



Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.  


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

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



Covalent agonists for studying G protein-coupled receptor activation.  


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 ?2-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

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



Benzocyclobutane, benzocycloheptane and heptene derivatives as melatonin agonists and antagonists.  


Two series of analogues were designed, synthesised and evaluated as potential human melatonin type?1 and?2 receptor (hMT1 and hMT2 ) ligands. Their biological effects were assessed by a well-established, specific model of melatonin action, the pigment response of Xenopus laevis melanophores. Compounds containing a benzocyclobutane scaffold and a methoxy group in the "melatonin" orientation were found to be potent agonists, with one of the analogues exhibiting activity comparable to melatonin. In contrast, analogues with a methoxy group in non-melatonin positions or with multiple methoxy groups showed either weaker agonist activity or were antagonists. Benzocycloheptene derivatives with one methoxy group are found to be weak agonists, whereas those with two methoxy groups were found to be antagonists, as were all of the benzocycloheptane derivatives evaluated. The most active compounds were assessed in a human receptor radio ligand binding assay but showed little discrimination between MT1 and MT2 . These results again show that the indole nitrogen of melatonin is not a necessary component for analogue activity and also illustrate that replacement of the indole ring with a 4-membered carbocycle can provide highly active compounds when the methoxy group is in the melatonin position. PMID:25044938

Tsotinis, Andrew; Afroudakis, Pandelis A; Garratt, Peter J; Bocianowska-Zbrog, Alina; Sugden, David



Agonist-induced calcium entry correlates with STIM1 translocation  

PubMed Central

The mechanisms of agonist-induced calcium entry (ACE) following depletion of intracellular calcium stores have not been fully established. We report here that calcium-independent phospholipase A (iPLA2) is required for robust Ca2+ entry in HaCaT keratinocytes following ATP or UTP stimulation. Lysophosphatidic acid (LPA), an unrelated agonist, evoked Ca2+ release without inducing robust Ca2+ entry. Both LPA and UTP induced the redistribution of STIM1 into puncta which localized to regions near or at the plasma membrane, as well as within the cytoplasm. Plasma membrane-associated STIM1 remained high for up to 10 min after UTP stimulation, whereas it had returned almost to baseline by that time point in LPA-stimulated cells. This correlated with faster reloading of the endoplasmic reticulum Ca2+ stores in LPA treated cells. Thus by differentially regulating store-refilling after agonist-mediated depletion, LPA and UTP may exert distinct effects on the duration of STIM1 localization at the plasma membrane, and thus, on the magnitude and duration of ACE. PMID:17299780

Ross, Kehinde; Whitaker, Michael; Reynolds, Nick J



Opposite effects of agonist and inverse agonist ligands of benzodiazepine receptor on self-defensive and submissive postures in the rat  

Microsoft Academic Search

The effects of benzodiazepine receptor ligands on different types of defensive behaviours were examined in intruder male rats confronted with offensive residents. Chronic administration, via a subcutaneous silastic pellet, of a full agonist (diazepam) for 15 days increased self-defensive postures as well as social and non-social behaviour whereas submissive postures and flight were reduced. Acute administration of a partial agonist

Bertrand Piret; Antoine Depaulis; Marguerite Vergnes



Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)? agonist fenofibrate and the PPAR? agonist pioglitazone  

PubMed Central

Background All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPAR? 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 PPAR? agonist fenofibrate (FENO) and the PPAR? 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 PPAR? and ? 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 PPAR? activation. PMID:19331671

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



Enhancement of D2 receptor agonist-induced inhibition by D1 receptor agonist in the ventral tegmental area.  

PubMed Central

1. A microiontophoretic study was performed on chloral hydrate-anaesthetized rats to examine the role of D1 receptors in the ventral tegmental area (VTA) neurones, which are inhibited by autoreceptor and D2 receptor agonists. 2. Inhibition by microiontophoretic application of quinpirole (a D2 agonist) of antidromic spikes elicited by stimulation of the nucleus accumbens in dopaminergic neurones of the VTA, was significantly enhanced by simultaneous application of SKF 38393 (D1 agonist), although SKF 38393 alone had little effect on the neurones. 3. In addition, quinpirole-induced inhibition was antagonized by iontophoretic application of domperidone (D2 antagonist), but was not affected by SCH 23390 (D1 antagonist). 4. Furthermore, SKF 38393-induced enhancement of inhibition by quinpirole was antagonized by simultaneous application of SCH 23390. 5. These results suggest that activation of D1 receptors located on the VTA dopaminergic neurones or on non-dopaminergic nerve terminals is not essential for inducing inhibition of the dopaminergic neurones, but enhances D2 receptor-mediated inhibition directly or indirectly via inhibitory neurones. Images Figure 1 PMID:7902179

Momiyama, T.; Sasa, M.; Takaori, S.



Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110)  

PubMed Central

BACKGROUND AND PURPOSE Many cells express proteinase activated receptor 2 (PAR2) on their plasma membrane. PAR2 is activated by proteolytic enzymes, such as trypsin and tryptase that cleave the receptor N-terminus, inititating signalling to intracellular G proteins. Studies on PAR2 have relied heavily upon activating effects of proteases and peptide agonists that lack stability and bioavailability in vivo. EXPERIMENTAL APPROACH A novel small molecule agonist GB110 and an antagonist GB88 were characterized in vitro against trypsin, peptide agonists, PAR2 antibody, PAR1 agonists and flow cytometry,in seven cell lines using intracellular Ca2+ mobilization and examined in vivo against PAR2- and PAR1-induced rat paw oedema. KEY RESULTS GB110 is a potent non-peptidic agonist activating PAR2-mediated Ca2+ release in HT29 cells (EC50?200 nM) and six other human cell lines, inducing PAR2 internalization. GB88 is a unique PAR2 antagonist, inhibiting PAR2 activated Ca2+ release (IC50?2 µM) induced by native (trypsin) or synthetic peptide and non-peptide agonists. GB88 was a competitive and surmountable antagonist of agonist 2f-LIGRLO-NH2, a competitive but insurmountable antagonist of agonist GB110, and a non-competitive insurmountable antagonist of trypsin. GB88 was orally active and anti-inflammatory in vivo, inhibiting acute rat paw oedema elicited by agonist GB110 and proteolytic or peptide agonists of PAR2 but not by corresponding agonists of PAR1 or PAR4. CONCLUSIONS AND IMPLICATIONS The novel PAR2 agonist and antagonist modulate intracellular Ca2+ and rat paw oedema, providing novel molecular tools for examining PAR2-mediated diseases. PMID:21806599

Suen, JY; Barry, GD; Lohman, RJ; Halili, MA; Cotterell, AJ; Le, GT; Fairlie, DP



Gonadotropin-releasing hormone agonist influences absolute levels of lymphocyte subsets in vivo in male mice  

Microsoft Academic Search

Our earlier studies have demonstrated that gonadotropin-releasing hormone (GnRH) agonists suppress immune system function in female mice. No systematic studies regarding the effect of gender on immune system function following GnRH agonist treatment, however, have been reported. This study, therefore, investigated sequential changes in lymphocyte subsets in 3- and 10-week-old male mice following agonist or placebo administration. Changes in immunophenotypic

LV Rao; RP Cleveland; RJ Kimmel; KM Ataya



Synthesis and biological evaluation of novel 2,4-disubstituted quinazoline analogues as GPR119 agonists.  


GPR119 agonist has emerged as a promising target for the treatment of type 2 diabetes. A series of novel 2,4-disubstituted quinazoline analogues was prepared and evaluated their agonistic activity against human GPR119. The analogues bearing azabicyclic amine substituents (12a, 12c and 12g) exhibited better EC(50) values than that of OEA though they appeared to be partial agonists. PMID:23357035

Pham, Tuan-Anh N; Yang, Zunhua; Fang, Yuanying; Luo, Jun; Lee, Jongkook; Park, Haeil



Heritable victimization and the benefits of agonistic relationships  

PubMed Central

Here, we present estimates of heritability and selection on network traits in a single population, allowing us to address the evolutionary potential of social behavior and the poorly understood link between sociality and fitness. To evolve, sociality must have some heritable basis, yet the heritability of social relationships is largely unknown. Recent advances in both social network analyses and quantitative genetics allow us to quantify attributes of social relationships and estimate their heritability in free-living populations. Our analyses addressed a variety of measures (in-degree, out-degree, attractiveness, expansiveness, embeddedness, and betweenness), and we hypothesized that traits reflecting relationships controlled by an individual (i.e., those that the individual initiated or were directly involved in) would be more heritable than those based largely on the behavior of conspecifics. Identifying patterns of heritability and selection among related traits may provide insight into which types of relationships are important in animal societies. As expected, we found that variation in indirect measures was largely explained by nongenetic variation. Yet, surprisingly, traits capturing initiated interactions do not possess significant additive genetic variation, whereas measures of received interactions are heritable. Measures describing initiated aggression and position in an agonistic network are under selection (0.3 < |S| < 0.4), although advantageous trait values are not inherited by offspring. It appears that agonistic relationships positively influence fitness and seemingly costly or harmful ties may, in fact, be beneficial. Our study highlights the importance of studying agonistic as well as affiliative relationships to understand fully the connections between sociality and fitness. PMID:21115836

Lea, Amanda J.; Blumstein, Daniel T.; Wey, Tina W.; Martin, Julien G. A.



Heritable victimization and the benefits of agonistic relationships.  


Here, we present estimates of heritability and selection on network traits in a single population, allowing us to address the evolutionary potential of social behavior and the poorly understood link between sociality and fitness. To evolve, sociality must have some heritable basis, yet the heritability of social relationships is largely unknown. Recent advances in both social network analyses and quantitative genetics allow us to quantify attributes of social relationships and estimate their heritability in free-living populations. Our analyses addressed a variety of measures (in-degree, out-degree, attractiveness, expansiveness, embeddedness, and betweenness), and we hypothesized that traits reflecting relationships controlled by an individual (i.e., those that the individual initiated or were directly involved in) would be more heritable than those based largely on the behavior of conspecifics. Identifying patterns of heritability and selection among related traits may provide insight into which types of relationships are important in animal societies. As expected, we found that variation in indirect measures was largely explained by nongenetic variation. Yet, surprisingly, traits capturing initiated interactions do not possess significant additive genetic variation, whereas measures of received interactions are heritable. Measures describing initiated aggression and position in an agonistic network are under selection (0.3 < |S| < 0.4), although advantageous trait values are not inherited by offspring. It appears that agonistic relationships positively influence fitness and seemingly costly or harmful ties may, in fact, be beneficial. Our study highlights the importance of studying agonistic as well as affiliative relationships to understand fully the connections between sociality and fitness. PMID:21115836

Lea, Amanda J; Blumstein, Daniel T; Wey, Tina W; Martin, Julien G A



Discovery of a highly potent series of TLR7 agonists.  


The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed. PMID:21885277

Jones, Peter; Pryde, David C; Tran, Thien-Duc; Adam, Fiona M; Bish, Gerwyn; Calo, Frederick; Ciaramella, Guiseppe; Dixon, Rachel; Duckworth, Jonathan; Fox, David N A; Hay, Duncan A; Hitchin, James; Horscroft, Nigel; Howard, Martin; Laxton, Carl; Parkinson, Tanya; Parsons, Gemma; Proctor, Katie; Smith, Mya C; Smith, Nicholas; Thomas, Amy



Peripheral biomarkers of cognitive response to dopamine receptor agonist treatment  

Microsoft Academic Search

Rationale  Using biological markers to objectively measure addiction severity or to identify individuals who might benefit most from\\u000a pro-cognitive treatment could potentially revolutionize neuropsychopharmacology. We investigated the use of dopamine receptor\\u000a mRNA levels in circulating blood cells as predictors of cognitive response following dopamine agonist treatment, and as biomarkers\\u000a of the severity of stimulant drug dependence.\\u000a \\u000a \\u000a \\u000a \\u000a Methodology  We employed a double-blind, placebo-controlled

Karen D. Ersche; Jonathan P. Roiser; Mark Lucas; Enrico Domenici; Trevor W. Robbins; Edward T. Bullmore



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

NASA Technical Reports Server (NTRS)

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.

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



Kappa opioid agonists inhibit transmitter release from guinea pig hippocampal mossy fiber synaptosomes  

Microsoft Academic Search

Opioid agonists specific for the µ, d, and ? opioid receptor subtypes were tested for their ability to modulate potassium-evoked release of L-glutamate and dynorphin B-like immunoreactivity from guinea pig hippocampal mossy fiber synaptosomes. The ? opioid agonists U-62,066E and (-) ethylketocyclazocine, but not the µ agonist [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAGO) nor the d agonist [D-Pen2,5]enkephalin (DPDE), inhibited the potassium-evoked release of

Robert L. Gannon; David M. Terrian



Two distinct classes of novel pyrazolinecarboxamides as potent cannabinoid CB1 receptor agonists.  


The synthesis and SAR of 3-alkyl-4-aryl-4,5-dihydropyrazole-1-carboxamides 1-23 and 1-alkyl-5-aryl-4,5-dihydropyrazole-3-carboxamides 24-27 as two novel cannabinoid CB(1) receptor agonist classes were described. The target compounds elicited high affinities to the CB(1) as well as the CB(2) receptor and were found to act as CB(1) receptor agonists. The key compound 19 elicited potent CB(1) agonistic and CB(2) inverse agonistic properties in vitro and showed in vivo activity in a rodent model for multiple sclerosis after oral administration. PMID:20688519

Lange, Jos H M; Attali, Amos; van der Neut, Martina A W; Wals, Henri C; Mulder, Arie; Zilaout, Hicham; Duursma, Ate; van Aken, Hans H M; van Vliet, Bernard J



Potential anxiogenic effects of cannabinoid CB1 receptor antagonists\\/inverse agonists in rats: Comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG7142  

Microsoft Academic Search

Cannabinoid CB1 inverse agonists suppress food-motivated behaviors, but may also induce psychiatric effects such as depression and anxiety. To evaluate behaviors potentially related to anxiety, the present experiments assessed the CB1 inverse agonist AM251 (2.0–8.0mg\\/kg), the CB1 antagonist AM4113 (3.0–12.0mg\\/kg), and the benzodiazepine inverse agonist FG-7142 (10.0–20.0mg\\/kg), using the open field test and the elevated plus maze. Although all three

K. S. Sink; K. N. Segovia; J. Sink; P. A. Randall; L. E. Collins; M. Correa; E. J. Markus; V. K. Vemuri; A. Makriyannis; J. D. Salamone




E-print Network


Menichi, Luc


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

SciTech Connect

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).

Buck, K.J.; Harris, R.A. (Univ. of Colorado Health Sciences Center, Denver (USA))



Galaxy clusters in DES  

NASA Astrophysics Data System (ADS)

Galaxy clusters are one of the four key cosmic acceleration probes used by the Dark Energy Survey (DES) to measure cosmological parameters with unprecedented precision. DES has recently completed commissioning of its instrument and accomplished a successful science verification data taking phase. The survey proper started in Aug 31, 2013. In this talk, I review the motivation for using clusters of galaxies in cosmology, discuss the DES expected performance and present the prospects to improve our understanding of dark energy by constraining cosmological models using galaxy clusters found by the Voronoi Tesselation galaxy cluster finding algorithm. We show results of our galaxy cluster analysis based on the early DES data sets.

Soares-Santos, Marcelle; DES Collaboration



Identification of the pregnancy hormone relaxin as glucocorticoid receptor agonist.  


The insulin-like peptide relaxin is a central hormone of pregnancy, but it also produces anti-fibrotic, myocardial, renal, central-nervous, and vascular effects. Recently, two G protein-coupled receptors, LGR7 and LGR8, have been identified as relaxin receptors. Prompted by reports on immunoregulatory effects of relaxin, we investigated possible interactions with the human glucocorticoid receptor (GR). Relaxin blunted the endotoxin-induced production of inflammatory cytokines (IL-1, IL-6, TNF-alpha) by human macrophages--an effect that was suppressed by the GR antagonist RU-486. In three different cell lines, relaxin induced GR activation, nuclear translocation, and DNA binding as assessed in GRE-luciferase assays. Co-immunoprecipitation experiments revealed physical interaction of endogenous and exogenous relaxin with cytoplasmic and nuclear GR. Relaxin competed with GR agonists for GR binding, both in vivo in whole-cell assays, and in vitro in fluorescence polarization assays. Relaxin was shown to up-regulate GR protein expression as well as the number of functionally active GR sites. In LGR7/8-free cells, the relaxin-mediated activation of GR was preserved. In conclusion, relaxin acts as GR agonist--a pathway pivotal to its effects on cytokine secretion by human macrophages. These findings may deepen our understanding of relaxin's abundant physiological actions, as well as our insights into general principles of hormone signaling. PMID:15289446

Dschietzig, Thomas; Bartsch, Cornelia; Stangl, Verena; Baumann, Gert; Stangl, Karl



Agonistic induction of PPAR? reverses cigarette smoke-induced emphysema.  


The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator-activated receptor ? (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPAR? in APCs using Cd11c-Cre Pparg(flox/flox) mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg(flox/flox) mice required OPN, suggesting an antiinflammatory mechanism in which PPAR? negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPAR? agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPAR? agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPAR? activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema. PMID:24569375

Shan, Ming; You, Ran; Yuan, Xiaoyi; Frazier, Michael V; Porter, Paul; Seryshev, Alexander; Hong, Jeong-Soo; Song, Li-zhen; Zhang, Yiqun; Hilsenbeck, Susan; Whitehead, Lawrence; Zarinkamar, Nazanin; Perusich, Sarah; Corry, David B; Kheradmand, Farrah



Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.  


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

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



Isothiouronium compounds as gamma-aminobutyric acid agonists.  

PubMed Central

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

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



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


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. PMID:24158775

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



Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists  

PubMed Central

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

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



Inhibition of lymphoma vascularization and dissemination by estrogen receptor ? agonists.  


Most lymphomas show an increased incidence and poorer prognosis in males vs females, suggesting endocrine regulation. We have previously shown that tumor growth in vivo of a murine T-cell-derived lymphoma is repressed following activation of estrogen receptor ? (ER?, ESR2). By using ER?-deficient mice, we now demonstrate that this inhibition is mediated via a direct effect on the tumor cells and not on the microenvironment. Furthermore, we show that the growth-suppressing effects of ER? agonist are also valid for human B-cell lymphomas as demonstrated in tumors derived from Granta-519 mantle cell lymphoma (MCL) and Raji Burkitt lymphoma (BL) cells. In Granta-519 MCL tumors, activation of ER? reduced expression of BAFF and GRB7, 2 important molecules involved in B-cell proliferation and survival. Importantly, activation of ER? inhibited angiogenesis and lymphangiogenesis, possibly mediated by impaired vascular endothelial growth factor C expression. Furthermore, using disseminating Raji BL cells, we show that ER? activation reduces dissemination of grafted Raji BL tumors. We also show by immunohistochemistry that ER? is expressed in primary MCL tissue. These results suggest that targeting ER? with agonists may be valuable in the treatment of some lymphomas, affecting several aspects of the malignant process, including proliferation, vascularization, and dissemination. PMID:24470591

Yakimchuk, Konstantin; Hasni, Mohammad Sharif; Guan, Jiyu; Chao, Mark P; Sander, Birgitta; Okret, Sam



Agonistic induction of PPAR? reverses cigarette smoke-induced emphysema  

PubMed Central

The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator–activated receptor ? (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPAR? in APCs using Cd11c-Cre Ppargflox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Ppargflox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPAR? negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPAR? agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPAR? agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPAR? activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema. PMID:24569375

Shan, Ming; You, Ran; Yuan, Xiaoyi; Frazier, Michael V.; Porter, Paul; Seryshev, Alexander; Hong, Jeong-Soo; Song, Li-zhen; Zhang, Yiqun; Hilsenbeck, Susan; Whitehead, Lawrence; Zarinkamar, Nazanin; Perusich, Sarah; Corry, David B.; Kheradmand, Farrah



March 2012 Timeline

DES Timeline Year Event 1938 Diethylstilbestrol (DES) was produced for use in pregnancy. 1940 DES was widely prescribed to women for use in threatened miscarriages and was promoted to physicians through medical publications and other communications.


Design and Evaluation of a Biomimetic Agonist-Antagonist Active Knee Prosthesis  

E-print Network

Design and Evaluation of a Biomimetic Agonist-Antagonist Active Knee Prosthesis by ARCHIVES Ernesto;Design and Evaluation of a Biomimetic Agonist-Antagonist Active Knee Prosthesis by Ernesto Carlos. This thesis presents the design and evaluation of a novel biomimetic active knee prosthesis capable

Herr, Hugh


Information content of male agonistic displays in the territorial tawny dragon ( Ctenophorus decresii )  

Microsoft Academic Search

Two potential signals used during male–male agonistic encounters were examined for signal content in the territorial agamid lizard Ctenophorus decresii, or tawny dragon. Males have black chest patches, which are apparent when they posture during agonistic encounters. Patches are not condition or size dependent. The area of the patches is positively associated with levels of aggression and likelihood of winning

Louise Osborne



Dominance relations and agonistic behaviour of Tundra Swans ( Cygnus columbianus columbianus ) during fall and spring migration  

Microsoft Academic Search

Social interactions and agonistic activities of Tundra Swans (Cygnus columbianus columbianus ) were docu- mented at Long Point, Ontario, to determine (i) dominance relations among social groups and (ii) the frequency and in- tensity of agonistic acts by swans. Families were involved in one-third as many interactions as were nonfamily groups. Nonfamily groups initiated interactions with other nonfamily groups more

Shannon S. Badzinski



GABA B receptor agonists for the treatment of drug addiction: a review of recent findings  

Microsoft Academic Search

A growing preclinical and clinical literature suggests that GABAB receptor agonists promote abstinence and reduce the use of cocaine, heroin, alcohol and nicotine. The purpose of this paper is to critically review these data. GABAB receptor agonists, such as baclofen, appear to reduce the reinforcing effects of abused drugs in animal models under multiple experimental procedures. This occurs at doses

Michael S. Cousins; David C. S. Roberts; Harriet de Wit



Design driven HtL: The discovery and synthesis of new high efficacy ? 2-agonists  

Microsoft Academic Search

The design and synthesis of a new series of high efficacy ?2-agonists devoid of the key benzylic alcohol present in previously described highly efficacious ?2-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of ?2-adrenoceptor crystal structure, other biophysical data and modeling studies.

Michael J. Stocks; Lilian Alcaraz; Andrew Bailey; Roger Bonnert; Elaine Cadogan; Jadeen Christie; Stephen Connolly; Anthony Cook; Adrian Fisher; Alice Flaherty; Stephen Hill; Alexander Humphries; Anthony Ingall; Stephen Jordan; Mandy Lawson; Alex Mullen; David Nicholls; Stuart Paine; Garry Pairaudeau; Stephen St-Gallay; Alan Young



Gonadotropin-releasing hormone agonist influences absolute levels of lymphocyte subsets in vivo in male mice.  


Our earlier studies have demonstrated that gonadotropin-releasing hormone (GnRH) agonists suppress immune system function in female mice. No systematic studies regarding the effect of gender on immune system function following GnRH agonist treatment, however, have been reported. This study, therefore, investigated sequential changes in lymphocyte subsets in 3- and 10-week-old male mice following agonist or placebo administration. Changes in immunophenotypic expression of lymphocytes from thymus, bone marrow, spleen, and blood were analysed at periodic intervals. Upon agonist administration, plasma testosterone levels were significantly increased in pre-pubertal mice, but were significantly decreased in post-pubertal males. Absolute thymic weights, thymocytes and T subsets were significantly increased from the third week regardless of gonadal status. Blood lymphocyte subsets showed a decreasing trend after agonist administration in pre-pubertal males, whereas no differences were observed in post-pubertal males. No significant differences were observed in spleen cells after agonist administration. These studies, together with earlier observations in female mice indicate that GnRH agonist effects on the immune system, are independent of steroid hormone levels. In contrast to suppressive effects in females, GnRH agonist induce no change or ultimately enhanced lymphocyte counts in males, indicating differential effects on the immune system between males and females. This may have important implications for the treatment of various diseases. PMID:8724000

Rao, L V; Cleveland, R P; Kimmel, R J; Ataya, K M



Discovery of tertiary aminoacids as dual PPARalpha/gamma agonists-I.  


A novel series of potent dual agonists of PPARalpha and PPARgamma, the alkoxybenzylglycines, was identified and explored using a solution-phase library approach. The synthesis and structure-activity relationships of this series of dual PPARalpha/gamma agonists are described. PMID:17292606

Devasthale, Pratik V; Chen, Sean; Jeon, Yoon; Qu, Fucheng; Ryono, Denis E; Wang, Wei; Zhang, Hao; Cheng, Lin; Farrelly, Dennis; Golla, Rajasree; Grover, Gary; Ma, Zhengping; Moore, Lisa; Seethala, Ramakrishna; Sun, Wei; Doweyko, Arthur M; Chandrasena, Gamini; Sleph, Paul; Hariharan, Narayanan; Cheng, Peter T W



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

PubMed Central

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-?1 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

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



Predicted 3D structure for the human 2 adrenergic receptor and its binding site for agonists  

E-print Network

and antagonists Peter L. Freddolino, M. Yashar S. Kalani, Nagarajan Vaidehi, Wely B. Floriano, Spencer E. Hall of the other eight subtypes of ARs, which should enable the development of subtype-specific antagonists by agonist therapy in the treatment of asthma. Unfortunately, 2 agonists also exhibit crossreactivity

Goddard III, William A.


Antiparkinsonian dopamine agonists: a review of the pharmacokinetics and neuropharmacology in animals and humans  

Microsoft Academic Search

Summary  With the intention of compensating for the deficit of endogenous dopamine (DA) in the basal ganglia of Parkinsonian patients by substitution with agents which directly stimulate central DA receptors, synthetic DA agonists have been introduced almost 20 years ago for the symptomatic treatment of Parkinson's disease. The original expectation that DA agonists would be able to completely restore extrapyramidal motor

H. Wachtel



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

E-print Network

Functional selectivity of dopamine D1 receptor agonists in regulating the fate of internalized dissimilar agonists with efficacies at these endpoints that equal or exceed those of dopamine would differ internalization in response to these two compounds with that of dopamine. We found that dopamine caused

Goddard III, William A.



E-print Network

in the year preceding the takeover. Key Words: Earnings management; Mergers and Acquisitions; InternationalLA GESTION DES RESULTATS COMPTABLES LORS DES FUSIONS ET ACQUISITIONS: UNE ANALYSE DANS LE CONTEXTE des résultats comptables lors des fusions et acquisitions: Une analyse dans le contexte Suisse Résumé

Paris-Sud XI, Université de



E-print Network

MIGRATION DES JOINTS DE GRAINS LA MIGRATION DES JOINTS INTERGRANULAIRES O. DIMITROV Centre d nombre de faits fondamentaux concernant la migration des joints de grains sont brièvement rappelés considérant les forces qui provoquent ou qui freinent la migration. L'évolution des modèles proposés pour

Boyer, Edmond


Elimination des noeuds dans le probleme newtonien des quatre corps  

Microsoft Academic Search

Résumé Nous appliquons la méthode des transformations canoniques à variables imposées à la réduction du problème newtonien des quatre corps. L'élimination du centre de gravité étant supposée faite, le problème est ramené à celui des trois corps fictifs. Alors nous menons à bien la réduction dûe aux intégrales des aires explicitement sous forme Hamiltonienne en tenant compte de l'aspect géométrique

Françoise Boigey; M. Curie



Facult des arts et des sciences Dpartement de communication  

E-print Network

Faculté des arts et des sciences Département de communication Plans de cours cadre Cours des programmes de premier cycle en sciences de la communication Comité des études de premier cycle Adopté par l..................................................................................................................................3 COM 1150 Rédaction en communication 1

Parrott, Lael


4?-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial Agonist Derived from a 4?-Methyl-5-(3-hydroxyphenyl)morphan Pure Antagonist  

PubMed Central

In previous studies we reported that addition of 7?-acylamino groups to N-phenylpropyl-4?-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7?-amino (5a), 7?-alkylamino (5b–e), or 7?-dialkylamino (5f–h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7?-amino and 7?-methylamino analogues were full agonists at the ? and ? receptors and antagonists at the ? receptor. The 7?-cyclopropylmethylamino analogue 5h was a full agonist at the ? receptor with weaker agonist activity at the ? and ? receptors. Whereas the addition of a 7?-acylamino group to the pure non-selective opioid receptor antagonist N-phenylpropyl-4?-methyl-5-(3-hydroxyphenyl)morphan (4) led to ? selective pure opioid receptor antagonist, the addition of a 7?-amino, 7?-alkylamino or 7?-dialkylamino group to 4 leads to opioid ligands that are largely ? or ? agonist with mixed agonist/antagonist properties. PMID:24144404

Carroll, F. Ivy; Gichinga, Moses G.; Williams, John D.; Vardy, Eyal; Roth, Bryan L.; Mascarella, S. Wayne; Thomas, James B.; Navarro, Hernán A.



Vincent Manet Mthode des  

E-print Network

Vincent Manet Méthode des éléments finis Vulgarisation des aspects mathématiques et illustration de la méthode Version 3 du 20 août 2013 cel-00763690,version3-22Aug2013 #12;Vincent Manet -- 2013 (Ceci


PPAR-Alpha Agonists as Novel Antiepileptic Drugs: Preclinical Findings  

PubMed Central

Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in ?4 or ?2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-? (PPAR?), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing ?2 subunits. On these bases, we tested whether PPAR? agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ?100% of mice. A single dose of the synthetic PPAR? agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPAR? antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPAR? agonists abolished nicotine-induced sIPSC increases. PPAR? within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role. PMID:23724059

Melis, Miriam; Lecca, Salvatore; Marrosu, Francesco; De Montis, Maria Graziella; Scheggi, Simona; Carta, Gianfranca; Murru, Elisabetta; Aroni, Sonia; Muntoni, Anna Lisa; Pistis, Marco



Discriminative stimulus properties of indorenate, a serotonin agonist.  

PubMed Central

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 the session, but not when administered 105 minutes before the session (i.e., 15 minutes before the administration of indorenate). CONCLUSION: (5-HT)IA receptors are of relevance to the stimulus function of indorenate. However, other receptor subtypes may also be involved. Hence, other agonists and specific antagonists should be studied before definite conclusions are drawn. PMID:10212554

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



Postsynaptic dopamine (DA) receptor stimulator properties of the putative DA autoreceptor-selective agonist BHT 920 uncovered by co-treatment with the D-1 agonist SK&F 38393  

Microsoft Academic Search

Postsynaptic dopaminergic behavioural effects of D-2 agonists can be promoted by concomitant D-1 receptor activation. The present experiment explored whether such effects could be elicited by the putative autoreceptor-selective D-2 agonist B-HT 920, when combined with the D-1 agonist SK&F 38393. Except for occasional jerks induced by B-HT 920, neither agonist caused significant dopaminergic stimulation when given separately, whereas combined

S. Hjorth; A. Carlsson



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

PubMed Central

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

Pitari, Giovanni M



Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats  

PubMed Central

BACKGROUND AND PURPOSE Imidazoline I2 receptors have been implicated in several CNS disorders. Although several I2 receptor agonists have been described, no simple and sensitive in vivo bioassay is available for studying I2 receptor ligands. This study examined I2 receptor agonist-induced hypothermia as a functional in vivo assay of I2 receptor agonism. EXPERIMENTAL APPROACH Different groups of rats were used to examine the effects of I2 receptor agonists on the rectal temperature and locomotion. The pharmacological mechanisms were investigated by combining I2 receptor ligands and different antagonists. KEY RESULTS All the selective I2 receptor agonists examined (2-BFI, diphenyzoline, phenyzoline, CR4056, tracizoline, BU224 and S22687, 3.2–56 mg·kg–1, i.p.) dose-dependently and markedly decreased the rectal temperature (hypothermia) in rats, with varied duration of action. Pharmacological mechanism of the observed hypothermia was studied by combining the I2 receptor agonists (2-BFI, BU224, tracizoline and diphenyzoline) with imidazoline I2 receptor/ ?2 adrenoceptor antagonist idazoxan, selective I1 receptor antagonist efaroxan, ?2 adrenoceptor antagonist/5-HT1A receptor agonist yohimbine. Idazoxan but not yohimbine or efaroxan attenuated the hypothermic effects of 2-BFI, BU224, tracizoline and diphenyzoline, supporting the I2 receptor mechanism. In contrast, both idazoxan and yohimbine attenuated hypothermia induced by the ?2 adrenoceptor agonist clonidine. Among all the I2 receptor agonists studied, only S22687 markedly increased the locomotor activity in rats. CONCLUSIONS AND IMPLICATIONS Imidazoline I2 receptor agonists can produce hypothermic effects, which are primarily mediated by I2 receptors. These data suggest that I2 receptor agonist-induced hypothermia is a simple and sensitive in vivo assay for studying I2 receptor ligands. PMID:22324428

Thorn, David A; An, Xiao-Fei; Zhang, Yanan; Pigini, Maria; Li, Jun-Xu



Therapeutic potential of adenosine receptor antagonists and agonists.  


The adenosine receptors (A(1), A(2A), A(2B) and A(3)) are important and ubiquitous mediators of cellular signalling, which play vital roles in protecting tissues and organs from damage. Launched drugs include the adenosine receptor antagonists theophylline and doxofylline (both used as bronchodilators in respiratory disorders such as asthma), while several compounds are presently in clinical trials for a range of indications, including heart failure, Parkinson's disease, rheumatoid arthritis, cancer, pain and chronic obstructive pulmonary disease. A host of companies and institutions are addressing the huge potential for the development of selective adenosine receptor agonists and antagonists, so that it appears we are on the verge of a new wave of compounds approaching the market for many unmet medical needs. This review presents an analysis of the patenting activity in the area for 2006 and an interpretation and reflection on the developments that we can expect in the future. PMID:20144084

Press, Neil J; Gessi, Stefania; Borea, Pier A; Polosa, Riccardo



TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis  

PubMed Central

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

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



Choosing the right dopamine agonist for patients with Parkinson's disease.  


Dopamine receptor agonists (DA) are assuming an increasing importance in the treatment of both early and advanced symptoms of Parkinson's disease (PD). However, choosing the right DA for patients with PD unfortunately remains more a pragmatic medical art than a science. The aim of this review is to provide a realistic point of view on the strengths and weaknesses of five DAs: bromocriptine, ropinirole, pergolide, pramipexole and piribedil. This has been done by analysing their respective: (1) flexibility in PD, i.e. in monotherapy, in early and in late combination with levodopa; (2) safety profile and (3) titration schedule. These five DAs are not evenly matched regarding these three criteria. The differences observed highlight the therapeutic value of piribedil, which has a flexible indication, adapted to all stages of PD, a safer profile and the most simple initiation schedule. PMID:12201621

Lebrun-Frenay, C; Borg, M



Revealing a steroid receptor ligand as a unique PPAR? agonist  

PubMed Central

Peroxisome proliferator-activated receptor gamma (PPAR?) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR? agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR? target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR? ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR? ligands in the treatment of insulin resistance. PMID:21986665

Lin, Shengchen; Han, Ying; Shi, Yuzhe; Rong, Hui; Zheng, Songyang; Jin, Shikan; Lin, Shu-Yong; Lin, Sheng-Cai; Li, Yong



The apparent hysteresis in hormone-agonist relationships  

PubMed Central

It has been noted in multiple studies that the calcium–PTH axis, among others, is subject to an apparent hysteresis. We sought to explain a major component of the observed phenomenon by constructing a simple mathematical model of a hormone and secretagogue system with concentration dependent secretion and containing two delays. We constructed profiles of the hormone–agonist axis in this model via four types of protocols, three of which emulating experiments from the literature, and observed a delay- and load-dependent hysteresis that is an expected mathematical artifact of the system described. In particular, the delay associated with correction allows for over-secretion of the hormone influencing the corrective mechanism; thus rate dependence is an artifact of the corrective mechanism, not a sensitivity of the gland to the magnitude of change. From these observations, the detected hysteresis is due to delays inherent in the systems being studied, not in the secretory mechanism. PMID:22154846

Pruett, William A.; Hester, Robert L.; Coleman, Thomas G.



PPAR-? agonist pioglitazone affects rat gouty arthritis by regulating cytokines.  


The objective was to study peroxisome proliferator-activated receptor gamma (PPAR?) agonist pioglitazone regulation effect and its mechanism of expression of cytokines on acute gouty arthritis synovial in rats. Rats with unilateral ankle were injected with artificial monosodium urate (MSU) crystals to make the acute gouty arthritis model. Taking the synovium 48 h after the injection of MSU and using RT-PCR, we assessed the effect of pioglitazone (20 mg·kg(-1)·day(-1), oral administration) on synovial expression, by detecting tumor necrosis factor-? (TNF-?), interleukin-1? (IL-1?), and interferon-? (IFN-?). The pioglitazone treatment group showed synovial expression of TNF-?, and IFN-? was significantly lower than in the control group; the inhibition rates were 78.5 and 60.4%. The IL-1 expression difference was not statistically significant between the two groups. Pioglitazone has anti-inflammatory effects on acute gouty arthritis by inhibiting the expression of TNF-? and IFN-?. PMID:25177938

Wang, R-C; Jiang, D-M



Comparative Transcriptional Network Modeling of Three PPAR-?\\/? Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes  

Microsoft Academic Search

AimsTo compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-?\\/? agonist, aleglitazar, with tesaglitazar (a dual PPAR-?\\/? agonist) or a combination of pioglitazone (Pio; PPAR-? agonist) and fenofibrate (Feno; PPAR-? agonist) in human hepatocytes.Methods and ResultsGene expression microarray profiles were obtained from primary human hepatocytes treated with EC50-aligned low, medium and high concentrations of the

Renée Deehan; Pia Maerz-Weiss; Natalie L. Catlett; Guido Steiner; Ben Wong; Matthew B. Wright; Gil Blander; Keith O. Elliston; William Ladd; Maria Bobadilla; Jacques Mizrahi; Carolina Haefliger; Alan Edgar



The affinities, potencies and efficacies of some benzodiazepine-receptor agonists, antagonists and inverse-agonists at rat hippocampal GABAA-receptors.  

PubMed Central

The abilities of some benzodiazepine-receptor agonists, antagonists and inverse agonists to modulate the inhibitory potency of the gamma-aminobutyric acid (GABA)A-receptor agonist, isoguvacine, on the CA1 population spike recorded from slices of rat hippocampus, were determined. Concentration-response curves were constructed of the extent to which the benzodiazepine-receptor ligands shifted the isoguvacine concentration-response curve to the left or right. These were compared to their displacement curves of [3H]-Ro15-1788 binding to rat hippocampal membranes under near physiological assay conditions. The above comparisons suggest that the effect on the potency of isoguvacine produced by the benzodiazepine-receptor agonists, diazepam and flunitrazepam, and the partial agonists, Ro16-6028 and Ro17-1812, closely parallels their degree of benzodiazepine-receptor occupancy. Thus, the partial agonists, Ro16-6028 and Ro17-1812, were unable to produce as large a maximum response as the full agonists, diazepam and flunitrazepam. The maximum effects produced by diazepam, flunitrazepam, Ro16-6028, Ro17-1812, the antagonist, propyl-beta-carboline-3-carboxylate, and the inverse agonist, methyl-6, 7-dimethyl-4-ethyl-beta-carboline-3-carboxylate (DMCM), on the potency of isoguvacine in the hippocampal slice corresponded to the change in their affinities produced by the addition of GABA in the radioligand binding studies (GABA-shift). This suggests that the changes in affinity of benzodiazepine-receptor ligands produced by GABAA-receptor activation reflects their ability to modify GABAA-receptor function. The benzodiazepine-receptor antagonists, Ro15-1788 and CGS 8216, had apparent agonist and inverse agonist effects, respectively, on the potency of isoguvacine. These effects occurred at concentrations above those required for saturation of the benzodiazepine-receptor, as labelled by [3H]-Ro15-1788, and were not in agreement with the absence of any effect of GABAA-receptor stimulation in the GABA-shift experiments.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3038246

Kemp, J. A.; Marshall, G. R.; Wong, E. H.; Woodruff, G. N.



Field Observations of Intraspecific Agonistic Behavior of Two Crayfish Species, Orconectes rusticus and Orconectes virilis, in Different Habitats  

Microsoft Academic Search

Agonistic behavior is a fundamental aspect of ecological theories on resource acquisition and sexual se- lection. Crustaceans are exemplary models for agonistic behavior within the laboratory, but agonistic behavior in natural habitats is often neglected. Laboratory studies do not achieve the same ecological realism as field studies. In an attempt to connect laboratory results to field data and in- vestigate




Evidence for lack of modulation of mu-opioid agonist action by delta-opioid agonists in the mouse vas deferens and guinea-pig ileum.  

PubMed Central

1. There is evidence from in vivo studies for an interaction of mu- and delta-opioid ligands. In the present work this concept has been investigated using the mouse vas deferens and guinea-pig ileum myenteric plexus-longitudinal preparations. 2. In field stimulated vasa deferentia of the mouse, co-administration of sub-effective concentrations of the delta-opioid agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) and [Met5]- or [Leu5]enkephalin had no effect on the dose-response curves of the mu-agonists [D-Ala2,MePhe4, Gly-ol5]enkephalin (DAMGO) and morphine. Similarly, the delta-opioid agonists did not alter the potency of morphine and DAMGO when added at different times prior to the mu-opioid agonists, or when EC50 concentrations of delta-opioid ligands were co-administered. Compounds with preferred activity for the putative delta 1-(DPDPE) or delta 2-([D-Ala2,Glu4]deltorphin II (Delt II)) opioid receptors were ineffective in this respect. 3. The guinea-pig ileum contains delta-opioid receptors. No function of these receptors in mediating blockage of field-stimulated contractions was observed with ligands having affinity for the putative delta 1 or delta 2 subtypes nor were the agonists able to modulate responses to mu-opioid ligands in this tissue. 4. The results demonstrate the modulation of mu-opioid agonists by delta-opioid agonists does not occur in the isolated peripheral tissues examined. Thus the findings do not support the concept of a functional coupling of opioid receptors, though the results may be explained by differences between opioid systems in the brain and peripheral tissues examined. PMID:7780641

Elliott, J; Traynor, J R



Dmographie Facult des arts et des sciences  

E-print Network

� sera maintenue). Professeur: LACHAUD, James Courriel: Local: C-5031'analyse explicative: les causes et cons�quences des ph�nom�nes. Le cours ciblera les r�gressions lin�aires et non-lin

Parrott, Lael


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


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. PMID:23764202

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



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

SciTech Connect

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.

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



Mixed kappa/mu partial opioid agonists as potential treatments for cocaine dependence.  


Cocaine use activates the dopamine reward pathway, leading to the reinforcing effects of dopamine. There is no FDA-approved medication for treating cocaine dependence. Opioid agonists and antagonists have been approved for treating opioid and alcohol dependence. Agonists that activate the ? opioid receptor increase dopamine levels in the nucleus accumbens, while ? receptor antagonists decrease dopamine levels by blocking the effects of endogenous opioid peptides. Activation of the ? opioid receptor decreases dopamine levels and leads to dysphoria. In contrast, inhibition of the ? opioid receptor decreases dopamine levels in the nucleus accumbens. Antagonists acting at the ? receptor reduce stress-mediated behaviors and anxiety. Mixed partial ?/? agonists have the potential of striking a balance between dopamine levels and attenuating relapse to cocaine. The pharmacological properties of mixed ?/? opioid receptor agonists will be discussed and results from clinical and preclinical studies will be presented. Results from studies with some of the classical benzomorphans and morphinans will be presented as they lay the foundation for structure-activity relationships. Recent results with other partial opioid agonists, including buprenorphine derivatives and the mixed ?/? peptide CJ-15,208, will be discussed. The behavioral effects of the mixed ?/? MCL-741, an aminothiazolomorphinan, in attenuating cocaine-induced locomotor activity will be presented. While not a mixed ?/? opioid, results obtained with GSK1521498, a ? receptor inverse agonist, will be discussed. Preclinical strategies and successes will lay the groundwork for the further development of mixed ?/? opioid receptor agonists to treat cocaine dependence. PMID:24484983

Bidlack, Jean M



Associations of Fraction of Exhaled Nitric Oxide with Beta Agonist Use in Children with Asthma  

PubMed Central

The fraction of exhaled nitric oxide (FeNO), a measure of airway inflammation, is a potential noninvasive tool to guide asthma management in children. It remains unclear, however, if FeNO adds any information beyond clinical assessment of asthma control. We evaluated the associations of FeNO level with short acting beta agonist use and compared it with other clinical asthma assessments. We examined a prospective cohort study of 225 tobacco-smoke-exposed children aged 6–12 years with doctor-diagnosed asthma, including measures of FeNO, reported days of short acting beta agonist use, and unscheduled asthma visits. FeNO was analyzed in relation to current and future (3 months later) short acting beta agonist use. Mean FeNO at baseline, 6, and 12 months was 15.5, 15.7, and 16.8?ppb. In multivariable analyses, higher FeNO level was associated with increased short acting beta agonist use but only among children who were not on inhaled corticosteroids. Among those not on an inhaled steroid, there was a 12% increase in current and 15% increase in future days of short acting beta agonist use for every 10?ppb increase in FeNO level. FeNO levels remained associated with current short acting beta agonist use even after adjusting for unscheduled asthma visits. FeNO levels remained associated with future short acting beta agonist use even after adjusting for current short acting beta agonist use or unscheduled asthma visits. We conclude that FeNO levels are associated with short acting beta agonist use but only among children who are not on an inhaled corticosteroid. PMID:22276224

Kahn, Robert S.; Hornung, Richard; Lierl, Michelle; Lanphear, Bruce P.



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

SciTech Connect

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-?-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.

Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail:



Comparison of human B cell activation by TLR7 and TLR9 agonists  

PubMed Central

Background Human B cells and plasmacytoid dendritic cells (pDC) are the only cells known to express both TLR7 and TLR9. Plasmacytoid dendritic cells are the primary IFN-? producing cells in response to TLR7 and TLR9 agonists. The direct effects of TLR7 stimulation on human B cells is less understood. The objective of this study was to compare the effects of TLR7 and TLR9 stimulation on human B cell function. Results Gene expression and protein production of cytokines, chemokines, various B cell activation markers, and immunoglobulins were evaluated. Purified human CD19+ B cells (99.9%, containing both naïve and memory populations) from peripheral blood were stimulated with a TLR7-selective agonist (852A), TLR7/8 agonist (3M-003), or TLR9 selective agonist CpG ODN (CpG2006). TLR7 and TLR9 agonists similarly modulated the expression of cytokine and chemokine genes (IL-6, MIP1 alpha, MIP1 beta, TNF alpha and LTA), co-stimulatory molecules (CD80, CD40 and CD58), Fc receptors (CD23, CD32), anti-apoptotic genes (BCL2L1), certain transcription factors (MYC, TCFL5), and genes critical for B cell proliferation and differentiation (CD72, IL21R). Both agonists also induced protein expression of the above cytokines and chemokines. Additionally, TLR7 and TLR9 agonists induced the production of IgM and IgG. A TLR8-selective agonist was comparatively ineffective at stimulating purified human B cells. Conclusion These results demonstrate that despite their molecular differences, the TLR7 and TLR9 agonists induce similar genes and proteins in purified human B cells. PMID:18652679

Hanten, John A; Vasilakos, John P; Riter, Christie L; Neys, Lori; Lipson, Kenneth E; Alkan, Sefik S; Birmachu, Woubalem



In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes.  


Beta 2 adrenergic receptor overstimulation during critical periods of prenatal development can induce a permanent shift in the balance of sympathetic-to-parasympathetic tone. This is a biologically plausible mechanism whereby beta 2 adrenergic agonists can induce functional and behavioral teratogenesis, which explains their association with increases in autism spectrum disorders, psychiatric disorders, poor cognitive, motor function and school performance, and changes in blood pressure in the offspring. The use of beta 2 adrenergic agonists should be limited to proven indications when alternate drugs are ineffective or unavailable; the risks of untreated disease to the mother and fetus are greater than the risk of the beta 2 adrenergic agonist. PMID:19961985

Witter, Frank R; Zimmerman, Andrew W; Reichmann, James P; Connors, Susan L



?3-receptor agonists for overactive bladder--new frontier or more of the same?  


The new information generated over the last decade on the physiology/pharmacology of the normal bladder and on the pathophysiology of the overactive bladder has resulted in the introduction of a new therapeutic principle, ?3-adrenoceptor (AR) agonism, and the approval of mirabegron, a selective agonist at ?3-ARs. It may be asked in what respects the ?3-AR agonists as a group, and mirabegron in particular, differ from the antimuscarinics, and what can clinically be gained by the ?3-AR agonists. In this short review, the mechanisms of action, clinical efficacy, and adverse effect profiles of the two groups of drugs are compared and discussed. PMID:23677692

Andersson, Karl-Erik



Interactions between metabotropic and ionotropic glutamate receptor agonists in the rat spinal cord in vivo  

Microsoft Academic Search

Microelectrophoretic application of the non-selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] and the group I selective mGluR agonist (RS)-3,5-dihydroxyphenylglycine [(RS)-3,5-DHPG] potentiated the responses of rat spinal neurones to the cyclically-ejected ionotropic excitatory amino acid (EAA) agonists NMDA, AMPA and kainate in vivo. Potentiation was not selective between the three ionotropic responses and was paralleled by an enhancement of

M. W. Jones; P. M. Headley



PHARMA -Rglement des examens et des jurys 2013-2014 Rglement des examens -Pharma juin 2013 1 / 16  

E-print Network

PHARMA - Règlement des examens et des jurys 2013-2014 Règlement des examens - Pharma juin 2013 1 missions décrites dans ce règlement. #12;PHARMA - Règlement des examens et des jurys 2013-2014 Règlement des examens - Pharma juin 2013 2 / 16 2 UNIVERSITE LIBRE DE BRUXELLES DEPARTEMENT ENSEIGNEMENT SERVICE

Cerf, Nicolas



E-print Network

PROC�DURE DE D�CLARATION DES ACCIDENTS, DES INCIDENTS ET DES SITUATIONS DANGEREUSES EN MILIEU DE de déclaration des accidents, des incidents et des situations dangereuses en milieu de travail. Ce, tout accident ou incident doit faire l'objet d'une déclaration officielle auprès de l'employeur. Selon

Meunier, Michel


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


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

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



New, potent, and selective peptidic oxytocin receptor agonists.  


Mothers of preterm babies frequently have difficulty establishing or maintaining lactation, thought to be due to interference with the milk ejection reflex. Administration of exogenous oxytocin can produce alveolar contraction and adequate breast emptying resulting in establishment of successful lactation. The natural hormone oxytocin is not receptor-selective and may cause hyponatremia via V2 receptor mediated antidiuresis. We have designed a series of potent oxytocin analogues containing N-alkylglycines in position 7 with excellent selectivity versus the related V1a, V1b, and V2 vasopressin receptors and short half-life: agonists 31 ([2-ThiMeGly(7)]dOT), 47 (carba-6-[Phe(2),BuGly(7)]dOT), 55 (carba-6-[3-MeBzlGly(7)]dOT), and 57 (carba-1-[4-FBzlGly(7)]dOT) have EC50 values at hOTR < 0.1 nM, selectivity ratios versus related human vasopressin receptors of >2000, IC50 at hV1aR > 500 nM, and total clearance in rats in the range of 60-80 mL min(-1) kg(-1). Compound 57 (FE 202767) is currently in clinical development for the treatment of preterm mothers requiring lactation support. PMID:24874785

Wi?niewski, Kazimierz; Alagarsamy, Sudarkodi; Galyean, Robert; Tariga, Hiroe; Thompson, Dorain; Ly, Brian; Wi?niewska, Halina; Qi, Steve; Croston, Glenn; Laporte, Regent; Rivière, Pierre J-M; Schteingart, Claudio D



'Carba'-Analogues of Fentanyl are Opioid Receptor Agonists  

PubMed Central

There is evidence to indicate that the Asp residue in the third transmembrane helix (TMH) of opioid receptors forms a salt bridge with the positively charged nitrogen of endogenous and exogenous opioid ligands. To further examine the role of this electrostatic interaction in receptor binding and activation, we synthesized ‘carba’-analogues of a published fentanyl analogue containing a 3-(guanidinomethyl)-benzyl group in place of the phenyl moiety attached to the ethylamido group (C. Dardonville et al., Bioorg. Med. Chem. 2006, 14, 6570–6580 (1)), in which the piperidine ring nitrogen was replaced with a carbon. As expected, the resulting cis and trans isomers (8a and 8b) showed reduced ? and ? opioid receptor binding affinities as compared to 1, but surprisingly, retained opioid full agonist activity with about half the potency of leucine-enkephalin in the guinea pig ileum assay. In conjunction with performed receptor docking studies, these results indicate that the electrostatic interaction of the protonated nitrogen in the piperidine ring of fentanyl analogues with the Asp residue in the third TMH is not a conditio sine qua non for opioid receptor activation. PMID:20218625

Weltrowska, Grazyna; Chung, Nga N.; Lemieux, Carole; Guo, Jianxin; Lu, Yixin; Wilkes, Brian C.; Schiller, Peter W.



QSAR and mode of action studies of insecticidal ecdysone agonists.  


A series of our SAR and QSAR studies of synthetic moulting hormone agonists, dibenzoylhydrazines (DBH), exhibiting insecticidal/larvicidal activity are reviewed in this article. We prepared a number of analogues where various substituents are introduced into the two benzene rings of DBH and measured their biological activity using various biological systems. Larvicidal activity was against larvae of the rice stem borer Chilo suppressalis and the moulting hormone activity was in terms of the stimulation of N-acetylglucosamine incorporation in a cultured integument system of the same insect species. Binding affinity to the ecdysone receptor was assayed with intact Sf-9 cell lines in which the ADME processes are negligible as well as using receptor proteins obtained by in vitro translation of the responsible cDNA cloned from cell-free preparation of integumentary tissue of C. suppressalis. Variations in the biological activity indices were either correlated between two types of activity or correlated using physicochemical molecular and substituent parameters in terms of the classical QSAR. Comparisons among correlations and with recently revealed X-ray crystallographic findings clearly indicate the physicochemical meaning of parameters significant in the correlation equations to help understanding molecular mechanism of the moulting hormonal action. PMID:17365960

Fujita, T; Nakagawa, Y



Juvenile hormone agonists affect the occurrence of male Daphnia.  


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. PMID:14505703

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



Resolvins: Natural Agonists for Resolution of Pulmonary Inflammation  

PubMed Central

Inappropriate or excessive pulmonary inflammation can contribute to chronic lung diseases. In health, the resolution of inflammation is an active process that terminates inflammatory responses. The recent identification of endogenous lipid-derived mediators of resolution has provided a window to explore the pathobiology of inflammatory disease and structural templates for the design of novel pro-resolving therapeutics. Resolvins (resolution-phase interaction products) are a family of pro-resolving mediators that are enzymatically generated from essential omega-3 polyunsaturated fatty acids. Two molecular series of resolvins have been characterized, namely E- and D-series resolvins which possess distinct structural, biochemical and pharmacological properties. Acting as agonists at specific receptors (CMKLR1, BLT1, ALX/FPR2 and GPR32), resolvins can signal for potent counter-regulatory effects on leukocyte functions, including preventing uncontrolled neutrophil swarming, decreasing the generation of cytokines, chemokines and reactive oxygen species and promoting clearance of apoptotic neutrophils from inflamed tissues. Hence, resolvins provide mechanisms for cytoprotection of host tissues to the potentially detrimental effects of unresolved inflammation. This review highlights recent experimental findings in resolvin research, and the impact of these stereospecific molecules on the resolution of pulmonary inflammation and tissue catabasis. PMID:20887750

Uddin, Mohib; Levy, Bruce D.



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


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. PMID:24365541

Blank, David; Yang, Weikang



Dissociation characteristics of endothelin ETA receptor agonists and antagonists.  


Endothelin (ET) binding to receptors has been shown to be almost irreversible. We studied the dissociation characteristics of ETA receptor agonists and antagonists using membranes prepared from rat pituitary cells (MMQ). Consistent with our previous report, competition studies comparing ET-1, ET-3, BQ123, FR139317, PD142893, and Ro46-2005 show that MMQ cells contained predominantly the ETA receptor. [125I]ET-1 bound to the receptor was difficult to dissociate. In contrast, bound BQ123, FR139317, and Ro46-2005 were easier to dissociate, suggesting that antagonist binding was more reversible. Although BQ123 (5 nM), FR139317 (1 nM), and Ro46-2005 (0.5 microM) inhibited 0.1 nM [125I]ET-1 binding by greater than 80% after 15 min of incubation, the inhibition decreased to less than 20% after 24 h of incubation. This decrease in binding inhibition was not the result of antagonist degradation. These results suggest that, similar to our previous observation made with the ETB receptor in porcine cerebellum, the ability of antagonists to inhibit [125I]ET-1 binding to the ETA receptor is critically dependent on the incubation time because of the difference in the dissociation characteristics between antagonists and ET-1. PMID:8587421

Wu-Wong, J R; Chiou, W J; Dixon, D B; Opgenorth, T J



Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.  


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. PMID:25379267

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



Identification of novel multitargeted PPAR?/?/? pan agonists by core hopping of rosiglitazone  

PubMed Central

The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPAR?) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPAR? is the main cause of these side effects. Multitargeted PPAR?/?/? pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPAR?/?/? pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPAR?/?/? active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPAR?/?/? pan agonist for novel antidiabetic drug research.

Wang, Xue-Jiao; Zhang, Jun; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling




PubMed Central

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

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



The Renoprotective Actions of Peroxisome Proliferator-Activated Receptors Agonists in Diabetes  

PubMed Central

Pharmaceutical agonists of peroxisome proliferator-activated receptors (PPARs) are widely used in the management of type 2 diabetes, chiefly as lipid-lowering agents and oral hypoglycaemic agents. Although most of the focus has been placed on their cardiovascular effects, both positive and negative, these agents also have significant renoprotective actions in the diabetic kidney. Over and above action on metabolic control and effects on blood pressure, PPAR agonists also appear to have independent effects on a number of critical pathways that are implicated in the development and progression of diabetic kidney disease, including oxidative stress, inflammation, hypertrophy, and podocyte function. This review will examine these direct and indirect actions of PPAR agonists in the diabetic kidney and explore recent findings of clinical trials of PPAR agonists in patients with diabetes. PMID:22448165

Thomas, M. C.; Jandeleit-Dahm, K. A.; Tikellis, C.



Combined Ligand- and Structure-based Virtual Screening Protocol Identifies Novel Submicromolar PPAR? Partial Agonists Title  

PubMed Central

PPAR? is involved in expression of genes that control glucose and lipid metabolism. PPAR? is the molecular target of the thiazolidinedione (TZD) class of antidiabetic drugs. However, despite their clinical use these drugs are related to numerous adverse effects, which are related to their full activation of PPAR? transcriptional responses. PPAR? partial agonists are the focus of development efforts towards second-generation PPAR? modulators with favourable pharmacology, potent insulin sensitization without the severe full agonists’ adverse effects. In order to identify novel PPAR? partial agonist lead compounds, we developed a virtual screening protocol based on 3D-ligand shape similarity and docking. 235 compounds were prioritized for experimental screening from a 340,000 MLSMR chemical library. Seven novel potent partial agonists were confirmed in cell-based transactivation and competitive binding assays. Our results illustrate a well-designed virtual screening campaign successfully identifying novel lead compounds as potential entry points for the development of antidiabetic drugs. PMID:21162086

Vidovic, Dusica; Busby, Scott A.; Griffin, Patrick R.; Schurer, Stephan C.



Potent agonists of a hematopoietic stem cell cytokine receptor, c-Mpl.  


Several growth factors feature prominently in the control of hematopoiesis. Thrombopoietin, a class?I hematopoietic cytokine, plays critical roles in regulating hematopoietic stem cell numbers and also stimulates the production and differentiation of megakaryocytes, the bone marrow cells that ultimately produce platelets. Thrombopoietin interacts with the c-Mpl cell-surface receptor. Recently, several peptide and small-molecule agonists and antagonists of c-Mpl have been reported. We conducted a bioinformatics and molecular modeling study aimed at understanding the agonist activities of peptides that bind to c-Mpl, and developed new potent peptide agonists with low nanomolar activity. These agonists also show very high activity in human CD34(+) primary cell cultures, and doubled the mean blood platelet counts when injected into mice. PMID:23554275

Tarasova, Anna; Haylock, David N; Meagher, Laurence; Be, Cheang Ly; White, Jacinta; Nilsson, Susan K; Andrade, Jessica; Cartledge, Kellie; Winkler, David A



Les agonistes bta-adrnergiques. Mcanismes d'action : lipomobilisation et anabolisme  

E-print Network

in commercial livestock with certain ¡3-adrenergic agonists (clenbuterol and cimaterol) having an anabolic and pigs. The effect of clenbuterol and cimaterol on carcass quality is to increase the deposition

Paris-Sud XI, Université de


R-(-)-beta-phenyl-GABA is a full agonist at GABAB receptors in brain slices but a partial agonist in the ileum.  


R-(-)-beta-phenyl-GABA has been compared at GABAB receptors using cortical and ileal preparations. R-(-)-beta-phenyl-GABA (EC50 = 25 microM) was a less potent full agonist than R,S-(+/-)-baclofen (EC50 = 2.5 microM), in depressing CA1 population spikes of rat hippocampal slices, and 5 times less potent in attenuating the spontaneous discharges of rat neocortex. However, R-(-)-beta-phenyl-GABA (100-400 microM) was only a weak partial agonist in the ileum. All these actions were sensitive to CGP 35348 (3-aminopropyl-(P-diethoxymethyl)-phosphinic acid) and therefore mediated by GABAB receptors. PMID:8386087

Ong, J; Kerr, D I; Doolette, D J; Duke, R K; Mewett, K N; Allen, R D; Johnston, G A



Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [N?-Bodipy]-des-Arg9-bradykinin  

Microsoft Academic Search

BACKGROUND: The kinin B1 receptor (B1R) is upregulated by pro-inflammatory cytokines, bacterial endotoxins and hyperglycaemia-induced oxidative stress. In animal models of diabetes, it contributes to pain polyneuropathy. This study aims at defining the cellular localization of B1R in thoracic spinal cord of type 1 diabetic rats by confocal microscopy with the use of a fluorescent agonist, [N?-Bodipy]-des-Arg9-BK (BdABK) and selective

Sébastien Talbot; Patrick Théberge-Turmel; Dalinda Liazoghli; Jacques Sénécal; Pierrette Gaudreau; Réjean Couture



Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor*  

PubMed Central

Understanding the molecular basis of drug action can facilitate development of more potent and selective drugs. Here, we explore the molecular basis for action of a unique small molecule ligand that is a type 1 cholecystokinin (CCK) receptor agonist and type 2 CCK receptor antagonist, GI181771X. We characterize its binding utilizing structurally related radioiodinated ligands selective for CCK receptor subtypes that utilize the same allosteric ligand-binding pocket, using wild-type receptors and chimeric constructs exchanging the distinct residues lining this pocket. Intracellular calcium assays were performed to determine biological activity. Molecular models for docking small molecule agonists to the type 1 CCK receptor were developed using a ligand-guided refinement approach. The optimal model was distinct from the previous antagonist model for the same receptor and was mechanistically consistent with the current mutagenesis data. This study revealed a key role for Leu7.39 that was predicted to interact with the isopropyl group in the N1 position of the benzodiazepine that acts as a “trigger” for biological activity. The molecular model was predictive of binding of other small molecule agonists, effectively distinguishing these from 1065 approved drug decoys with an area under curve value of 99%. The model also selectively enriched for agonist compounds, with 130 agonists identified by ROC analysis when seeded in 2175 non-agonist ligands of the type 1 CCK receptor (area under curve 78%). Benzodiazepine agonists in this series docked in consistent pose within this pocket, with a key role played by Leu7.39, whereas the role of this residue was less clear for chemically distinct agonists. PMID:23754289

Harikumar, Kaleeckal G.; Cawston, Erin E.; Lam, Polo C. H.; Patil, Achyut; Orry, Andrew; Henke, Brad R.; Abagyan, Ruben; Christopoulos, Arthur; Sexton, Patrick M.; Miller, Laurence J.



Effects of inhaled ? agonist and corticosteroid treatment on nuclear transcription factors in bronchial mucosa in asthma  

Microsoft Academic Search

BACKGROUNDInhaled corticosteroids and ? agonists are the most commonly used treatments in asthma and are often used together. Recent evidence suggests that many of the anti-inflammatory actions of corticosteroids are mediated by cross-talk between the activated glucocorticoid receptor (GR) and other transcription factors such as the pro-inflammatory nuclear factor kappa B (NF?B). Beta agonists can activate the transcription factor cAMP

Robert J Hancox; David A Stevens; Ian M Adcock; Peter J Barnes; D Robin Taylor



Corticosteroids: Potential  2Agonist and Anticholinergic Interactions in Chronic Obstructive Pulmonary Disease  

Microsoft Academic Search

Corticosteroids are often used in combination with 2-agonist and anticholinergicbronchodilatorsinthetreatmentofchronicobstruc- tive pulmonary disease (COPD). Corticosteroids activate the 2- receptor gene, increasing receptornumber and decreasing desensi- tization. Long-acting 2-agonists prime the glucocorticoid receptor and enhance nuclear translocation via activation of CCAAT en- hancerbindingprotein-.Corticosteroidscanalsoincreaseprejunc- tional auto-inhibitory M2-receptor gene expression in airway smooth muscle. There is evidence of a synergistic inhibition of cytokine

Malcolm Johnson



Luteinizing Hormone-Releasing Hormone and Its Agonistic, Antagonistic, and Targeted Cytotoxic Analogs in Prostate Cancer  

Microsoft Academic Search

\\u000a Chronic administration of luteinizing hormone-releasing hormone I (LHRH-I) or its agonistic analogs leads to downregulation\\u000a of pituitary receptors for LHRH, and a gradual suppression of circulating levels of gonadotropins and sex steroids. The creation\\u000a of a state of sex-hormone deprivation produced by periodic administration of sustained delivery system of LHRH agonists forms\\u000a the basis of therapy for advanced prostate cancer

Andrew V. Schally; Norman L. Block


Liver X receptor agonist regulation of Th17 lymphocyte function in autoimmunity  

PubMed Central

CD4+ Th17 cells are believed to play an important role in the development of a variety of autoimmune diseases including EAE, an animal model of MS. Previously, we and others demonstrated that LXR agonists suppressed the activation of primary glial cells and blocked the development of EAE. The present studies demonstrated that the LXR agonist T0901317 suppressed IL-17A expression from splenocytes derived from V?2.3/V?8.2 TCR transgenic mice and from MOG35–55-immunized C57BL/6 mice. Furthermore, in vitro treatment with IL-23 alone or in combination with MOG35–55 induced IL-17A expression from splenocytes derived from MOG35–55-immunized mice, and T0901317 blocked this induction. In vitro treatment with the LXR agonist suppressed IL-23R expression by splenocytes. In addition, in vivo treatment with the LXR agonist suppressed IL-17A and IL-23R mRNA and protein expression in EAE mice. These studies suggest that LXR agonists suppress EAE, at least in part by suppressing IL-23 signaling. Recent studies indicate that the cytokines IL-21 and IL-22 are produced by Th17 cells and modulate immune responses. Our studies demonstrate that the LXR agonist T0901317 suppressed MOG35–55-induced expression of IL-21 and IL-22 mRNA in splenocytes derived from MOG35–55-immunized mice. Finally, we demonstrate that the LXR agonist T0901317 suppressed the development of EAE in an experimental paradigm involving treatment of established EAE. Collectively, these studies suggest that LXR agonists may be effective in the treatment of MS. PMID:19406833

Xu, Jihong; Wagoner, Gail; Douglas, James C.; Drew, Paul D.



Behavioral effects of dopaminergic agonists and antagonists alone and in combination in the squirrel monkey  

Microsoft Academic Search

The effects on schedule-controlled operant behavior of the D2 receptor agonist, quinpirole, and the D1 agonist, SKF 38393, were assessed alone and in combination with selective dopamine-receptor antagonists. Squirrel monkeys (Saimiri sciureus) were trained to press a response key under fixed-interval and fixed-ratio schedules of food reinforcement. The fixed-interval schedule maintained relatively low rates of responding that increased up to

Jonathan L. Katz; Jeffrey M. Witkin



Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects.  


Following the characterization of the lactate receptor (GPR81), a focused screening effort afforded 3-hydroxybenzoic acid 1 as a weak agonist of both GPR81 and GPR109a (niacin receptor). An examination of structurally similar arylhydroxy acids led to the identification of 3-chloro-5-hydroxybenzoic acid 2, a selective GPR81 agonist that exhibited favorable in vivo effects on lipolysis in a mouse model of obesity. PMID:24900524

Dvorak, Curt A; Liu, Changlu; Shelton, Jonathan; Kuei, Chester; Sutton, Steven W; Lovenberg, Timothy W; Carruthers, Nicholas I



Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects  

PubMed Central

Following the characterization of the lactate receptor (GPR81), a focused screening effort afforded 3-hydroxybenzoic acid 1 as a weak agonist of both GPR81 and GPR109a (niacin receptor). An examination of structurally similar arylhydroxy acids led to the identification of 3-chloro-5-hydroxybenzoic acid 2, a selective GPR81 agonist that exhibited favorable in vivo effects on lipolysis in a mouse model of obesity. PMID:24900524



Toll-Like Receptor 4 or 2 Agonists Decrease Allergic Inflammation  

Microsoft Academic Search

Toll-like receptors (TLRs) recognize highly conserved microbial mo- lecular patterns, such as found in endotoxin. This study tested whether TLR4 and TLR2 stimulation in vivo would modulate subse- quent adaptive (allergic) immune responses. We analyzed the ef- fects of pulmonary administration of a TLR4 agonist, lipid A (LpA), and two TLR2 agonists, peptidoglycan (Ppg) and PamCys, in a mu- rinemodelof

German Velasco; Monica Campo; Oscar J. Manrique; Abdelouahab Bellou; Hongzhen He; Ruth S. S. Arestides; Bianca Schaub; David L. Perkins; Patricia W. Finn


Guiding principles applied in the design of GPCR-selective hypothalamic hormone agonists and antagonists  

Microsoft Academic Search

Strategies for the design of peptide agonists and antagonists of gonadotropin releasing hormone (GnRH, one ligand and one\\u000a receptor) and of receptor-selective agonists and antagonists of somatostatin (SRIF, three ligands and five receptors) and\\u000a corticotropin releasing factor (CRF, three ligands and two receptors) are described. These strategies include the use of unusual\\u000a amino acids, a versatile scaffold based on aminoglycine

J. Rivier; J. Gulyas; J. Erchegyi; S. C. Koerber; C. R. R. Grace; R. Riek; M. DiGruccio; M. Perrin; C. Rivier; V. Eltschinger; B. Waser; R. Cescato; J. C. Reubi; W. Vale


The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression  

Microsoft Academic Search

Background: On the basis of experiments in rats, serotonin 4 receptor (5-hydroxytryptamine 4 [5-HT4]) agonists have been proposed as a novel therapeutic strategy for the selective treatment of respiratory depression caused by opioids while leaving analgesic effects unaffected. The effects in rats have been seen with the 5-hydroxytryptamine 4a (5-HT4a) agonist BIMU8, which is currently not available for use in

Jörn Lötsch; Carsten Skarke; Andreas Schneider; Thomas Hummel; Gerd Geisslinger



Evaluation of peroxisome proliferator-activated receptor agonists on interleukin-5-induced eosinophil differentiation.  


Peroxisome proliferator-activated receptor (PPAR) agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists has been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report that PPAR agonists can inhibit the differentiation of several cell types. To date, no studies have examined the effects of PPAR agonists on interleukin-5 (IL-5) -induced eosinophil differentiation from haemopoietic progenitor cells. Non-adherent mononuclear cells or CD34(+) cells isolated from the peripheral blood of allergic subjects were grown for 2 weeks in Methocult(®) cultures with IL-5 (10 ng/ml) and IL-3 (25 ng/ml) in the presence of 1-1000 nm PPAR? agonist (GW9578), PPAR?/? agonist (GW501516), PPAR? agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony-forming units (Eo/B CFU) was quantified by light microscopy. The signalling mechanism involved was assessed by phosphoflow. Blood-extracted CD34(+) cells cultured with IL-5 or IL-5 + IL-3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 nm, P < 0·01) but not GW9578 or GW501516. In addition, rosglitazone significantly inhibited IL-5-induced phosphorylation of extracellular signal-regulated kinase 1/2. We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro, mediated by attenuation of the extracellular signal-regulated kinase 1/2 signalling pathway. These findings indicate that the PPAR? agonist can attenuate tissue eosinophilia by interfering with local differentiative responses. PMID:24628018

Smith, Steven G; Hill, Mike; Oliveria, John-Paul; Watson, Brittany M; Baatjes, Adrian J; Dua, Benny; Howie, Karen; Campbell, Heather; Watson, Rick M; Sehmi, Roma; Gauvreau, Gail M



The selectivity of ?-adrenoceptor agonists at human ?1-, ?2- and ?3-adrenoceptors  

PubMed Central

Background and purpose: There are two important properties of receptor–ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor–ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 ?-adrenoceptor agonists at the three human ?-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. Experimental approach: Stable clonal CHO-K1 cell lines, transfected with either the human ?1, ?2 or ?3-adrenoceptor, were used, and whole-cell [3H]-CGP 12177 radioligand binding and [3H]-cAMP accumulation were measured. Key results: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the ?2-adrenoceptor over the ?1 or ?3), while others (e.g. isoprenaline) had little affinity–selectivity. However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for ?1; clenbuterol, AZ 40140d, salbutamol for ?2) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the ?1- and ?3-adrenoceptors. Conclusions and implications: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. This article is commented on by Kenakin, pp. 1045–1047 of this issue. To view this commentary visit PMID:20590599

Baker, Jillian G



A comparison of the effects of agonist and antagonist muscle fatigue on performance of rapid movements  

Microsoft Academic Search

The aim of this study was to investigate the effects of agonist and antagonist muscle fatigue on the performance of rapid,\\u000a self-terminating movements. Six subjects performed rapid, consecutive elbow flexion and extension movements between two targets\\u000a prior to and after fatiguing either the elbow flexor or elbow extensor muscles. The experiments demonstrated consistent results.\\u000a Agonist muscle fatigue was associated with

Slobodan Jari?; Saša Radovanovi?; Sladjan Milanovi?; Miloš Ljubisavljevi?; Radmila Anastasijevi?



The CRTH2 agonist Pyl A prevents lipopolysaccharide-induced fetal death but induces preterm labour  

PubMed Central

We have previously demonstrated that the anti-inflammatory prostaglandin 15-deoxy-? 12,14-prostaglandin J2 (15dPGJ2) delays inflammation-induced preterm labour in the mouse and improves pup survival through the inhibition of nuclear factor-?B (NF-?B) 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-?B, 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-?B, IL-1?, KC-GRO, interferon-? and tumour necrosis factor-?. 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

Sykes, Lynne; Herbert, Bronwen R; MacIntyre, David A; Hunte, Emma; Ponnampalam, Sathana; Johnson, Mark R; Teoh, Tiong G; Bennett, Phillip R



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

PubMed Central

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

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



Agonist and blocking actions of choline and tetramethylammonium on human muscle acetylcholine receptors  

Microsoft Academic Search

Choline has been used widely as an agonist for the investigation of gain-of-function mutants of the nicotinic acetylcholine receptor. It is useful because it behaves like a partial agonist. The efficacy of choline is difficult to measure because choline blocks the channel at concentrations about four times lower than those that activate it. We have fitted activation mechanisms to single-channel

Remigijus Lape; Paraskevi Krashia; David Colquhoun; Lucia G. Sivilotti



Long-acting beta(2)-agonists: how are they used in an optimal way?  


Inhaled long-acting beta(2)-agonists are frequently used for the treatment of asthma. When introduced to the market, the drug was accompanied by a debate among physicians and scientists raising warnings against the use of beta(2)-agonists, leading to a risk of tachyphylaxis and worsening of asthma control. During recent years, much of these warnings have been counter proved and there has been a tendency to institute treatment with long-acting beta(2)-agonists somewhat earlier in the course than before. However, the exact place for long-acting beta(2)-agonists in the asthma treatment plans, still needs to be established. While beta(2)-agonists have been shown to have anti-inflammatory activity in vitro and after single allergen exposure, this effect seems to disappear with regular treatment. The same phenomena have been shown to protect against obstruction caused by metacholine inhalation or exercise. Although the protective effect diminishes or even disappears, no signs of rebound phenomena or increased susceptibility to provocative stimulus has been shown. Thus, in contrast to earlier reports after regular use of short-acting beta(2)-agonists, no signs of tachyphylaxis have been reported after use of long-acting beta(2)-agonists. Moreover, the bronchodilatatory effect seems to be fairly stable after regular treatment, even though some reports claims that this effect diminishes over time. The present article is a review of some data involved in this debate. The authors conclude that long-acting beta(2)-agonists are a valuable contribution to the asthma treatment repertoire. However, the drugs should be regarded as long-acting bronchodilatators, supplementing the use of inhaled corticosteroids. The rapid appearing tolerance towards allergen-induced and provoked bronchial obstruction prevents these drugs from being used as monotherapy; they should be used only in combination with sufficient anti-inflammatory treatment, i.e. inhaled corticosteroids. PMID:9488891

Bjermer, L; Larsson, L



Comparison of the receptor binding characteristics of opiate agonists interacting with mu- or kappa-receptors.  

PubMed Central

1 The receptor binding characteristics of various morphine-like and ketazocine-like opiate agonists were measured by inhibition of [3H]-naloxone binding in homogenates of brain and of ileal myenteric plexus-longitudinal muscle of the guinea-pig. No differences were found for the two tissues. 2 The depressant effect of Na+ on the inhibition of [3H]-naloxone binding by opiate agonists varies widely, giving sodium shifts between 5 and 140. The relationship between Na+ concentration and inhibition of binding is non-linear, the magnitude of the sodium shift varying directly with the slope of the regression of log IC50 on log [NaCl]. 3 The sodium shift of ketazocine-like agonists is lower than that of morphine-like agonists but higher than that of opiates with dual agonist and antagonist action. A working hypothesis is proposed which suggests that the kappa-receptors for the ketazocine-like drugs are less susceptible to the Na+ effect than the mu-receptors for the morphine-like drugs. 4 For most of the morphine-like but not the ketazocine-like agonists, a good correlation has been found for the pharmacological activity in the myenteric plexus-longitudinal muscle preparation and the inhibition of binding of [3H]-naloxone at 12 mM Na+. An exception is fentanyl which has a much greater pharmacological potency than may be expected from its potency in inhibiting [3H]-naloxone binding. PMID:215262

Kosterlitz, H W; Leslie, F M



?-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent.  


Inhaled ?-agonists are effective at reversing bronchoconstriction in asthma, but the mechanism by which they exert this effect is unclear and controversial. PKA is the historically accepted effector, although this assumption is made on the basis of associative and not direct evidence. Recent studies have asserted that exchange protein activated by cAMP (Epac), not PKA, mediates the relaxation of airway smooth muscle (ASM) observed with ?-agonist treatment. This study aims to clarify the role of PKA in the prorelaxant effects of ?-agonists on ASM. Inhibition of PKA activity via expression of the PKI and RevAB peptides results in increased ?-agonist-mediated cAMP release, abolishes the inhibitory effect of isoproterenol on histamine-induced intracellular calcium flux, and significantly attenuates histamine-stimulated MLC-20 phosphorylation. Analyses of ASM cell and tissue contraction demonstrate that PKA inhibition eliminates most, if not all, ?-agonist-mediated relaxation of contracted smooth muscle. Conversely, Epac knockdown had no effect on the regulation of contraction or procontractile signaling by isoproterenol. These findings suggest that PKA, not Epac, is the predominant and physiologically relevant effector through which ?-agonists exert their relaxant effects. PMID:24973219

Morgan, Sarah J; Deshpande, Deepak A; Tiegs, Brian C; Misior, Anna M; Yan, Huandong; Hershfeld, Alena V; Rich, Thomas C; Panettieri, Reynold A; An, Steven S; Penn, Raymond B



Scaffold-Based Pan-Agonist Design for the PPAR?, PPAR? and PPAR? Receptors  

PubMed Central

As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPAR?, PPAR? and PPAR?, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPAR?/? and PPAR?/? dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPAR?, PPAR? and PPAR?. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPAR?, PPAR? and PPAR? receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME) predictions showed that the 7 compounds (especially Cpd#1) hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes. PMID:23119024

Xu, Wei-Ren; Wang, Run-Ling; Wang, Jing-Fang



Dopamine agonists rather than deep brain stimulation cause reflection impulsivity in Parkinson's disease  

PubMed Central

Objectives To assess the role of dopamine agonist therapy and deep brain stimulation on reflection impulsivity in non-demented patients with Parkinson’s disease (PD). Methods We recruited 61 PD patients, 20 treated with L-dopa in combination with a dopamine agonist, 14 taking L-dopa monotherapy, a further 16 PD patients with bilateral subthalamic nucleus deep brain stimulation treated with L-dopa in combination with a dopamine agonist, and 11 PD patients with bilateral subthalamic nucleus deep brain stimulation taking L-dopa but not a dopamine agonist. Results were compared with 18 healthy controls. Patients who had evidence of impulsive compulsive behaviour were excluded. Reflection impulsivity was assessed with the beads task, which is a validated information sampling task. Results All patients treated with a dopamine agonist gathered significantly less information and made more irrational decisions than all other groups regardless of whether they had surgical treatment. Conclusions Our results imply that dopamine agonist therapy but not deep brain stimulation lead to “reflection impulsivity“ in PD. PMID:23938343

Djamshidian, Atbin; O'Sullivan, Sean S.; Foltynie, Thomas; Aviles-Olmos, Iciar; Limousin, Patricia; Noyce, Alastair; Zrinzo, Ludvic; Lees, Andrew J.; Averbeck, Bruno B.



The Good, the Bad, and the Ugly: Agonistic Behaviour in Juvenile Crocodilians  

PubMed Central

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

Brien, Matthew L.; Lang, Jeffrey W.; Webb, Grahame J.; Stevenson, Colin; Christian, Keith A.



Beta3-Adrenoceptor Agonists: Possible Role in the Treatment of Overactive Bladder  

PubMed Central

In the present review article, we present an overview of beta-adrenoceptor (?-AR) subtype expression at the mRNA and receptor protein levels in the human detrusor, the in vitro and in vivo bladder function of the ?3-AR, the in vivo effect of ?3-AR agonists on detrusor overactivity in animal models, and the available results of clinical trials of ?3-AR agonists for treating overactive bladder (OAB). There is a predominant expression of ?3-AR mRNA in human bladder, constituting 97% of total ?-AR mRNA. Also, functionally, the relaxant response of human detrusor to catecholamines is mainly mediated through the ?3-ARs. Moreover, the presence of ?1-, ?2-, and ?3-AR mRNAs in the urothelium and suburothelial layer of human bladder has been identified. Stimulation of urothelial ?-ARs results in the release of nitric oxide and an unknown substance inhibiting detrusor contractions from the urothelium. Intravenous application of CL316,243, a selective ?3-AR agonist, in rats selectively inhibits mechano-sensitive A?-fiber activity of the primary bladder afferents. A number of selective ?3-AR agonists are currently being evaluated in clinical trials for OAB with promising preliminary results. In conclusion, the ?3-AR agonists are the most notable alternative class of agents to antimuscarinics in the pharmacological treatment of OAB. The ?3-AR agonists act to facilitate bladder storage function probably through at least two mechanisms: first, direct inhibition of the detrusor, and second, inhibition of bladder afferent neurotransduction. PMID:21221199

Aizawa, Naoki; Homma, Yukio



Pharmacological profile of ?3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome.  


?(3)-Adrenoceptor agonists are an emerging drug class for the treatment of the overactive bladder syndrome, and clinical proof-of-concept data have been obtained for three representatives of this class, mirabegron, ritobegron, and solabegron. We review here the pharmacological profile of these three drugs and discuss the potential clinical relevance of differences between them. In the absence of direct comparative studies, it appears that all three are strong agonists selective for ?(3)- vs. ?(1)- and ?(2)-adrenoceptors in studies with cloned receptor subtypes. The potency of these agonists may be species-dependent, with all three having high potency in the human detrusor. All three agonists were effective in one or more animal models of bladder dysfunction, which typically involved reductions of micturition frequency. Agonist doses effective for bladder function lowered blood pressure in some cases, but the relevance of this for clinical use is difficult to determine due to species differences in the importance of cardiovascular ?(3)-adrenoceptors. While limited effects on other organ systems are expected for ?(3)-adrenoceptor agonists, this requires further investigation. PMID:23263450

Igawa, Yasuhiko; Michel, Martin C



The good, the bad, and the ugly: agonistic behaviour in juvenile crocodilians.  


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

Brien, Matthew L; Lang, Jeffrey W; Webb, Grahame J; Stevenson, Colin; Christian, Keith A



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

SciTech Connect

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.

Rosenthal, M.D.; Garcia, M.C.; Sprecher, H. (Eastern Virginia Medical School, Norfolk (USA))



Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor  

PubMed Central

The nociceptin/orphanin FQ (NOP) receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q2 of 0.501, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity. PMID:22272114

Bao, Pingping; Zhang, Xiaole; Ren, Hong; Li, Yan; Mu, Zulin; Zhang, Shuwei; Li, Guohui; Yang, Ling



Plan de cours Facult des arts et des sciences  

E-print Network

Powerpoint sont en anglais tandis que je parle surtout en fran�ais et la plupart des discussions en classe se �tudiants devront pr�parer des diapositives en utilisant le logiciel PowerPoint. Les �tudiants doivent donc l'enseignement du fonctionnement des logiciels tels que PowerPoint, QuarkXPress, InDesign ou autre

Parrott, Lael



E-print Network

, clandestine immigrants, piracy, toxic waste pollution, accidents, etc.). Key words: Maritime border security1 SURVEILLANCE ET CONTROLE DES ACTIVITES DES NAVIRES EN MER ScanMaris Michel MOREL (DCNS), Aldo produits illicites, l'immigration clandestine, la sur exploitation des ressources halieutiques, les

Boyer, Edmond


La modelisation mathematique des plasmas au service des technologies spatiales  

E-print Network

1 La mod�elisation math�ematique des plasmas au service des technologies spatiales C. Besse (1) P'activit�e solaire sur l'environnement terrestre . . . . . . . . . . 13 2.3 Qu'est ce qu'un plasma.3.2 Plasmas froids et plasmas chauds . . . . . . . . . . . . . . . . . . . . . . 14 2.3.3 Autres aspects des

Vignal, Marie-Hélène


Qualit des composts et des digestats Fabienne MULLER  

E-print Network

Qualité des composts et des digestats Fabienne MULLER Direction consommation durable et déchets organiques se construit, avec aujourd'hui le développement important de la méthanisation. Les composts actuellement produits, peuvent l'être avec des digestats ou non. Les quantités de compost produit ne cessent d

Boyer, Edmond


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

PubMed Central

Background Long-acting bronchodilators comprising long-acting beta2-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta2-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear. Objectives To assess the relative effects of treatment with tiotropium in addition to long-acting beta2-agonist compared to tiotropium or long-acting beta2-agonist alone in patients with chronic obstructive pulmonary disease. Search methods We searched the Cochrane Airways Group Specialised Register of trials and up to January 2012. Selection criteria We included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta2-agonist against tiotropium or long-acting beta2-agonist alone for patients with chronic obstructive pulmonary disease. Data collection and analysis Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. Main results Five trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta2-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta2-agonist (formoterol) alone. Two studies used the long-acting beta2-agonist indacaterol, two used formoterol and one used salmeterol. Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long-acting beta2-agonist resulted in a slightly larger improvement in the mean health-related quality of life (St George’s Respiratory Questionnaire (SGRQ) MD ?1.61; 95% CI ?2.93 to ?0.29). In the control arm, tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with both treatments the improvement was a fall of 6.1 units from baseline (on average). High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality). The secondary outcome of pre-bronchodilator FEV1 showed a small mean increase with the addition of long-acting beta2-agonist (MD 0.07 L; 95% CI 0.05 to 0.09) over the control arm, which showed a change from baseline ranging from 0.03 L to 0.13 L on tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There were wide confidence intervals around these outcomes and moderate heterogeneity for both exacerbations and withdrawals. The results from the one trial comparing the combination of tiotropium and long-acting beta2-agonist to long-acting beta2-agonist alone (417 participants) were insufficient to draw firm conclusions for this comparison. Authors’ conclusions The results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta2-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta2-agonists to tiotropium as there were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta2-agonist compared to long-acting beta2-agonist alone. There were insufficient data to make comparisons between the different long-acting

Karner, Charlotta; Cates, Christopher J



Des conflits toutes les chelles  

E-print Network

Des conflits à toutes les échelles Des conflits à toutes les échelles La ressource en eau se raréfie et la demande s'accroît. Cette situation peut être source de tensions ou raviver des conflits déjà ayant droits d'amont et ceux d'aval, - différends entre deux rives d'un même canal, - conflits entre des


Die pharmakologische Wirkung des Ephedrins  

Microsoft Academic Search

Zusammenfassung 1.Die pharmakologische Wirkung des Ephedrins wurde zu analysieren versucht durch Studium der Beeinflussung des Blutdrucks, der Herzaktion und der Gefäße, des Effekts am Atemzentrum und an den Bronchien, der Wirkung auf die Pupillenweite, auf den Darm und den Uterus, auf die Sekretion verschiedener Drüsen und den Blutzuckerspiegel.2.Es wurden folgende Wirkungen gefunden: Der Blutdruck wird erhöht durch kleine Dosen, erniedrigt

H. Kreitmair




E-print Network

SYNTH�SE DES RUNS ORCA05 AVEC RAPPEL Octobre 2009 Patrice Bellec et Thierry Huck Laboratoire de Physique des Océans (UMR 6523 CNRS IFREMER IRD UBO) #12;Sommaire DESCRIPTION DES RUNS ORCA05 ........................................................................................3 ORCA05-BPB14 : run libre de 1958 à 2008

Huck, Thierry



E-print Network

NOTE TECHNIQUE RECHERCHE DES SALMONELLA PAR IMMUNOFLUORESCENCE M. CATSARAS J. ANANI Laboratoire Salmonella, 366 prélèvements, dans 125 boucheries, pour lesquels nous avons comparé les techniques d, dus à des coliformes. Ses avantages et ses inconvénients pour la recherche des Salmonella sont

Paris-Sud XI, Université de


LHRH agonists and the prevention of breast and ovarian cancer.  

PubMed Central

Early age at natural menopause or bilateral ovariectomy substantially reduce a woman's lifetime risk of breast cancer. Reversible 'bilateral ovariectomy' can now in effect be achieved by 'high-dose' luteinising hormone releasing hormone (LHRH) agonists (LHRHAs). The harmful effects of such medical reversible bilateral ovariectomy, in particular the increased risks of coronary heart disease and osteoporosis, can in all likelihood be obviated by 'low-dose' oestrogen replacement therapy (ERT), specifically 0.625 mg of conjugated equine oestrogens (CEE) for 21 days in each 28-day treatment cycle, and such ERT use will only negate to a relatively small extent the beneficial effect of such bilateral ovariectomy on breast cancer risk. We calculate that such an LHRHA plus low-dose ERT regimen given to a premenopausal woman for 10 years will, in addition to being a most effective contraceptive, decrease her lifetime risk of breast cancer by more than 50%. We calculate that such a 10-year regimen will also decrease her risk of ovarian cancer by two-thirds. This regimen should leave endometrial cancer risk and bone metabolism unaltered, and may reduce the risk of heart disease. The addition of a 'low-dose' progestogen to the regimen for 12 days in each 28-day treatment cycle would be beneficial to the endometrium, but it will adversely affect risk factors for heart disease and it may significantly reduce the benefit of the regimen as regards breast cancer. A satisfactory compromise may be to add a low-dose progestogen for 12 days at less frequent intervals. Another possibility may be to deliver a progestogen solely to the endometrium with an intra-uterine device; the benefits of such a regimen would be a significant reduction in the incidence of breast, ovarian and endometrial cancer. PMID:2679844

Pike, M. C.; Ross, R. K.; Lobo, R. A.; Key, T. J.; Potts, M.; Henderson, B. E.



Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B  

PubMed Central

TAM-163, an agonist monoclonal antibody targeting tyrosine receptor kinase-B (TrkB), is currently being investigated as a potential body weight modulatory agent in humans. To support the selection of the dose range for the first-in-human (FIH) trial of TAM-163, we conducted a mechanistic analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) data (e.g., body weight gain) obtained in lean cynomolgus and obese rhesus monkeys following single doses ranging from 0.3 to 60 mg/kg. A target-mediated drug disposition (TMDD) model was used to describe the observed nonlinear PK and Emax approach was used to describe the observed dose-dependent PD effect. The TMDD model development was supported by the experimental determination of the binding affinity constant (9.4 nM) and internalization rate of the drug-target complex (2.08 h?1). These mechanistic analyses enabled linking of exposure, target (TrkB) coverage, and pharmacological activity (e.g., PD) in monkeys, and indicated that ? 38% target coverage (time-average) was required to achieve significant body weight gain in monkeys. Based on the scaling of the TMDD model from monkeys to humans and assuming similar relationship between the target coverage and pharmacological activity between monkey and humans, subcutaneous (SC) doses of 1 and 15 mg/kg in humans were projected to be the minimally and the fully pharmacologically active doses, respectively. Based on the minimal anticipated biological effect level (MABEL) approach for starting dose selection, the dose of 0.05 mg/kg (3 mg for a 60 kg human) SC was recommended as the starting dose for FIH trials, because at this dose level < 10% target coverage was projected at Cmax (and all other time points). This study illustrates a rational mechanistic approach for the selection of FIH dose range for a therapeutic protein with a complex model of action. PMID:23529133

Vugmeyster, Yulia; Rohde, Cynthia; Perreault, Mylene; Gimeno, Ruth E.; Singh, Pratap



GABAA agonist reduces visual awareness: a masking-EEG experiment.  


Consciousness can be manipulated in many ways. Here, we seek to understand whether two such ways, visual masking and pharmacological intervention, share a common pathway in manipulating visual consciousness. We recorded EEG from human participants who performed a backward-masking task in which they had to detect a masked figure form its background (masking strength was varied across trials). In a within-subject design, participants received dextromethorphan (a N-methyl-d-aspartate receptor antagonist), lorazepam (LZP; a GABA(A) receptor agonist), scopolamine (a muscarine receptor antagonist), or placebo. The behavioral results show that detection rate decreased with increasing masking strength and that of all the drugs, only LZP induced a further decrease in detection rate. Figure-related ERP signals showed three neural events of interest: (1) an early posterior occipital and temporal generator (94-121 msec) that was not influenced by any pharmacological manipulation nor by masking, (2) a later bilateral perioccipital generator (156-211 msec) that was reduced by masking as well as LZP (but not by any other drugs), and (3) a late bilateral occipital temporal generator (293-387 msec) that was mainly affected by masking. Crucially, only the intermediate neural event correlated with detection performance. In combination with previous findings, these results suggest that LZP and masking both reduce visual awareness by means of modulating late activity in the visual cortex but leave early activation intact. These findings provide the first evidence for a common mechanism for these two distinct ways of manipulating consciousness. PMID:22264199

van Loon, Anouk M; Scholte, H Steven; van Gaal, Simon; van der Hoort, Björn J J; Lamme, Victor A F



Agonist-induced peroxynitrite production from endothelial cells.  


Nitric oxide reacts with superoxide to form peroxynitrite, a potential mediator of oxidant-induced cellular injury. The endothelium is a primary target of injury in many pathological states, including acute lung injury, sepsis, multiple organ failure syndrome, and atherosclerosis, where enhanced production of nitric oxide and superoxide occurs simultaneously. It was hypothesized that stimulation of endothelial cell nitric oxide production would result in formation of peroxynitrite. Immediate oxidant production was detected by luminol- and lucigenin-enhanced chemiluminescence from cultured bovine aortic endothelial cells exposed to bradykinin or to the calcium ionophore A23187. Luminol-enhanced chemiluminescence was efficiently inhibited by the nitric oxide synthase inhibitor nitro-L-arginine methyl ester and by superoxide dismutase, implying dependence on the presence of both nitric oxide and superoxide for oxidant production. Inhibition of luminol-enhanced chemiluminescence by nitro-L-arginine methyl ester was partially reversed by L-arginine, but not by D-arginine. Cysteine, methionine, and urate, known inhibitors of peroxynitrite-mediated oxidation, inhibited luminol-enhanced chemiluminescence, while the hydroxyl radical scavengers, mannitol and dimethylsulfoxide, and catalase did not. Bicarbonate increased luminol-enhanced chemiluminescence in a concentration-dependent manner. Superoxide production, detected by lucigenin-enhanced chemiluminescence, was slightly increased in the presence of nitro-L-arginine methyl ester, suggesting that endothelial cell-produced superoxide was partially metabolized by reaction with nitric oxide. These results are consistent with agonist-induced peroxynitrite production by endothelial cells and suggests that peroxynitrite may have an important role in oxidant-induced endothelial injury. PMID:8179319

Kooy, N W; Royall, J A



Characterization of a potent human interleukin-11 agonist.  

PubMed Central

Human interleukin-11 (hIL-11) is a multi-potential cytokine that is involved in numerous biological activities, such as haematopoiesis, osteoclastogenesis, neurogenesis and female fertility, and also displays anti-inflammatory properties. IL-11 is used clinically to treat chemotherapy-induced thrombocytopenia. Because of its broad spectrum of action, improved IL-11 agonists, as well as IL-11 antagonists, could be of interest for numerous clinical applications. IL-11 signalling is dependent on the formation of a tripartite ligand-receptor complex consisting of IL-11, the IL-11R (IL-11 receptor) alpha subunit (responsible for the specificity of the interaction) and gp130 (glycoprotein 130) receptor beta subunit (responsible for signal transduction). The interaction between IL-11 and IL-11Ralpha subunit occurs at its recently assigned site I. We have designed an IL-11 mutein whose hydrophobicity at site I has been increased. The mutein has been characterized in terms of structure, affinity, specificity and bioactivity. Electrophoretic analysis, gel filtration, IR spectroscopy and CD indicate that this new protein is more compact than wild-type IL-11. It binds to IL-11Ralpha with a three-fold-enhanced affinity, and retains the ability to recruit gp130 through site II. However, analysis of its biological activity revealed a complex pattern: although this mutein is 60-400-fold more active than wild-type IL-11 on the proliferation of 7TD1 murine hybridoma cell, it is less active than IL-11 on the proliferation of B9 cells, another murine hybridoma cell line. The results are interpreted on the basis of an IL-11 conformational change induced by the mutations, and the preferential use by the mutein of another unknown transducing receptor chain. PMID:12919066

Harmegnies, Dimitri; Wang, Xiao-Ming; Vandenbussche, Paul; Leon, Arnaud; Vusio, Patricia; Grotzinger, Joachim; Jacques, Yannick; Goormaghtigh, Erik; Devreese, Bart; Content, Jean



Agonist-bound structure of the human P2Y12 receptor  

PubMed Central

The P2Y12 receptor (P2Y12R), one of eight members of the P2YR family expressed in humans, has been identified as one of the most prominent clinical drug targets for inhibition of platelet aggregation. Consequently, extensive mutagenesis and modeling studies of the P2Y12R have revealed many aspects of agonist/antagonist binding1-4. However, the details of agonist and antagonist recognition and function at the P2Y12R remain poorly understood at the molecular level. Here, we report the structures of the human P2Y12R in complex with a full agonist 2-methylthio-adenosine-5?-diphosphate (2MeSADP, a close analogue of endogenous agonist ADP) at 2.5 Å resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5?-triphosphate (2MeSATP) at 3.1 Å resolution. Analysis of these structures, together with the structure of the P2Y12R with antagonist ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283)5, reveals dramatic conformational changes between nucleotide and non-nucleotide ligand complexes in the extracellular regions, providing the first insight into a different ligand binding landscape in the ?-group of class A G protein-coupled receptors (GPCRs). Agonist and non-nucleotide antagonist adopt different orientations in the P2Y12R, with only partially overlapped binding pockets. The agonist-bound P2Y12R structure answers long-standing ambiguities surrounding P2Y12R-agonist recognition, and reveals interactions with several residues that had not been reported to be involved in agonist binding. As a first example of a GPCR where agonist access to the binding pocket requires large scale rearrangements in the highly malleable extracellular region, the structural studies therefore will provide invaluable insight into the pharmacology and mechanisms of action of agonists and different classes of antagonists for the P2Y12R and potentially for other closely related P2YRs. PMID:24784220

Zhang, Jin; Zhang, Kaihua; Gao, Zhan-Guo; Paoletta, Silvia; Zhang, Dandan; Han, Gye Won; Li, Tingting; Ma, Limin; Zhang, Wenru; Muller, Christa E.; Yang, Huaiyu; Jiang, Hualiang; Cherezov, Vadim; Katritch, Vsevolod; Jacobson, Kenneth A.; Stevens, Raymond C.; Wu, Beili; Zhao, Qiang



Une charte pour scuriser la pratique des stages charte des stages des tudiants en entreprise  

E-print Network

Une charte pour sécuriser la pratique des stages charte des stages des étudiants en entreprise Le 26 avril 2006, une charte, dont l'objectif est de sécuriser la pratique des stages, a été conclue parcours pédagogique. Un stage ne peut être considéré comme un emploi. Cette charte, rédigée par les

Di Girolami, Cristina


Historic Des Moines  

NSDL National Science Digital Library

The early 20th century was a bustling time for many cities in the Midwest, and Des Moines was no exception. During this time, the city added streetcars, built many new public schools, and welcomed thousands of new residents. This digital collection from Drake University's Cowles Library offers hundreds of images of the city from 1904 through 1914. First-time visitors should read the introductory essay by John Zeller titled "From the Real to the Ideal; Images of Des Moines in the Progressive Era." After reading this piece, visitors will have a sense of the historical context of the images in the archive and Des Moines's history during this period. Visitors can browse at their leisure, and they can also use the interactive map to wander virtually around the city. Visitors should use the map to look at some of the wonderful homes around Union Park, including the L. Aulmann residence at 1712 Pennsylvania Avenue.



Cigarette smoke exposure inhibits contact hypersensitivity via the generation of platelet-activating factor agonists.  


Previous studies have established that pro-oxidative stressors suppress host immunity because of their ability to generate oxidized lipids with platelet-activating factor receptor (PAF-R) agonist activity. Although exposure to the pro-oxidative stressor cigarette smoke (CS) is known to exert immunomodulatory effects, little is known regarding the role of PAF in these events. The current studies sought to determine the role of PAF-R signaling in CS-mediated immunomodulatory effects. We demonstrate that CS exposure induces the generation of a transient PAF-R agonistic activity in the blood of mice. CS exposure inhibits contact hypersensitivity in a PAF-R-dependent manner as PAF-R-deficient mice were resistant to these effects. Blocking PAF-R agonist production either by systemic antioxidants or treatment with serum PAF-acetyl hydrolase enzyme blocked both the CS-mediated generation of PAF-R agonists and PAF-R-dependent inhibition of contact hypersensitivity (CHS) reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that cyclooxygenase-2 acts downstream of the PAF-R in mediating CS-induced systemic immunosuppression. Moreover, CS exposure induced a significant increase in the expression of the regulatory T cell reporter gene in Foxp3(EGFP) mice but not in Foxp3(EGFP) mice on a PAF-R-deficient background. Finally, regulatory T cell depletion via anti-CD25 Abs blocked CS-mediated inhibition of CHS, indicating the potential involvement of regulatory T cells in CS-mediated systemic immunosuppression. These studies provide the first evidence, to our knowledge, that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation. PMID:23355733

Sahu, Ravi P; Petrache, Irina; Van Demark, Mary J; Rashid, Badri M; Ocana, Jesus A; Tang, Yuxuan; Yi, Qiaofang; Turner, Matthew J; Konger, Raymond L; Travers, Jeffrey B



PPAR agonists regulate brain gene expression: Relationship to their effects on ethanol consumption.  


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 (PPAR?/?; 1.5 mg/kg) and fenofibrate (PPAR?; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPAR?/?/?; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior. PMID:25036611

Ferguson, Laura B; Most, Dana; Blednov, Yuri A; Harris, R Adron



Agonistic onset during development differentiates wild house mouse males (Mus domesticus)  

NASA Astrophysics Data System (ADS)

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.

Krackow, Sven



Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists  

PubMed Central

Sigma1 receptors (?1Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective ?1R 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 ?1R agonist. In contrast, after subjects self-administered cocaine ?1R 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 ?1R agonists, extinguished when injections were discontinued, and reconditioned when ?1R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of ?1R 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 ?R 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 ?1R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced ?1R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse. PMID:23187725

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



Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics  

PubMed Central

The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs) using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPAR? agonists (such as fibrates) and the glycemic advantages of the PPAR? agonists (such as thiazolidinediones), are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type 2 diabetes) did in activating PPAR? and PPAR?, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPAR? and PPAR? among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes. PMID:23630413

Liu, Lei; Ma, Ying; Wang, Run-Ling; Xu, Wei-Ren; Wang, Shu-Qing; Chou, Kuo-Chen



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


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, ?-chlornaltrexamine (?-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 ?-CNA, there was an increase in the time it took to reach a peak current. The decrease in the rate of agonist-induced GIRK conductance was receptor selective and dependent on receptor number. The results indicate that opioid receptor desensitization reduced the number of functional receptor and that the remaining active receptors have a reduced agonist affinity. PMID:24748657

Williams, John T



Detecting associations between behavioral addictions and dopamine agonists in the Food & Drug Administration's Adverse Event database  

PubMed Central

Background/Aims: Studies have reported higher prevalences of four behavioral addictions (binge eating, compulsive shopping, hypersexuality, and pathological gambling) in dopamine agonist-treated Parkinson’s disease relative to non-dopamine agonist-treated Parkinson’s. However, recent case-control and epidemiological studies suggest that prevalences of behavioral addictions in dopamine agonist-treated Parkinson’s may be similar to background population rates. This study tests that hypothesis by examining the FDA Adverse Event Reporting System (FAERS) for evidence of these associations, taking into account the potential impact of publicity on reporting rates. Methods: FAERS reports in 2004 (pre-publicity for all but pathological gambling) and 2007 (post-publicity for all four behaviors) were analyzed. A threshold consisting of ?3 cases, proportional reporting ratio ?2, and ?2 with Yates’ correction ?4 was used to detect signals (drug-associated adverse reactions) involving any of five dopamine agonists and any of four behavioral addictions. Results: No reports containing compulsive shopping and no signal for binge eating and dopamine agonists were found in either year. A weak signal was found for hypersexuality in 2004, with a stronger signal in 2007. A robust signal was found for pathological gambling in 2004, with a more robust signal in 2007. Discussion/Conclusions: These results suggest that publicity may increase reporting rates in the FAERS. Findings for binge eating, compulsive shopping, and hypersexuality suggest that prevalences of these behaviors among those treated with dopamine agonists may be similar to background population rates and thus may not reflect an adverse safety signal. Further investigation of the relationship between dopamine agonists and behavioral addictions is warranted.

Gendreau, Katherine E.; Potenza, Marc N.



Interactions of dopamine agonists with brain D1 receptors labeled by /sup 3/H-antagonists. Evidence for the presence of high and low affinity agonist-binding states  

SciTech Connect

The interactions of dopaminergic agonists and antagonists with /sup 3/H-antagonist labeled D1 dopamine receptors of rat striatum have been characterized. (/sup 3/H)Flupentixol has been found to selectively label D1 dopamine receptors when its binding to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone. Antagonist//sup 3/H-antagonist competition curves are of uniformly steep slope (nH . 1.0) suggesting the presence of a single D1 dopamine receptor. Agonist//sup 3/H-antagonist competition curves are extremely shallow (nH less than or equal to 0.5) for agonists of high relative efficacy, suggesting the presence of heterogeneous populations of agonist-binding states of the D1 dopamine receptor. Computer-modeling techniques were used to estimate affinities and relative site densities for these heterogeneous binding states. This analysis indicates that the ratio of agonist affinities for low and high affinity agonist-binding states is correlated with agonist relative efficacies in activating adenylate cyclase in membrane homogenates. Under the assay conditions employed, the addition of saturating concentrations of guanine nucleotides reduced, but did not abolish, the relative density of high affinity agonist-binding sites. These binding data can, at least in part, be explained by postulating two states of the D1 dopamine receptor, inducible by agonists but not by antagonists and modulated by guanine nucleotides.

Leff, S.E.; Hamblin, M.W.; Creese, I.



Effect of 3-week treatment with [D-Trp6, des-Gly-NH10(2)]LHRH ethylamide, aminoglutethimide, ketoconazole or flutamide alone or in combination on testicular, serum, adrenal and prostatic steroid levels in the dog.  


Adult male mongrel dogs were treated with the LHRH agonist [D-Trp6, des-Gly-NH10(2)]LHRH ethylamide, aminoglutethimide, ketoconazole or flutamide alone or in combination for 21 days before measurement of steroid levels in the testes, prostate, adrenals and serum. Ketoconazole alone caused a marked stimulation of the intra-testicular concentration of pregnenolone, 17OH-pregnenolone, progesterone and 17OH-progesterone with no or little change of androstenedione, testosterone and dihydrotestosterone. Aminoglutethimide caused a 30-95% inhibition in the concentration of all steroids in the tests while treatment with the LHRH agonist caused a near complete inhibition of all testicular steroids. When administered concomitantly with the LHRH agonist, ketoconazole partly prevented the inhibitory effect of the LHRH agonist on testicular steroid levels. Serum levels of dehydroepiandrosterone, androst-5-ene-3 beta,17 beta-diol, androstenedione and androstane-3 alpha, 17 beta-diol were 75 to 95% inhibited by the LHRH agonist while serum testosterone and dihydrotestosterone concentrations were reduced below detection limits by the same treatment. Moreover, treatment with the LHRH agonist caused a 70-95% reduction in the intraprostatic concentration of testosterone and dihydrotestosterone in all the groups although maximal effect was observed when the LHRH agonist was combined with any of the three other agents. The present data show that while treatment with ketoconazole, aminoglutethimide or Flutamide alone has only partial inhibitory effects on androgen levels, combination with an LHRH agonist provides maximal inhibition. In addition to its direct blockade of the androgen receptor, some of the effect of Flutamide could be related to its blockade of testicular 3 beta-hydroxy-steroid dehydrogenase activity. PMID:2671505

Lacoste, D; Caron, S; Bélanger, A; Labrie, F



Alpha 2 agonists in regional anesthesia and analgesia.  


Clonidine is a partial alpha 2 adrenergic agonist that has a variety of different actions including antihypertensive effects as well as the ability to potentiate the effects of local anesthetics. It can provide pain relief by an opioid-independent mechanism. It has been shown to result in the prolongation of the sensory blockade and a reduction in the amount or concentration of local anesthetic required to produce perioperative analgesia. Different routes for the administration of regional anesthesia, including intravenous, intrathecal and epidural ones, as well as the addition of clonidine for peripheral neural blockade, have been described. It has been also used for intra-articular administration. The latest articles describing the use of clonidine in regional anesthesia are discussed. Most authors agree that the use of clonidine for regional neural blockade in combination with a local anesthetic results in increased duration of sensory blockade with no difference in onset time. The addition of clonidine to the local anesthetic opioid mixtures seems to produce analgesia of longer duration, more rapid onset and higher quality. The higher doses of clonidine were associated with a more cephalad spread of the spinal blockade and increased sedation and hypertension. When clonidine is added to a fentanyl-bupivacaine mixture for epidural labor analgesia, it seems to provide satisfactory analgesia of a longer duration than that produced by the fentanyl-bupivacaine combination alone. Similar results were found when epidural analgesia using levobupivacaine with clonidine was used in patients undergoing total hip arthroplasty. Less clear results were seen when clonidine was used for caudal anesthesia in a pediatric patient population. The addition of clonidine to intravenous regional anesthesia resulted in prolongation of the tourniquet time and improvement of postoperative analgesia. However, the latter was found to be short-lived. In another study, the effects of clonidine used for intra-articular administration in combination with morphine were investigated. These authors found a significantly higher rate of satisfaction in the group of patients receiving clonidine plus morphine. Although several recent studies have shown certain benefits from the use of clonidine for regional anesthesia, further investigations are necessary to clarify its role. PMID:17019175

Gabriel, J S; Gordin, V



Des Vents et des Jets Astrophysiques  

NASA Astrophysics Data System (ADS)

Plasma outflows from a central gravitating object are a widespread phenomenon in astrophysics. They include the solar and stellar winds, jets from Young Stellar Objects, jets from compact stellar objects and extra-galactic jets associated with Active Galactic Nuclei and quasars. Beyond this huge zoology, a common theoretical ground exists. The aim of this review is to present qualitatively the various theories of winds (Part 1) and how different astrophysical domains interplay. A more or less complete catalog of the ideas proposed for explaining the acceleration and the morphologies of winds and jets is intended. All this part avoids getting into any mathematical formalism. Some macroscopic properties of such outflows may be described by solving the time-independent and axisymmetric magnetohydrodynamic equations. This formalism, underlying most of the theories, is presented in Part 2. It helps to introduce quantitatively the free integrals that such systems possess. Those integrals play an important role in the basic physics of acceleration and collimation, in particular the mass loss rate, the angular momentum loss rate and the energy of the magnetic rotator. Most of the difficulty in modelling flows lies in the necessity to cross critical points, characteristic of non linear equations. The physical nature and the location of such critical points is debated because they are the clue towards the resolution. We thus introduce the notions of topology and critical points (Parts 3 and 4) from the simplest hydrodynamic and spherically symmetric case to the most sophisticated, MHD and axisymmetric cases. Particular attention is given to self-similar models which allows to give some general and simple ideas on the problem due to their semi-analytical treatment. With the use of these notions, a more quantitative comparison of the various models is given (Parts 3 and 4), especially on the shape of the flows. It is thus shown that magnetic collimation of winds into jets is a well expected result from the theory. Although, collimation may be conical, paraboloidal or cylindrical (Part 4), cylindrical collimation is the more likely to occur. The shape of outflows may then be used as a tool to predict physical conditions on the flows or on their source. L'éjection continue de plasma autour d'objets massifs est un phénomène largement répandu en astrophysique, que ce soit sous la forme du vent solaire, de vents stellaires, de jets d'étoiles en formation, de jets stellaires autour d'objets compacts ou de jets extra-galactiques. Cette zoologie diversifiée fait pourtant l'objet d'un commun effort de modélisation. Le but de cette revue est d'abord de présenter qualitativement le développement, depuis leur origine, des diverses théories de vents (Partie 1) et l'inter disciplinarité dans ce domaine. Il s'agit d'une énumération, plus ou moins exhaustive, des idées proposées pour expliquer l'accélération et la morphologie des vents et des jets, accompagnée d'une présentation sommaire des aspects observationnels. Cette partie s'abstient de tout aspect faisant appel au formalisme mathématique. Ces écoulements peuvent être décrits, au moins partiellement, en résolvant les équations magnétohydrodynamiques, axisymétriques et stationnaires. Ce formalisme, à la base de la plupart des théories, est exposé dans la Partie 2. Il permet d'introduire quantitativement les intégrales premières qu'un tel système possède. Ces dernières sont amenées à jouer un rôle important dans la compréhension des phénomènes d'accélération ou de collimation, en particulier le taux de perte de masse, le taux de perte de moment angulaire ou l'énergie du rotateur magnétique. La difficulté de modélisation réside dans l'existence de points critiques, propres aux équations non linéaires, qu'il faut franchir. La nature physique et la localisation de ces points critiques fait l'objet d'un débat important car ils sont la clef de voute de la résolution. Nous introduisons donc la notion de topologie des points critiques (Parties 3 et 4

Sauty, C.


Bitter taste receptor agonists elicit G-protein-dependent negative inotropy in the murine heart.  


G-protein-coupled receptors (GPCRs) are key mediators in cardiovascular physiology, yet frontline therapies for heart disease target only a small fraction of the cardiac GPCR repertoire. Moreover, there is emerging evidence that GPCRs implicated in taste (Tas1r and Tas2rs) have specific functions beyond the oral cavity. Our recent description of these receptors in heart tissue foreshadows a potential novel role in cardiac cells. In this study, we identified novel agonist ligands for cardiac-Tas2rs to enable the functional investigation of these receptors in heart tissue. Five Tas2rs cloned from heart tissue were screened against a panel of 102 natural or synthetic bitter compounds in a heterologous expression system. We identified agonists for Tas2r108, Tas2r137, and Tas2r143 that were then tested in Langendorff-perfused mouse hearts (from 8-wk-old male C57BL/6 mice). All Tas2r agonists tested exhibited concentration-dependent effects, with agonists for Tas2r108 and Tas2r137, leading to a ?40% decrease in left ventricular developed pressure and an increase in aortic pressure, respectively. These responses were abrogated in the presence of G?i and G?? inhibitors (pertussis toxin and gallein). This study represents the first demonstration of profound Tas2r agonist-induced, G protein-dependent effects on mouse heart function. PMID:25002118

Foster, Simon R; Blank, Kristina; See Hoe, Louise E; Behrens, Maik; Meyerhof, Wolfgang; Peart, Jason N; Thomas, Walter G



Study on the agonists for the human Toll-like receptor-8 by molecular modeling.  


Toll-like receptor-8 agonists could be promising candidates for vaccine adjuvants, especially for neonatal vaccines. In this study, we established reliable models and explored valuable information which could explain the known experimental facts at the molecular level. Firstly, we divided the whole dataset into four splits and obtained many dependable models based on the simplified molecular input line entry system (SMILES). Secondly, the whole dataset was divided into three splits and other reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were established. Thirdly, we validated the prediction ability of these models using various validation methods for the test set. Lastly, for a better understanding of the binding modes between agonists and Toll-like receptor-8, molecular docking was applied to reveal the structural factors that impact the activity of agonists towards Toll-like receptor-8. Furthermore, molecular dynamics simulation was employed to further validate the docking results. The results obtained from molecular modeling support each other, which not only provides models to predict the activities of agonists but also leads to a better understanding of the essential features that should be considered when designing novel agonists with desired activities. PMID:24918397

Deng, Fangfang; Ma, Shuying; Xie, Meihong; Zhang, Xiaoyun; Li, Peizhen; Zhai, Honglin



BAY60-6583 acts as a partial agonist at adenosine A2B receptors.  


BAY60-6583 [2-({6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-yl}sulfanyl)acetamide] is the most potent and selective adenosine A2B receptor (A2B AR) agonist known to date. Therefore, it has been widely used for in vitro and in vivo experiments. In the present study, we investigated the binding and functional properties of BAY60-6583 in various native and recombinant cell lines with different A2B AR expression levels. In cAMP accumulation and calcium mobilization assays, BAY60-6583 was found to be significantly less efficacious than adenosine or the adenosine derivative NECA. When it was tested in human embryonic kidney (HEK)293 cells, its efficacy correlated with the A2B expression level of the cells. In Jurkat T cells, BAY60-6583 antagonized the agonistic effect of NECA and adenosine as determined in cAMP accumulation assays. On the basis of these results, we conclude that BAY60-6583 acts as a partial agonist at adenosine A2B receptors. At high levels of the physiologic agonist adenosine, BAY60-6583 may act as an antagonist and block the effects of adenosine at A2B receptors. This has to be considered when applying the A2B-selective "agonist" BAY60-6583 in pharmacological studies, and previous research results may have to be reinterpreted. PMID:24633424

Hinz, Sonja; Lacher, Svenja K; Seibt, Benjamin F; Müller, Christa E



Gonadotropin-releasing hormone: an update review of the antagonists versus agonists.  


Gonadotropin-releasing hormone agonists and antagonists provide androgen-deprivation therapy for prostate cancer. Unlike agonists, gonadotropin-releasing hormone antagonists have a direct mode of action to block pituitary gonadotropin-releasing hormone receptors. There are two licensed gonadotropin-releasing hormone antagonists, degarelix and abarelix. Of these, degarelix is the more extensively studied and has been documented to be more effective than the well-established, first-line agonist, leuprolide, in terms of substantially faster onset of castration, faster suppression of prostate-specific antigen, no risk for testosterone surge or clinical flare, and improved prostate-specific antigen progression-free survival, suggesting a delay in castration resistance. Other than minor injection-site reactions, degarelix is generally well tolerated, without systemic allergic reactions and with most adverse events consistent with androgen suppression or the underlying condition. In conclusion, degarelix provides a rational, first-line androgen-deprivation therapy suitable for the treatment of prostate cancer, with faster onset of castration than with agonists, and no testosterone surge. Furthermore, data suggest that degarelix improves disease control compared with leuprolide, and might delay the onset of castration-resistant disease. In view of these clinical benefits and the lack of need for concomitant anti-androgen treatment, gonadotropin-releasing hormone antagonists might replace gonadotropin-releasing hormone agonists as first-line androgen-deprivation therapy in the future. PMID:22416801

Van Poppel, Hein; Klotz, Laurence



Identification of Adiponectin Receptor Agonist Utilizing a Fluorescence Polarization Based High Throughput Assay  

PubMed Central

Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (-)-arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases. PMID:23691032

Sun, Yiyi; Zang, Zhihe; Zhong, Ling; Wu, Min; Su, Qing; Gao, Xiurong; Zan, Wang; Lin, Dong; Zhao, Yan; Zhang, Zhonglin



Simulations of Biased Agonists in the ?2 Adrenergic Receptor with Accelerated Molecular Dynamics  

PubMed Central

The biased agonism of the G protein-coupled receptors (GPCRs), where in addition to a traditional G protein-signaling pathway a GPCR promotes intracellular signals though ?-arrestin, is a novel paradigm in pharmacology. Biochemical and biophysical studies have suggested that a GPCR forms a distinct ensemble of conformations signaling through the G protein and ?-arrestin. Here we report on the dynamics of the ?2 adrenergic receptor bound to the ?-arrestin and G protein-biased agonists and the empty receptor to further characterize the receptor conformational changes caused by biased agonists. We use conventional and accelerated molecular dynamics (aMD) simulations to explore the conformational transitions of the GPCR from the active state to the inactive state. We found that aMD simulations enable monitoring of the transition within the nanosecond time scale while capturing the known microscopic characteristics of the inactive states, such as the ionic lock, the inward position of F6.44, and water clusters. Distinct conformational states are shown to be stabilized by each biased agonist. In particular, in simulations of the receptor with the ?-arrestin-biased agonist N-cyclopentylbutanepherine, we observe a different pattern of motions in helix 7 when compared to simulations with the G protein-biased agonist salbutamol that involves perturbations of the network of interactions within the NPxxY motif. Understanding the network of interactions induced by biased ligands and the subsequent receptor conformational shifts will lead to development of more efficient drugs. PMID:23879802



Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled receptor 119.  


A series of GPR119 agonists based on a 2,6-diazatricyclo[,7?]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules. PMID:23234271

Darout, Etzer; Robinson, Ralph P; McClure, Kim F; Corbett, Matthew; Li, Bryan; Shavnya, Andrei; Andrews, Melissa P; Jones, Christopher S; Li, Qifang; Minich, Martha L; Mascitti, Vincent; Guimarães, Cristiano R W; Munchhof, Michael J; Bahnck, Kevin B; Cai, Cuiman; Price, David A; Liras, Spiros; Bonin, Paul D; Cornelius, Peter; Wang, Ruduan; Bagdasarian, Victoria; Sobota, Colleen P; Hornby, Sam; Masterson, Victoria M; Joseph, Reena M; Kalgutkar, Amit S; Chen, Yue



Conservation des Textiles  

E-print Network

Conservation des Textiles Les 22 et 23 mai 2013 Soit 2 jours - 14 heures OBJECTIFS DE LA FORMATION essentielles dans la gestion de collections textiles, depuis leur identification jusqu'à leur conservation conservation d'éléments et de collections textiles, et toutes personnes travaillant dans le domaine du

Brest, Université de


Therapiestrategien des fortgeschrittenen Nierenkarzinoms  

Microsoft Academic Search

Die Therapie des metastasierten Nierenkarzinoms hat in den letzten Jahren eine grundlegende Wandlung erfahren. Galt diese Entität früher als infaust und inoperabel, so gilt mittlerweile als gesichert, dass die Tumornephrektomie auch bei metastasierten Primärtumoren als urologisch-onkologischer Standard gilt, sofern im individuellen Fall vertretbar und technisch machbar. Auch die operative Entfernung von Metastasen, sofern eine komplette Resektion möglich ist, gilt als

M. Staehler; N. Haseke; G. Schöppler; T. Stadler; C. Adam; C. G. Stief



Induction of Selective Blood-Tumor Barrier Permeability and Macromolecular Transport by a Biostable Kinin B1 Receptor Agonist in a Glioma Rat Model  

PubMed Central

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[dPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites. PMID:22629405

Côté, Jérôme; Bovenzi, Veronica; Savard, Martin; Dubuc, Céléna; Fortier, Audrey; Neugebauer, Witold; Tremblay, Luc; Müller-Esterl, Werner; Tsanaclis, Ana-Maria; Lepage, Martin; Fortin, David; Gobeil, Fernand



Hormonal induction of spawning in 4 species of frogs by coinjection with a gonadotropin-releasing hormone agonist and a dopamine antagonist  

PubMed Central

Background It is well known that many anurans do not reproduce easily in captivity. Some methods are based on administration of mammalian hormones such as human chorionic gonadotropin, which are not effective in many frogs. There is a need for simple, cost-effective alternative techniques to induce spawning. Methods Our new method is based on the injection of a combination of a gonadotropin-releasing hormone (GnRH) agonist and a dopamine antagonist. We have named this formulation AMPHIPLEX, which is derived from the combination of the words amphibian and amplexus. This name refers to the specific reproductive behavior of frogs when the male mounts and clasps the female to induce ovulation and to fertilize the eggs as they are laid. Results We describe the use of the method and demonstrate its applicability for captive breeding in 3 different anuran families. We tested several combinations of GnRH agonists with dopamine antagonists using Lithobates pipiens. The combination of des-Gly10, D-Ala6, Pro-LHRH (0.4 microrams/g body weight) and metoclopramide (10 micrograms/g BWt. MET) was most effective. It was used in-season, after short-term captivity and in frogs artificially hibernated under laboratory conditions. The AMPHIPLEX method was also effective in 3 Argentinian frogs, Ceratophrys ornata, Ceratophrys cranwelli and Odontophrynus americanus. Conclusion Our approach offers some advantages over other hormonally-based techniques. Both sexes are injected only once and at the same time, reducing handling stress. AMPHIPLEX is a new reproductive management tool for captive breeding in Anura. PMID:20398399



Sex-specific differences in Type 2 Diabetes Mellitus and dyslipidemia therapy: PPAR agonists.  


The influence of sex on the development of obesity, Type 2 Diabetes Mellitus (T2DM), and dyslipidemia is well documented, although the molecular mechanism underlying those differences reminds elusive. Ligands of peroxisome proliferator-activated receptors (PPARs) are used as oral antidiabetics (PPARgamma agonists: thiazolidinediones, TZDs), or for the treatment of dyslipidemia and cardiovascular diseases, due to their lipid-lowering properties (PPARalpha agonists: fibrates), as PPARs control transcription of a set of genes involved in the regulation of lipid and carbohydrate metabolism. Given a high prevalence of those metabolic disorders, and thus a broad use of PPAR agonists, the present review will discuss distinct aspects of sex-specific differences in antiobesity treatment using those groups of PPAR ligands. PMID:23027460

Benz, Verena; Kintscher, Ulrich; Foryst-Ludwig, Anna



Opioid kappa-receptor agonists suppress sexual behaviors in male rough-skinned newts (Taricha granulosa).  


Four experiments were performed to evaluate a possible opioid involvement in the regulation of sexual behavior (amplectic clasping of a female) in intact adult male rough-skinned newts (Taricha granulosa) during the breeding season. It was found that an ip injection of bremazocine, a kappa-receptor opiate agonist, can markedly reduce sexual activity and that an ip injection of naloxone can reverse this inhibition in a dose-dependent fashion. In contrast, in male newts that were sexually inactive before treatment, injections of naloxone failed to induce sexual behavior, suggesting that opioid mechanisms do not normally exert a tonic inhibition of amphibian sexual behavior. In addition, an injection of ethylketocyclazocine (another kappa-receptor agonist), but not morphine (a mu-receptor agonist) suppressed sexual behaviors of male newts. These results indicate that opioid mechanisms that include kappa-type opioid receptors may contribute to the regulation of sexual behavior in nonmammalian vertebrates. PMID:2822565

Deviche, P; Moore, F L



Search for new type of PPAR? agonist-like anti-diabetic compounds from medicinal plants.  


Potent ligands of peroxisome proliferator-activated receptor ? (PPAR?) such as thiazolidinediones (pioglitazone, troglitazone, etc.) improve insulin sensitivity by increasing the levels of adiponectin, an important adipocytokine associated with insulin sensitivity in adipose tissue. Several constituents from medicinal plants were recently reported to show PPAR? agonist-like activity in 3T3-L1 cells, but did not show agonistic activity at the receptor site different from thiazolidinediones. Our recent studies on PPAR? agonist-like constituents, such as hydrangenol and hydrangeic acid from the processed leaves of Hydrangea macrophylla var. thunbergii, piperlonguminine and retrofractamide A from the fruit of Piper chaba, and tetramethylkaempferol and pentamethylquercetin from the rhizomes of Kaempferia parviflora, are reviewed. PMID:24882400

Matsuda, Hisashi; Nakamura, Seikou; Yoshikawa, Masayuki



Optimizing long-term therapy for Parkinson disease: levodopa, dopamine agonists, and treatment-associated dyskinesia.  


The treatment of Parkinson disease (PD) involves pharmacological treatment, often with levodopa or dopamine agonists, to restore the dopaminergic deficit associated with parkinsonian symptoms. Either agent provides symptom relief that becomes less effective in the course of PD, and switching or combining these agents or adding other therapies becomes necessary for symptom control. In an effort to delay the development of motor complications, dopamine agonists are often used in the initial treatment of PD. However, control of PD symptoms is superior with levodopa. Moreover, dopamine agonists are less well tolerated overall and are associated with a number of rare but serious adverse effects. In the long-term management of PD, treatment-associated dyskinesia often becomes sufficiently troublesome as to compromise the effective dosing of antiparkinsonian medication. More effective strategies for managing dyskinesia are needed. PMID:18303491

Stacy, Mark; Galbreath, Andrew



Driving Under the Influence of Synthetic Cannabinoid Receptor Agonist XLR-11.  


The case of a 22-year-old male Caucasian driver is presented. He was involved in a traffic collision. At the roadside, he displayed blank stare and mellow speech with a barely audible voice. A DRE found low body temperature, rigid muscle tone, normal pulse, lack of horizontal and vertical gaze nystagmus, nonconvergence of the eyes, dilated pupil size, and normal Pupillary reaction to light. A standard toxicology DUID protocol was performed on the driver's whole blood including ELISA and GC-MS drug screens with negative results. Additional drug screening was undertaken for bath salts and synthetic cannabinoid receptor agonists by LC-MS/MS by a commercial laboratory and identified the synthetic cannabinoid receptor agonist XLR-11 in the driver's blood. XLR-11 was subsequently quantified at 1.34 ng/mL. This is the first documented case involving a driver operating a motor vehicle under the influence of the synthetic cannabinoid receptor agonist XLR-11. PMID:25088081

Lemos, Nikolas P



Stimulation of innate immune cells by light-activated TLR7/8 agonists.  


The innate immune response is controlled, in part, by the synergistic interaction of multiple Toll-like receptors (TLRs). This multi-receptor cooperation is responsible for the potent activity of many vaccines, but few tools have been developed to understand the spatio-temporal elements of TLR synergies. In this Communication, we present photo-controlled agonists of TLR7/8. By strategically protecting the active agonist moiety based on an agonist-bound crystal structure, TLR activity is suppressed and then regained upon exposure to light. We confirmed NF-?B production upon light exposure in a model macrophage cell line. Primary cell activity was confirmed by examining cytokine and cell surface marker production in bone-marrow-derived dendritic cells. Finally, we used light to activate dendritic cell sub-populations within a larger population. PMID:25029205

Ryu, Keun Ah; Stutts, Lalisa; Tom, Janine K; Mancini, Rock J; Esser-Kahn, Aaron P



Peroxisome Proliferator-Activated Receptor Agonists: Do They Increase Cardiovascular Risk?  

PubMed Central

Cardiovascular disease is a major cause of morbidity and mortality among people with type 2 diabetes mellitus. The peroxisome proliferator-activated receptor (PPAR) agonists have a significant role on glucose and fat metabolism. Thiazolidinediones (TZDs) are predominantly PPAR? agonists, and their primary benefit appears to be the prevention of diabetic complications by improving glycemic control and lipid profile. Recently, the cardiovascular safety of rosiglitazone was brought to center stage following meta analyses and the interim analysis of the RECORD trial. Current evidence points to rosiglitazone having a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas. This review article discusses the mechanism of action of PPAR agonists and correlates it with clinical and laboratory outcomes in the published literature. In addition, this review article attempts to discuss some of the molecular mechanisms regarding the association between TZDs therapy and the nontraditional cardiovascular risks. PMID:19696948

Aljada, Ahmad; Shah, Kshitij Ashwin; Mousa, Shaker A.



Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons  

NASA Technical Reports Server (NTRS)

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.

Zheng, F.; Gallagher, J. P.



Identification of multiple 5-HT? partial agonist clinical candidates for the treatment of Alzheimer's disease.  


The cognitive impairments observed in Alzheimer's disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT(4)) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT(4) agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure-response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT(4) partial agonist candidates 2d and 3 were chosen for clinical development. PMID:22974325

Brodney, Michael A; Johnson, David E; Sawant-Basak, Aarti; Coffman, Karen J; Drummond, Elena M; Hudson, Emily L; Fisher, Katherine E; Noguchi, Hirohide; Waizumi, Nobuaki; McDowell, Laura L; Papanikolaou, Alexandros; Pettersen, Betty A; Schmidt, Anne W; Tseng, Elaine; Stutzman-Engwall, Kim; Rubitski, David M; Vanase-Frawley, Michelle A; Grimwood, Sarah



Apprendre dialoguer avec des lves : le cas des dialogues philosophiques  

E-print Network

.*, & Daniel, M.-F. (2009). Apprendre à dialoguer > avec des élèves : le cas des dialogues philosophiques Daniel Laboratoire P.A.E.D.I. Iufm d'Auvergne, JE2432 & Laboratoire de psychologie cognitive et clinique maître qu'aux élèves ? Du côté du maître, existe-t-il des gestes professionnels susceptibles d'amener

Paris-Sud XI, Université de


Expos de synthse Etude immunochimique des molcules du CMH des  

E-print Network

Exposé de synthèse Etude immunochimique des molécules du CMH des bovins (BoLA) D. Levy, J'histocompatibilité - réunion scientifique - structure - fonction Bovine CMH (BoLA) molecules : immunochemical study major'histocom- patibilité (CMH) des bovins (BOLA) pré- sente un triple intérêt : - sur le plan économique, les bovins

Boyer, Edmond


charnues, des sauges, et des cosmos peine sor-  

E-print Network

°39 L'hebdo de l'�cole normale supérieure NOUVELLES DES SERVICES ELLES se nomment Lili Marlen, Queen'esprit de l'as- sidu du snack vers des nourritures moins terrestres, distraire le candidat au concours de des savoirs [cf. normale sup' info n°4] qui a pour vocation de mettre à la disposition de tous les

Gutkin, Boris


UNIVERSIT DE MONTRAL Facult des arts et des sciences  

E-print Network

UNIVERSIT� DE MONTR�AL Faculté des arts et des sciences Département d'informatique et de recherche'étudiant :_____________________________________________________________ (en caractère d'imprimerie) Code permanent : ________________________________________ Programme : M.Sc. Maîtrise (2-175-1-0) Informatique Ph.D. Doctorat (3-175-1-0) Informatique Trimestre/Année du début des

Montréal, Université de


Peroxidative metabolism of beta2-agonists salbutamol and fenoterol and their analogues.  


Phenolic beta(2)-adrenoreceptor agonists salbutamol, fenoterol, and terbutaline relax smooth muscle cells that relieve acute airway bronchospasm associated with asthma. Why their use sometimes fails to relieve bronchospasm and why the drugs appear to be less effective in patients with severe asthma exacerbations remains unclear. We show that in the presence of hydrogen peroxide, both myeloperoxidase, secreted by activated neutrophils present in inflamed airways, and lactoperoxidase, which is naturally present in the respiratory system, catalyze oxidation of these beta(2)-agonists. Azide, cyanide, thiocyanate, ascorbate, glutathione, and methimazole inhibited this process, while methionine was without effect. Inhibition by ascorbate and glutathione was associated with their oxidation to corresponding radical species by the agonists' derived phenoxyl radicals. Using electron paramagnetic resonance (EPR), we detected free radical metabolites from beta(2)-agonists by spin trapping with 2-methyl-2-nitrosopropane (MNP). Formation of these radicals was inhibited by pharmacologically relevant concentrations of methimazole and dapsone. In alkaline buffers, radicals from fenoterol and its structural analogue, metaproteronol, were detected by direct EPR. Analysis of these spectra suggests that oxidation of fenoterol and metaproterenol, but not terbutaline, causes their transformation through intramolecular cyclization by addition of their amino nitrogen to the aromatic ring. Together, these results indicate that phenolic beta(2)-agonists function as substrates for airway peroxidases and that the resulting products differ in their structural and functional properties from their parent compounds. They also suggest that these transformations can be modulated by pharmacological approaches using appropriate peroxidase inhibitors or alternative substrates. These processes may affect therapeutic efficacy and also play a role in adverse reactions of the beta(2)-agonists. PMID:19462961

Reszka, Krzysztof J; McGraw, Dennis W; Britigan, Bradley E



Differential gene expression in mouse primary hepatocytes exposed to the peroxisome proliferator-activated receptor ? agonists  

PubMed Central

Background Fibrates are a unique hypolipidemic drugs that lower plasma triglyceride and cholesterol levels through their action as peroxisome proliferator-activated receptor alpha (PPAR?) agonists. The activation of PPAR? leads to a cascade of events that result in the pharmacological (hypolipidemic) and adverse (carcinogenic) effects in rodent liver. Results To understand the molecular mechanisms responsible for the pleiotropic effects of PPAR? agonists, we treated mouse primary hepatocytes with three PPAR? agonists (bezafibrate, fenofibrate, and WY-14,643) at multiple concentrations (0, 10, 30, and 100 ?M) for 24 hours. When primary hepatocytes were exposed to these agents, transactivation of PPAR? was elevated as measured by luciferase assay. Global gene expression profiles in response to PPAR? agonists were obtained by microarray analysis. Among differentially expressed genes (DEGs), there were 4, 8, and 21 genes commonly regulated by bezafibrate, fenofibrate, and WY-14,643 treatments across 3 doses, respectively, in a dose-dependent manner. Treatments with 100 ?M of bezafibrate, fenofibrate, and WY-14,643 resulted in 151, 149, and 145 genes altered, respectively. Among them, 121 genes were commonly regulated by at least two drugs. Many genes are involved in fatty acid metabolism including oxidative reaction. Some of the gene changes were associated with production of reactive oxygen species, cell proliferation of peroxisomes, and hepatic disorders. In addition, 11 genes related to the development of liver cancer were observed. Conclusion Our results suggest that treatment of PPAR? agonists results in the production of oxidative stress and increased peroxisome proliferation, thus providing a better understanding of mechanisms underlying PPAR? agonist-induced hepatic disorders and hepatocarcinomas. PMID:17118139

Guo, Lei; Fang, Hong; Collins, Jim; Fan, Xiao-hui; Dial, Stacey; Wong, Alex; Mehta, Kshama; Blann, Ernice; Shi, Leming; Tong, Weida; Dragan, Yvonne P



alpha7 receptor-selective agonists and modes of alpha7 receptor activation.  


The alpha7-selective agonists 3-(2, 4-dimethoxybenzylidene)-anabaseine (GTS-21), also known as DMXB, and 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21) produce a variety of behavioral and cytoprotective effects that may be related to the activation of either large transient currents at high concentrations or small sustained currents at lower agonist concentrations. We are using acutely dissociated hypothalamic neurons, which express a central nervous system (CNS) alpha7-type receptor, to test a model for the concentration-dependent desensitization of alpha7-mediated responses. Our results confirm that 4OH-GTS-21 is a potent activator of neuronal alpha7 nicotinic-acetylcholine receptor. The rapid application of agonist leads to a brief period of maximal receptor-activation followed by desensitization. Rise rates, decay rates, and the degree to which current was desensitized were all concentration-dependent. Following the initial peak response to a 300-microM 4OH-GTS-21 application, current is reduced to baseline values within about 100 ms. Application of 30 microM 4OH-GTS-21 produced both a transient peak current and a sustained current that decayed only slowly after the removal of agonist. In the case of a 300-microM 4OH-GTS-21 application, after agonist was removed, we saw a rebound response up to the level of the 30-microM sustained current. The data, therefore, suggest that a sufficient level of agonist occupation can be retained on the receptor to promote activation for up to several hundred milliseconds. PMID:10771012

Papke, R L; Meyer, E; Nutter, T; Uteshev, V V



Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists  

PubMed Central

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 TGF?. 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 ?3) 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

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.



Recovery of brain biomarkers following peroxisome proliferator-activated receptor agonist neuroprotective treatment before ischemic stroke  

PubMed Central

Background Lipid lowering agent such as agonists of peroxisome proliferator-activated receptors (PPAR) are suggested as neuroprotective agents and may protect from the sequelae of brain ischemic stroke. Although the demonstration is not clearly established in human, the underlying molecular mechanism may be of interest for future therapeutic purposes. To this end, we have used our well established rodent model of ischemia-reperfusion pre-treated or not with fenofibrate or atorvastatin and performed a differential proteomics analyses of the brain and analysed the protein markers which levels returned to “normal” following pre-treatments with PPAR? agonists. Results In order to identify potential therapeutic targets positively modulated by pre-treatment with the PPAR? agonists, two-dimensional gel electrophoresis proteome profiles between control, ischemia-reperfusion and pre-treated or not, were compared. The polypeptide which expression was altered following ischemia – reperfusion but whose levels remain unchanged after pre-treatment were characterized by mass spectrometry and further investigated by Western-blotting and immunohistochemistry. A series of 28 polypeptides were characterized among which the protein disulfide isomerase reduction – a protein instrumental to the unfolded protein response system - was shown to be reduced following PPAR? agonists treatment while it was strongly increased in ischemia-reperfusion. Conclusions Pre-treatment with PPAR? agonist or atorvastatin show potential neuroprotective effects by inhibiting the PDI overexpression in conjunction with the preservation of other neuronal markers, several of which are associated with the regulation of protein homeostasis, signal transduction and maintenance of synaptic plasticity. This proteomic study therefore suggests that neuroprotective effect of PPAR? agonists supposes the preservation of the expression of several proteins essential for the maintenance of protein homeostasis not necessarily directly linked to PPAR? known-regulated targets. PMID:24944524



Peroxidative Metabolism of ?2-Agonists Salbutamol and Fenoterol and Their Analogs  

PubMed Central

Phenolic ?2-adrenoreceptor agonists salbutamol, fenoterol and terbutaline relax smooth muscle cells that relieve acute airway bronchospasm associated with asthma. Why their use sometimes fails to relieve bronchospasm, and why the drugs appear to be less effective in patients with severe asthma exacerbations, remains unclear. We show that in the presence of hydrogen peroxide, both myeloperoxidase, secreted by activated neutrophils present in inflamed airways, and lactoperoxidase, which is naturally present in the respiratory system, catalyze oxidation of these ?2-agonists. Azide, cyanide, thiocyanate, ascorbate, glutathione, and methimazole inhibited this process, while methionine was without effect. Inhibition by ascorbate and glutathione was associated with their oxidation to corresponding radical species by the agonists’-derived phenoxyl radicals. Using electron paramagnetic resonance (EPR), we detected free radical metabolites from ?2-agonists by spin trapping with 2-methyl-2-nitrosopropane (MNP). Formation of these radicals was inhibited by pharmacologically-relevant concentrations of methimazole and dapsone. In alkaline buffers radicals from fenoterol and its structural analog, metaproteronol, were detected by direct EPR. Analysis of these spectra suggests that oxidation of fenoterol and metaproterenol, but not terbutaline, causes their transformation through intramolecular cyclization by addition of their amino nitrogen to the aromatic ring. Together, these results indicate that phenolic ?2-agonists function as substrates for airway peroxidases and that the resulting products differ in their structural and functional properties from their parent compounds. They also suggest that these transformations can be modulated by pharmacological approaches using appropriate peroxidase inhibitors or alternative substrates. These processes may affect therapeutic efficacy and also play a role in adverse reactions of the ?2-agonists. PMID:19462961

Reszka, Krzysztof J.; McGraw, Dennis W.; Britigan, Bradley E.



Putative kappa-2 opioid agonists are antihyperalgesic in a rat model of inflammation.  


It has been demonstrated that kappa-2 opioid receptor agonists can inhibit the current that flows through the N-methyl-o-aspartate (NMDA) subclass of excitatory amino acid receptor. NMDA receptor antagonists have been shown to be effective antihyperalgesic agents when administered intrathecally into rats. Antihyperalgesia is defined as the ability to block enhanced sensitivity, usually produced by nerve injury or inflammation, to nociceptive stimuli. Thus, the hypothesis was proposed that kappa-2 opioid receptor agonists would be antihyperalgesic when injected intrathecally into rats with an inflamed hind paw. The kappa agonists bremazocine and GR89,696 were effective at reversing the hyperalgesia associated with the inflamed hind paw but did not influence the sensitivity of the noninflamed hind paw to noxious heat. The kappa-1-selective agonist U69,593 had no effect on the heat sensitivity of either the inflamed paw or the noninflamed paw. Intrathecal injection of the mu-selective agonist [D-Ala2,N-MePhe4,Gly5-ol]enkephalin or the delta-selective agonist [D-Pen(2,5)]enkephalin elevated paw withdrawal latencies to heat in both hind paws. These findings indicate that activation of presumed kappa-2 receptors in the rat spinal cord results in suppression of the hyperalgesic state without influencing normal sensitivity to noxious stimuli. It is proposed that the antihyperalgesic effect of kappa-2 receptor activation is mediated by the ability of the opioid receptor to reduce the flow of current through the NMDA receptor ionophore. PMID:9103490

Ho, J; Mannes, A J; Dubner, R; Caudle, R M



?2-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats  

PubMed Central

Aims/hypothesis We have previously reported that local activation of ?2-adrenergic receptors (B2ARs) in the ventromedial hypothalamus (VMH) enhances hypoglycaemic counter-regulation. This study examines whether peripheral delivery of a selective B2AR agonist could also promote counter-regulatory responses and thereby has potential therapeutic value to limit hypoglycaemia risk. Methods Conscious male Sprague–Dawley rats received an intra-arterial injection of the B2AR specific agonist, formoterol, or a control solution either before a hyperinsulinaemic–hypoglycaemic clamp study or immediately before recovery from insulin-induced hypoglycaemia. In addition, the capacity of a VMH-targeted microinjection of a B2AR antagonist to limit the anti-insulin effect of the B2AR agonist was assessed. Results Systemic delivery of B2AR agonist markedly reduced the exogenous glucose infusion rate (GIR) required during the hypoglycaemic clamp study. This effect was mediated by blockade of insulin’s inhibitory effect on endogenous glucose production. Local blockade of B2ARs within the VMH using a specific antagonist partially diminished the effect of systemic activation of B2ARs during hypoglycaemia at least in part by diminishing the adrenaline (epinephrine) response to hypoglycaemia. Peripheral B2AR agonist injection also enhanced glucose recovery from insulin-induced hypoglycaemia. Conclusions/interpretation Systemic B2AR agonist administration acts to limit insulin-induced hypoglycaemia by offsetting insulin’s inhibitory effect on hepatic glucose production. This effect appears to be predominately mediated via a direct effect on liver B2ARs, but a small stimulatory effect on B2ARs within the VMH cannot be excluded. Our data suggest that formoterol may have therapeutic value to limit the risk of hypoglycaemia in patients with diabetes. PMID:23933834

Szepietowska, Barbara; Zhu, Wanling; Sherwin, Robert S.



Die Kommerzialisierung des Kinderfernsehens unter besonderer Berücksichtigung des Merchandising.  

E-print Network

??Die vorliegende Arbeit thematisiert die Kommerzialisierungsentwicklungen im Kinderfernsehprogramm im deutschsprachigen Raum unter besonderer Berücksichtigung der Praxis des Merchandising. Die Beobachtung, dass uns Figuren aus dem… (more)

Nigl, Andrea



Les protéines des corps d'inclusion des Baculovirus  

Microsoft Academic Search

Résumé  La comparaison des granules ou des protéines de granules desBaculovirus dePieris brassicae, Pygaera anastomosis, Hyphantria cunea, Carpocapsa pomonella, Mythimna unipuncta, Mamestra oleracea a été entreprise par les techniques d'électrophorèse, d'agglutination, d'immunofluorescence et de précipitation en gel. L'électrophorèse\\u000a fait apparaître l'étroite ressemblance qui existe entre les protéines des six sortes de corps d'inclusion. L'analyse immunochimique\\u000a montre que chaque granule est bien

G. Croizier; G. Meynadier



Die Theorie des Radikalen Konstruktivismus im Kommunikationsmodell des NLP.  

E-print Network

??Der Radikale Konstruktivismus setzt sich mit dem Verhältnis von Wissen und Wirklichkeit auseinander. In der Theorie des Radikalen Konstruktivismus ist die Wirklichkeit keine objektive Voraussetzung,… (more)

Brezna, Christa



Synthesis and pharmacological characterization of beta2-adrenergic agonist enantiomers: zilpaterol.  


The beta-adrenergic agonist 1 (zilpaterol) is used as production enhancer in cattle. Binding experiments of separated enantiomers on recombinant human beta(2)-adrenergic and mu-opioid receptors and functional studies showed that the (-)-1 enantiomer accounts for essentially all the beta(2)-adrenergic agonist activity and that it exhibits less affinity toward the mu-opioid receptor than (+)-1, which is a mu-opioid receptor antagonist. X-ray crystallography revealed the absolute configuration of (-)-1 to be 6R,7R. PMID:19245211

Kern, Christopher; Meyer, Thorsten; Droux, Serge; Schollmeyer, Dieter; Miculka, Christian



Acute overdose of a new dopamine agonist, CV 205-502.  


CV 205-502 is a new dopamine agonist used for hyperprolactinaemia. We report a case of acute overdose (one month treatment, i.e. 2.25 mg) in a 25-year-old male patient. Clinical symptoms were restricted to nausea and mild hypotension. Treatment consisting of ipeca cuanha, charcoal and intravenous fluids allowed a rapid, successful outcome. This case illustrates the particular features of CV 205-502 intoxication when compared to other dopamine agonists, pointing out the tolerance of the drug which can be considered for wider indications and safer prescriptions. PMID:7910531

Tauveron, I; Gesta, J M; Jalenques, I; Thieblot, P



Influence of the selective ORL1 receptor agonist, Ro64-6198, on rodent neurological function  

Microsoft Academic Search

Identification of synthetic agonists and antagonists at orphan receptors represents an important step for understanding their physiological function and therapeutic potential. Accordingly, we have recently described a non-peptide agonist at the opioid receptor like (ORL1) receptor (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro64-6198; Jenck et al., PNAS 94 (2000) 4938; Wichmann et al., Eur. J. Med. Chem. 35 (2000) 839). We have investigated the effects

G. A Higgins; A. J Grottick; T. M Ballard; J. G Richards; J Messer; H Takeshima; M Pauly-Evers; F Jenck; G Adam; J Wichmann



Toll-like receptor 3 agonist enhances IFN-? and TNF-? production by murine uterine NK cells  

Microsoft Academic Search

To understand the response of murine uterine natural killer (uNK) cells to Toll-like receptor (TLR) 3 agonist at the early gestation stage, CBA×DBA\\/2 mice were intraperitoneally (i.p.) injected with polyinosinic–polycytidylic acid (poly I:C), the specific TLR3 agonist, at a dose of 10 ?g\\/g BW or PBS at gestation day (gd) 6.5. The CD69 expression of uNK (DX5+CD3?) cells was highly up-regulated

Jianhong Zhang; Rui Sun; Haiming Wei; Dongmei Wu; Zhigang Tian



Thiazolidinediones (PPARg agonists) but not PPARa agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes1  

Microsoft Academic Search

Thiazolidinediones (TZD) improve insu- lin sensitivity in human as well as in different animal models of insulin resistance and Type 2 diabetes. However, no clear link to the insulin signaling events has been identified. Using differentiated 3T3-L1 adipo- cytes, we found that TZD rapidly and markedly in- creased IRS-2 gene expression. This effect was specific for PPARg agonists and was



Molecular Determinants of Agonist Selectivity in Glutamate-Gated Chloride Channels Which Likely Explain the Agonist Selectivity of the Vertebrate Glycine and GABAA-? Receptors  

PubMed Central

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 ?-alanine, GABA and taurine. Like the Aplysia receptor, the vertebrate glycine and GABAA-? 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 receptor also explain the agonist profile seen in the glycine and GABAA-? receptors. PMID:25259865

Blarre, Thomas; Bertrand, Hugues-Olivier; Acher, Francine C.; Kehoe, JacSue



Protective effects of a peroxisome proliferator-activated receptor-h/y agonist in experimental autoimmune encephalomyelitis  

E-print Network

Protective effects of a peroxisome proliferator-activated receptor-h/y agonist in experimental Agonists of the peroxisome proliferator-activated receptor gamma (PPARg) exert anti-inflammatory and anti. Introduction Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear hormone receptors. In response

Omiecinski, Curtis


Activity of mu- and delta-opioid agonists in vas deferens from mice deficient in MOR gene  

PubMed Central

Mice lacking the mu-opioid receptor have been recently generated. Centrally mediated responses of mu-opioid agonists are suppressed whereas some of the delta-opioid responses are preserved in these mutant mice. The vas deferens bioassay has been used in this study to investigate the functional activity at a peripheral level of mu- and delta-opioid agonists in mice lacking mu-opioid receptors. The different mu-opioid agonists evaluated, morphine, DAMGO, dermorphin and [Lys7]-dermorphin produced an inhibitory response in vas deferens from wild-type mice but had no relevant activity on vas deferens from mutant mice. The selective delta-opioid agonists DPDPE, BUBU, deltorphin I, deltorphin II and [D-Met2]-deltorphin induced inhibitory effects in vas deferens from both wild-type and mutant mice. However, the biological activities of these ligands were slightly reduced in preparations from mutant mice. The inhibitory responses of all these delta-opioid agonists were prevented by the administration of the selective delta-opioid antagonist naltrindole. These data indicate that delta-opioid agonists, but not mu-opioid agonists, are biologically active in vas deferens from mice lacking mu-opioid receptors. The decreased response of delta-agonists in mutant mice suggests that some cooperativity may exist between mu- and delta-opioid receptors in these vas deferens preparations. PMID:11264242

Maldonado, Rafael; Severini, Cintia; Matthes, Hans W D; Kieffer, Brigitte L; Melchiorri, Pietro; Negri, Lucia



Self-Administration of Agonists Selective for Dopamine D2, D3, and D4 Receptors by Rhesus Monkeys  

PubMed Central

Dopamine receptor mechanisms are thought to play a role in the reinforcing effects of cocaine and other abused drugs. The lack of receptor-selective agonists has made it difficult to determine the role of the individual dopamine receptors in mediating these reinforcing effects. In this study, rhesus monkeys with a history of intravenous cocaine self-administration were tested for the reinforcing effects of several D3-preferring agonists, a D2-preferring agonist, and a D4 agonist. The D2-preferring agonist did not maintain responding in any monkeys, and the D4 agonist was self-administered at low rates, just above those maintained by saline in one monkey. The D3-preferring agonists were self-administered by approximately half of the animals, although at lower rates than cocaine. These results indicate the apparent limited reinforcing effectiveness of D2-like agonists requires activity at D3 receptors. Previous data from this laboratory and others also suggest that these drugs may not serve as reinforcers directly; the behavior may be maintained by response-contingent delivery of stimuli previously paired with cocaine. The ability of drug-related stimuli to maintain responding apparently differs among monkeys and other organisms, and may be related to individual differences in drug-taking behavior in humans. PMID:22785383

Koffarnus, Mikhail N.; Collins, Gregory T.; Rice, Kenner C.; Chen, Jianyong; Woods, James H.; Winger, Gail



The GABA B agonist baclofen reduces cigarette consumption in a preliminary double-blind placebo-controlled smoking reduction study  

Microsoft Academic Search

The surge in dopamine in ventral striatal regions in response to drugs of abuse and drug-associated stimuli is a final common pathway of addiction processes. GABA B agonists exert their effects indirectly, by quieting dopaminergic afferents. The ability of the GABA B agonist, baclofen to ameliorate nicotine and drug motivated behavior is established within the animal literature, however its potential

Teresa R. Franklin; Derek Harper; Kyle Kampman; Susan Kildea-McCrea; Will Jens; Kevin G. Lynch; Charles P. O’Brien; Anna Rose Childress



Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal ?7 nicotinic acetylcholine receptor  

PubMed Central

The pentameric acetylcholine-binding protein (AChBP) is a soluble surrogate of the ligand binding domain of nicotinic acetylcholine receptors. Agonists bind within a nest of aromatic side chains contributed by loops C and F on opposing faces of each subunit interface. Crystal structures of Aplysia AChBP bound with the agonist anabaseine, two partial agonists selectively activating the ?7 receptor, 3-(2,4-dimethoxybenzylidene)-anabaseine and its 4-hydroxy metabolite, and an indole-containing partial agonist, tropisetron, were solved at 2.7–1.75 Å resolution. All structures identify the Trp 147 carbonyl oxygen as the hydrogen bond acceptor for the agonist-protonated nitrogen. In the partial agonist complexes, the benzylidene and indole substituent positions, dictated by tight interactions with loop F, preclude loop C from adopting the closed conformation seen for full agonists. Fluctuation in loop C position and duality in ligand binding orientations suggest molecular bases for partial agonism at full-length receptors. This study, while pointing to loop F as a major determinant of receptor subtype selectivity, also identifies a new template region for designing ?7-selective partial agonists to treat cognitive deficits in mental and neurodegenerative disorders. PMID:19696737

Hibbs, Ryan E; Sulzenbacher, Gerlind; Shi, Jianxin; Talley, Todd T; Conrod, Sandrine; Kem, William R; Taylor, Palmer; Marchot, Pascale; Bourne, Yves



Muscle Activation Is Different When the Same Muscle Acts as an Agonist or an Antagonist During Voluntary Movement  

Microsoft Academic Search

During movement, the intrinsic muscle force-velocity property decreases the net force for the shortening muscle (agonist) and increases it for the lengthening muscle (antagonist). The authors present a quantitative analysis of the effect of that muscle property on activation and force output of the same muscle acting as agonist and antagonist in fast and medium speed goaloriented movements. They compared

Mark B. Shapiro; Janey Prodoehl; Daniel M. Corcos; Gerald L. Gottlieb



Exercise as an Adjunct Treatment for Opiate Agonist Treatment: Review of the Current Research and Implementation Strategies  

Microsoft Academic Search

Opiate dependence is a significant public health concern linked to poor quality of life, co-morbid psychiatric disorders, and high costs to society. Current opiate agonist treatments are an effective but limited intervention. Adjunctive interventions could improve and augment opiate agonist treatment outcomes, including drug abstinence, quality of life, and physical health. This article reviews exercise as an adjunctive intervention for

Jeremiah Weinstock; Heather K. Wadeson; Jaci L. VanHeest



The G Protein-Biased ?-Opioid Receptor Agonist RB-64 Is Analgesic with a Unique Spectrum of Activities In Vivo.  


The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although ?-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein-biased agonists have not been available to test this idea. Here we provide data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas ?-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein-biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein-biased KOR agonists. PMID:25320048

White, Kate L; Robinson, J Elliott; Zhu, Hu; DiBerto, Jeffrey F; Polepally, Prabhakar R; Zjawiony, Jordan K; Nichols, David E; Malanga, C J; Roth, Bryan L



Programmation des activits pdagogiques  

E-print Network

Programmation des activités pédagogiques B.Sc. Biochimie de la santé Version 9 S'adresse aux 411 *Enzymologie de la cellule humaine (BCM 318).....................2 BCM 420 *Bio-informatique (BCL dans le programme. 22 mai 2014 Activités pédagogiques à option (16 crédits) Automne CHM 400 Biochimie

Spino, Claude


Agonist-specific voltage sensitivity at the dopamine D2S receptor--molecular determinants and relevance to therapeutic ligands.  


Voltage sensitivity has been demonstrated for some GPCRs. At the dopamine D(2S) receptor, this voltage sensitivity is agonist-specific; some agonists, including dopamine, exhibit decreased potency at depolarized potentials, whereas others are not significantly affected. In the present study, we examined some of the receptor-agonist interactions contributing to these differences, and investigated how dopamine D(2S) receptor voltage sensitivity affects clinically used dopamine agonists. GIRK channel activation in voltage-clamped Xenopus oocytes was used as readout of receptor activation. Structurally distinct agonists and complementary site-directed mutagenesis of the receptor's binding site were used to investigate the role of agonist-receptor interactions. We also confirmed that the depolarization-induced decrease of dopamine potency in GIRK activation is correlated by decreased binding of radiolabeled dopamine, and by decreased potency in G protein activation. In the mutagenesis experiments, a conserved serine residue as well as the conserved aspartate in the receptor's binding site were found to be important for voltage sensitive potency of dopamine. Furthermore, the voltage sensitivity of the receptor had distinct effects on different therapeutic D(2) agonists. Depolarization decreased the potency of several compounds, whereas for others, efficacy was reduced. For some agonists, both potency and efficacy were diminished, whereas for others still, neither parameter was significantly altered. The present work identifies some of the ligand-receptor interactions which determine agonist-specific effects of voltage at the dopamine D(2S) receptor. The observed differences between therapeutic agonists might be clinically relevant, and make them potential tools for investigating the roles of dopamine D(2) receptor voltage sensitivity in native tissue. PMID:21752340

Sahlholm, Kristoffer; Barchad-Avitzur, Ofra; Marcellino, Daniel; Gómez-Soler, Maricel; Fuxe, Kjell; Ciruela, Francisco; Arhem, Peter



Comparative gene expression profiles induced by PPAR{gamma} and PPAR{alpha}/{gamma} agonists in rat hepatocytes  

SciTech Connect

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.

Rogue, Alexandra [UMR INSERM U991, Faculte des Sciences Pharmaceutiques et Biologiques, 35043 Rennes (France); Universite de Rennes 1, 35065 Rennes Cedex (France); Biologie Servier, 45520 Gidy (France); Renaud, Marie Pierre [Biologie Servier, 45520 Gidy (France); Claude, Nancy [Institut de Recherches Servier, 92400 Courbevoie (France); Guillouzo, Andre, E-mail: [UMR INSERM U991, Faculte des Sciences Pharmaceutiques et Biologiques, 35043 Rennes (France); Universite de Rennes 1, 35065 Rennes Cedex (France); Spire, Catherine, E-mail: [Biologie Servier, 45520 Gidy (France)



ORGANISATION DES ETUDES La licence professionnelle Gestion des  

E-print Network

: · coordinateur(trice) du Personnel. · assistant(e) Ressources Humaines. · assistant(e) gestion du personnel. · gestionnaire de paie / collaborateur (trice) de paie. I U T La licence professionnelle forme des coordinateurs/trices, projets RH, ...). Licence Professionnelle Gestion des ressources humaines Spécialité Coordinateur/trice du

Pellier, Damien


Inhibitory GTP binding protein G/sub i/ regulates US -adrenoceptor affinity towards US -agonists  

SciTech Connect

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.

Marbach, I.; Levitzki, A.



Opiate Agonists Activate Feeding in Limax: Comparison of In Vivo and In Vitro Effects  

Microsoft Academic Search

The neural control system for feeding in the terrestrial mollusc Limax maximus is modulated by at least two major families of peptides. Sequence homology between one of the peptides known to modulate Limax feeding and some members of the opioid peptide family suggested that opioid peptides might also modulate Limax feeding. Experiments with the mu agonist morphine and the kappa

M. Wong; K. Delaney; A. Gelperin



A robotic BG1Luc reporter assay to detect estrogen receptor agonists.  


Endocrine disrupting chemicals with estrogenic activity (EA) have been associated with various adverse health effects. US agencies (ICCVAM/NICEATM) tasked to assess in vitro transcription activation assays to detect estrogenic receptor (ER) agonists for EA have recently validated a BG1Luc assay in manual format, but prefer robotic formats. We have developed a robotic BG1Luc EA assay to detect EA that demonstrated 100% concordance with ICCVAM meta-analyses and ICCVAM BG1Luc results in manual format for 27 ICCVAM test substances, i.e. no false negatives or false positives. This robotic assay also consistently assessed other, more problematic ICCVAM test substances such as clomiphene citrate, L-thyroxin, and tamoxifen. Agonist responses using this robotic BG1Luc assay were consistently inhibited by the ER antagonist ICI 182,780, confirming that agonist responses were due to binding to ERs rather than to a non-specific agonist response. This robotic assay also detected EA in complex mixtures of substances such as extracts of personal care products, plastic resins or plastic consumer products. This robotic BG1Luc assay had at least as high accuracy and greater sensitivity and repeatability when compared to its manual version or to the other ICCVAM/OECD validated assays for EA (manual BG1Luc and CERI). PMID:24747293

Stoner, Matthew A; Yang, Chun Z; Bittner, George D



Systemic and Pulmonary Hemodynamic Responses to Adrenergic and Cholinergic Agonists during Fetal Development  

Microsoft Academic Search

Systemic and pulmonary hemodynamic responses to adrenergic and cholinergic agonists were investigated in fetal lambs between 60 days and term gestation. The cardiovascular response to these agents increases with fetal age, and the increase is related to maturation of the effector system rather than the vascular receptors. The fetal pulmonary vascular bed and the ductus arteriosus are the primary components

B. Nuwayhid; C. R. Brinkman; III; C. Su; J. A. Bevan; N. S. Assali



Estrogenic Agonist Activity of ICI 182,780 (Faslodex) in Hippocampal Neurons: Implications for Basic Science  

E-print Network

to estrogen therapy for the prevention of post- menopausal cognitive decline and late-onset Alzheimer's dis of the development of resistance to TMX therapy for the treat- ment of estrogen-dependent breast cancers (Howell etEstrogenic Agonist Activity of ICI 182,780 (Faslodex) in Hippocampal Neurons: Implications

Brinton, Roberta Diaz


Thymic development of CS8[alpha][alpha]? TCR[alpha][beta]? agonist selected IEL  

E-print Network

Thymic Epithelium The exposure of developing thymocytes to self-peptide/Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.Peptide-independent folding and CD8alphaalpha binding by the nonclassical class I molecule, thymic

Gangadharan, Denise Michelle



Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?  


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-1?, 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 PPAR? 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

Freitag, Caroline M; Miller, Richard J



The role of prior agonistic experience in dominance relationships in male crickets Gryllus bimaculatus (Orthoptera: Gryllidae)  

Microsoft Academic Search

Experiments were carried out to study the effect of social conditioning (prior experience of dominance and submission) in dominance relationships between adult male Gryllus bimaculatus. The dominance status of a male cricket appears to be directly linked to its immediate prior agonistic experience. An experience of dominance increases the probability of victory and one of submission decreases it. The effect

M Campan



Nebulized PPAR? Agonists: A Novel Approach to Augment Neonatal Lung Maturation and Injury Repair  

PubMed Central

BACKGROUND By stimulating lipofibroblast maturation, parenterally administered PPAR? agonists promote lung homeostasis and injury repair in the neonatal lung. In this study, we determined whether PPAR? agonists could be delivered effectively via nebulization to neonates, and whether this approach would also protect against hyperoxia-induced lung injury. METHODS One-day old Sprague-Dawley rat pups were administered PPAR? agonists rosiglitazone (RGZ, 3 mg/kg), pioglitazone (PGZ, 3 mg/kg), or the diluent, via nebulization every 24h; animals were exposed to 21% or 95% O2 for up to 72h. Twenty-four and 72h following initial nebulization, the pups were sacrificed for lung tissue and blood collection to determine markers of lung maturation, injury repair, and RGZ and PGZ plasma levels. RESULTS Nebulized RGZ and PGZ enhanced lung maturation in both males and females, as evidenced by the increased expression of markers of alveolar epithelial and mesenchymal maturation. This approach also protected against hyperoxia-induced lung injury, since hyperoxia-induced changes in bronchoalveolar lavage cell and protein contents and lung injury markers were all blocked by nebulized PGZ. CONCLUSIONS Nebulized PPAR? agonist administration promotes lung maturation and prevents neonatal hyperoxia-induced lung injury in both males and females. PMID:24488089

Morales, Edith; Sakurai, Reiko; Husain, Sumair; Paek, Dave; Gong, Ming; Ibe, Basil; Li, Yishi; Husain, Maleha; Torday, John S.; Rehan, Virender K.



ACCELERATED COMMUNICATION Di(2-ethylhexyl) phthalate Is a Highly Potent Agonist for the  

E-print Network

the common plasticizer, di(2- ethylhexyl) phthalate (DEHP), as a highly potent and uniquely selective agonist of CAR2. Results from reporter transactivation and mammalian two-hybrid assays reveal that DEHP activates mouse, rat, and marmoset models of DEHP toxicity cannot accurately profile potential human toxic- ity

Omiecinski, Curtis


Inhibition of AMPA Receptors by Polyamine Toxins is Regulated by Agonist Efficacy and Stargazin.  


The ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are glutamate-gated cation channels mediating the majority of fast excitatory synaptic transmission in the central nervous system (CNS). Polyamine toxins derived from spiders and wasps are use- and voltage-dependent channel blockers of Ca(2+)-permeable AMPARs. Recent studies have suggested that AMPAR block by polyamine toxins is modulated by auxiliary subunits from the class of transmembrane AMPAR regulatory proteins (TARPs), which may have implications for their use as tool compounds in native systems. We have explored the effect of the TARP ?-2 (also known as stargazin) on the inhibitory potency of three structurally different polyamine toxins at Ca(2+)-permeable homomeric GluA1 AMPARs expressed in oocytes. We find that polyamine toxin IC50 is differentially affected by presence of stargazin depending on the efficacy of the agonists used to activate GluA1. Co-assembly of GluA1 receptors with stargazin increases the potency of the polyamine toxins when activated by the weak partial agonist kainate, but has no effect in presence of full-agonist L-glutamate (Glu) and partial agonist (RS)-willardiine. PMID:24557991

Poulsen, Mette H; Lucas, Simon; Strømgaard, Kristian; Kristensen, Anders S



Pyridopyrimidine based cannabinoid-1 receptor inverse agonists: Synthesis and biological evaluation  

Microsoft Academic Search

The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.

John S. Debenham; Christina B. Madsen-Duggan; Junying Wang; Xinchun Tong; Julie Lao; Tung M. Fong; Marie-Therese Schaeffer; Jing Chen Xiao; Cathy C. R.-R. Huang; Chun-Pyn Shen; D. Sloan Stribling; Lauren P. Shearman; Alison M. Strack; D. Euan MacIntyre; Jeffrey J. Hale; Thomas F. Walsh



Lead optimization of 5,6-diarylpyridines as CB1 receptor inverse agonists  

Microsoft Academic Search

Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.

Christina B. Madsen-Duggan; John S. Debenham; Thomas F. Walsh; Richard B. Toupence; Song X. Huang; Junying Wang; Xinchun Tong; Julie Lao; Tung M. Fong; Marie-Therese Schaeffer; Jing Chen Xiao; Cathy R.-R. C. Huang; Chun-Pyn Shen; D. Sloan Stribling; Lauren P. Shearman; Alison M. Strack; D. Euan MacIntyre; Mark T. Goulet



PLZF Turns on the Effector T cell Program Without Requirement for Agonist TCR Signaling  

PubMed Central

Thymocytes expressing the NKT cell semi-invariant ?? TCR are thought to undergo agonist interactions with CD1d ligands prior to expressing PLZF, a BTB-POZ transcription factor that directs acquisition of the effector program of these innate-like T cells. Whether PLZF can mediate this effector conversion independently of agonist signaling has not been investigated. We demonstrated that transgenic expression of PLZF under the CD4 promoter induced the innate effector program in two different MHC class II-restricted TCR transgenic Rag1?/? models examined. In CD4 thymocytes expressing a fixed transgenic TCR ? chain, the associated TCR ? sequences in wild-type and PLZF-transgenic mice overlapped extensively, further demonstrating that PLZF could induce the effector program in most CD4 T cells that would normally be selected as naÔve cells. In contrast, PLZF altered the negative selection of thymocytes expressing TCR ? chains reactive against several retroviral superantigens. Thus, PLZF is the first example of a transcription factor inducing an effector program in the absence of T cell agonist interactions or cell division. Its expression may also enhance the survival of agonist-signaled thymocytes. PMID:21478405

Savage, Adam K; Constantinides, Michael G.; Bendelac, Albert



Effect of beta-adrenergic agonists in animal production and their mode of action  

E-print Network

Review Effect of beta-adrenergic agonists in animal production and their mode of action L.O. FIEMS and improve nitrogen retention. Glycolysis, lactate production and oxygen consumption are increased, while plasma insulin levels are decreased and adipocytes become less sensitive to insulin. Energy expenditure

Paris-Sud XI, Université de


The Effects of the Herbicide Metolachlor on Agonistic Behavior in the Crayfish, Orconectes rusticus  

E-print Network

The Effects of the Herbicide Metolachlor on Agonistic Behavior in the Crayfish, Orconectes rusticus that agricultural herbicides interfere with olfactory-mediated behavior, such as responses to alarm signals the impact of exposure to sublethal levels of the herbicide metolachlor on the ability of crayfish to respond

Moore, Paul A.


Synthesis and evaluation of a conditionally-silent agonist for the ?7 nicotinic acetylcholine receptor  

PubMed Central

We introduce the term ‘silent agonists’ to describe ligands that can place the ?7 nicotinic acetylcholine receptor (nAChR) into a desensitized state with little or no apparent activation of the ion channel, forming a complex that can subsequently generate currents when treated with an allosteric modulator. KC-1 (5?-phenylanabaseine) was synthesized and identified as a new silent agonist for the ?7 nAChR; it binds to the receptor but does not activate ?7 nAChR channel opening when applied alone, and its agonism is revealed by co-application with the type II positive allosteric modulator PNU-120596 in the Xenopus oocyte system. The concise synthesis was accomplished in three steps with the C–C bonds formed via Pd-catalyzed mono-arylation and organolithium coupling with N-Boc piperidinone. Comparative structural analyses indicate that a positive charge, an H-bond acceptor, and an aryl ring in a proper arrangement are needed to constitute one class of silent agonist for the ?7 nAChR. Because silent agonists may act on signaling pathways not involving ion channel opening, this class of ?7 nAChR ligands may constitute a new alternative for the development of ?7 nAChR therapeutics. PMID:23746476

Chojnacka, Kinga; Papke, Roger L.; Horenstein, Nicole A.



The effects of dopaminergic agonists on genital reflexes in paradoxical sleep-deprived male rats.  


Dopamine (DA) agonists provide evidence that different receptor subtypes in the central nervous system (CNS) have influence in sexual behavior. Sleep deprivation induces supersensibility of DA receptors and previous work has shown that the DA agonist apomorphine enhances spontaneous genital reflexes (penile erection-PE and ejaculation-EJ) in rats deprived of paradoxical sleep. The present study sought to extend the latter finding by assessing the effects of other DA agonists in paradoxical sleep-deprived (PSD) male rats. The DA drugs (bromocriptine and piribedil) were acutely administered to rats that had been deprived of sleep for 4 days and to normal controls. Sleep deprivation alone induced PE and this effect was potentiated by piribedil, with maximal effects occurring with the 8 mg/kg dose, whereas only one dose of bromocriptine (8 mg/kg) induced more PE in PSD rats than in non-deprived treated controls. EJs were increased in piribedil PSD groups but this response was absent after bromocriptine treatment in the dose range tested. Our data show the genital reflexes that occurred in PSD rats are potentialized by piribedil and not by bromocriptine. These DA agonists showed distinct effects in sexual response suggesting that these effects are probably due to PSD-induced DA receptor supersensitivity even though different mechanisms are involved. PMID:15708772

Andersen, Monica L; Tufik, Sergio



D-Amino Acid Oxidase Generates Agonists of the Aryl Hydrocarbon Receptor from D-Tryptophan  

PubMed Central

The aryl hydrocarbon receptor (AHR) is well known for its role in mediating the toxic and adaptive responses to xenobiotic compounds. Recent studies also indicate that AHR ligands are endogenously produced and may be essential for normal development. Previously, we showed that the endogenous enzyme, aspartate aminotransferase (AST), generates the AHR proagonist, indole-3-pyruvic acid (I3P), by deamination of its substrate L-tryptophan. We hypothesized that other enzymatic pathways capable of producing I3P may generate AHR agonists in vivo. We now demonstrate that the enzyme D-amino acid oxidase (DAAO) catalyzes the production of AHR agonists through the enzymatic conversion of D-tryptophan to I3P. Moreover, we provide evidence that the non-enzymatic oxidation and condensation of I3P is a critical step in the generation of receptor agonists by DAAO and AST. Products of this process include two novel agonists, 1,3-di(1H-indol-3-yl)propan-2-one and 1-(1H-indol-3-yl)-3-(3H-indol-3-ylidene) propan-2-one (characterized in the accompanying paper, Chowdhury et al., Chem. Res. Toxicol. tx-2009-000418), both of which can potently activate the AHR at concentrations in the nanomolar range. These results show that endogenous AHR activity can be modulated by I3P production from amino acid precursors through multiple enzymatic pathways, including those catalyzed by DAAO and AST. PMID:19860415

Nguyen, Linh P.; Hsu, Erin L.; Chowdhury, Goutam; Dostalek, Miroslav; Guengerich, F. Peter; Bradfield, Christopher A.



Antiobesity and antidiabetic beta-agonists: lessons learned and questions to be answered.  


In several species of obese animals, a group of phenethanolamine beta-agonists stimulates lipolysis and thermogenesis, resulting in the loss of body fat and weight. Brown adipose tissue is considered to be the major target tissue for the antiobesity activity of these compounds. Independent of this antiobesity activity, some of these compounds are also antidiabetic and increase muscle mass. Based on the pharmacological profile of these compounds, a beta3-receptor was proposed and characterized in mouse, rat, and humans. The beta3-receptor in brown adipose tissue has been suggested to mediate the antiobesity activity of these beta-agonists. Whether this receptor is responsible for the antidiabetic activity and whether there is a linkage between the antiobesity/antidiabetic activity and the nutrient partitioning activity is not clear. Clinical trials with these mixed beta-agonists showed marginal antiobesity effects when caloric intake of subjects was restricted. Insulin sensitivity was also improved in some of the trials designed to test the antidiabetic activity of these compounds. Side effects included tachycardia and tremor. To eliminate these side effects, a second generation of compounds was selected for its agonist activity on rat beta3-receptors. Clinical trials with these compounds have shown little increase of energy expenditure even at high doses. Successful development of an antiobesity and antidiabetic drug from this class of compounds will require the elucidation of the physiological role of the human beta3-receptor and the regulatory mechanism between fuel efficiency and feeding behavior. PMID:16353599

Yen, T T



The use of Toll-like receptor 7/8 agonists as vaccine adjuvants.  


Small molecule Toll-like receptor (TLR) 7/8 agonists have demonstrated potential as vaccine adjuvants, since they directly activate APCs and can enhance both humoral and cellular immune responses, especially Th1 responses. Although the natural ligands for TLR7 and TLR8 are ssRNA, the vast majority of vaccine studies performed thus far have been performed with synthetic small molecule imidazoquinolines, such as imiquimod and resiquimod. Despite the approved clinical use of the topical TLR7 agonist, imiquimod (Aldara(®) Imiquimod 5% cream; 3M, MN, USA), for external genital warts, superficial basal cell carcinoma and actinic keratosis, no vaccines using TLR7, TLR8 or TLR7/8 agonists have progressed beyond early-phase clinical studies thus far. This review will highlight the nonclinical and clinical studies that indicate promise for TLR7/8 ligands as vaccine adjuvants, reasons for inconsistent results thus far, problems with current technology and potential paths forward for TLR7/8 agonists as vaccine adjuvants. PMID:23885825

Vasilakos, John P; Tomai, Mark A



Regular inhaled beta agonist in asthma: effects on exacerbations and lung function  

Microsoft Academic Search

BACKGROUND: A comparison of the effects of regular upsilon as needed inhaled beta agonist treatment on the control of asthma in the last 16 weeks of each of two 24 week treatment periods has been reported. This paper presents additional information on exacerbations of asthma and trends in lung function, airways hyperresponsiveness to methacholine, and bronchodilator responsiveness during the entire

D R Taylor; M R Sears; G P Herbison; E M Flannery; C G Print; D C Lake; D M Yates; M K Lucas; Q Li



Effects of peroxisome proliferator-activated receptor  \\/  agonists on HDL-cholesterol in vervet monkeys  

Microsoft Academic Search

The objective of this study was to demonstrate the efficacy of a novel peroxisome proliferator-activated re- ceptor (PPAR) agonist and known PPARand PPARago- nists to increase HDL-cholesterol (HDL-C) in the St. Kitts vervet, a nonhuman primate model of atherosclerosis. Four groups (n ? 6) were studied and each group was assigned one of the following \\

Jeanne M. Wallace; Margrit Schwarz; Peter Coward; Jonathan Houze; Janet K. Sawyer; Kathryn L. Kelley; Anne Chai; Lawrence L. Rudel




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...


Sphingosine 1-phosphate and dioleoylphosphatidic acid are low affinity agonists for the orphan receptor GPR63  

E-print Network

,5,3,6,8). In this study, we show that S1P, dihydro-sphingosine 1-phosphate (dihydro-S1P) and dioleoylphosphatidic acid (do; Sphingosine 1-phosphate; Dioleoylphosphatidic acid; Lysophosphatidic acid; Intracellular Ca2+ ; ProliferationSphingosine 1-phosphate and dioleoylphosphatidic acid are low affinity agonists for the orphan

Hall, Randy A


Risk of non-fatal cardiac failure and ischaemic heart disease with long acting ?2 agonists  

Microsoft Academic Search

BACKGROUNDThe long term safety of ? agonists, particularly in patients with heart disease, has not been fully established.METHODSThis study accessed the results of three cohort studies involving: 12 294 patients receiving at least one prescription for nedocromil between November 1986 and September 1988; 15 407 patients prescribed salmeterol between December 1990 and May 1991; and 8098 patients prescribed bambuterol between

Richard M Martin; Nicholas R Dunn; Shayne N Freemantle; Ronald D Mann



Discovery of isoindoline and tetrahydroisoquinoline derivatives as potent, selective PPAR? agonists.  


Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor ? (PPAR?. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes. PMID:21094606

Luckhurst, Christopher A; Stein, Linda A; Furber, Mark; Webb, Nicola; Ratcliffe, Marianne J; Allenby, Gary; Botterell, Sara; Tomlinson, Wendy; Martin, Barrie; Walding, Andrew



Peroxisome Proliferator-Activated Receptor Gamma Agonists in Kidney Disease – Future Promise, Present Fears  

Microsoft Academic Search

The peroxisome proliferator-activated receptor superfamily (PPARs) comprises a class of nuclear receptors with significant effects in regulating multiple cellular pathways. Much research and clinical interest has surrounded the PPAR-? isoform because of its key role in the transcriptional regulation of metabolic pathways and the efficacy of thiazolidinediones, the most clinically used PPAR-? agonist, in the management of type 2 diabetes

Zhiguo Mao; Albert C. M. Ong




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...


Asthma, ?-agonists, and development of congestive heart failure: Results of the ABCHF study  

Microsoft Academic Search

Background: Previous studies demonstrated an association between asthma and idiopathic dilated cardiomyopathy (IDCM), raising concerns regarding chronic ?-agonist inhaler use. The purpose of this investigation was to replicate that association. Methods and Results: We identified 67 patients with IDCM and 130 controls with predominately ischemic cardiomyopathy. Patients were administered a structured, detailed phone survey by blinded interviewers, and had chart

David M. Sengstock; Omar Obeidat; Venkat Pasnoori; Pradeep Mehra; Keisha R. Sandberg; Peter A. McCullough



Changes in agonist EMG activation level during MVC cannot explain early strength improvement  

Microsoft Academic Search

A substantial gain in strength is often observed in the early phase of resistance training. The aim of this study was to address whether improved strength in the early phase of resistance training, can be attributed to increased activation, or to intra-muscular changes of the agonist muscle during maximal isometric torque production. Fourteen male subjects trained maximal isometric dorsiflexion during

Andreas Holtermann; Karin Roeleveld; Beatrix Vereijken; Gertjan Ettema



Functional Evaluation of THIQ, a Melanocortin 4 Receptor Agonist, in Models of Food Intake and Inflammation  

Microsoft Academic Search

The central melanocortinergic system plays an important role in regulating different aspects of energy homeostasis and the immunomodulatory response. In the present study, we evaluated the in vivo activities of food intake suppression and anti-inflammatory activity of THIQ, which has been proposed to possess high and selective melanocortin-4 receptor agonistic activity in vitro . The results showed that THIQ (0.1,

Ruta Muceniece; Liga Zvejniece; Reinis Vilskersts; Edgars Liepinsh; Larisa Baumane; Ivars Kalvinsh; Jarl E. Wikberg; Maija Dambrova



Effects of age and hypertension on cardiac responses to the ? 1-agonist phenylephrine in humans  

Microsoft Academic Search

Both aging and hypertension decrease the responsiveness of several receptor systems. The purpose of this study was to investigate the effect of aging versus hypertension on the blood pressure (BP), heart rate, and left ventricular (LV) responses to the ?1-agonist phenylephrine in humans. Fourteen young (age, 21–40 years; range, 30 ± 1 years; mean ± SEM), and 18 older (age,

Michel White; Anne Fourney; Etel Mikes; Frans H. H. Leenen



New mechanism-based anticancer drugs that act as orphan nuclear receptor agonists  

E-print Network

?³ (PPAR�³) agonists that exhibit antitumorigenic activity. In this study, the PPAR�³-active compounds decreased HT-29, HCT-15, RKO, HCT116 and SW480 colon cancer cell survival and KU7 and 253JB-V33 bladder cancer cell survival. In HT- 29, HCT-15, SW480...

Chintharlapalli, Sudhakar Reddy



Discovery of a novel series of indoline carbamate and indolinylpyrimidine derivatives as potent GPR119 agonists.  


GPR119 has emerged as an attractive target for anti-diabetic agents. We identified a structurally novel GPR119 agonist 22c that carries a 5-(methylsulfonyl)indoline motif as an early lead compound. To generate more potent compounds of this series, structural modifications were performed mainly to the central alkylene spacer. Installation of a carbonyl group and a methyl group on this spacer significantly enhanced agonistic activity, resulting in the identification of 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]propyl 7-fluoro-5-(methylsulfonyl)-2,3-dihydro-1H-indole-1-carboxylate (20). To further expand the chemical series of indoline-based GPR119 agonists, several heterocyclic core systems were introduced as surrogates of the carbamate spacer that mimic the presumed active conformation. This approach successfully produced an indolinylpyrimidine derivative 37, 5-(methylsulfonyl)-1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]-2,3-dihydro-1H-indole, which has potent GPR119 agonist activity. In rat oral glucose tolerance tests, these two indoline-based compounds effectively lowered plasma glucose excursion and glucose-dependent insulin secretion after oral administration. PMID:24508142

Sato, Kenjiro; Sugimoto, Hiromichi; Rikimaru, Kentaro; Imoto, Hiroshi; Kamaura, Masahiro; Negoro, Nobuyuki; Tsujihata, Yoshiyuki; Miyashita, Hirohisa; Odani, Tomoyuki; Murata, Toshiki




EPA Science Inventory

Possible mechanisms of AlC13-induced inhibition of agonist-stimulated inositol phosphate (IP) accumulation were investigated using rat brain cortex slices, synaptosomes or homogenates. nder conditions in which AlC13 inhibits carbachol (CARB) stimulated IP accumulation (Gp-mediate...


Clenbuterol, a ? 2Adrenoceptor Agonist, Improves Locomotor and Histological Outcomes after Spinal Cord Contusion in Rats  

Microsoft Academic Search

An important goal of rehabilitation following spinal cord injury is recovery of locomotor function and muscular strength. In the present studies, we determined whether the ?2-agonist, clenbuterol, can improve recovery of locomotor function following spinal cord injury. A model of spinal cord injury was examined in which four graded levels of contusion injury were produced in rats at the level

Richard J. Zeman; Yong Feng; Hong Peng; Joseph D. Etlinger



Effects of the @Adrenergic Agonist Clenbuterol in Cows: Lipid Metabolism, Milk Production, Pharmacokinetics, and Residues  

Microsoft Academic Search

The effects of the 0-adrenergic agonist clenbuterol on lipid metabolism, milk production, pharmacokinetics, and residues were studied in six lactating Brown Swiss cows. Four of these were treated with the growth-promoting dose of 5 pg of clenbuterolkg of BW, mixed within the concentrate, and administered twice a day for 3 wk. The remaining two cows served as controls. All animals

B. Stoffel; H. H. D. Meyer


Development of an immunochromatographic lateral flow test strip for detection of ?-adrenergic agonist Clenbuterol residues  

Microsoft Academic Search

A rapid immunochromatographic lateral flow test strip was developed in a competitive format with the gold-conjugated monoclonal antibody to specifically determine the residues of Clenbuterol (CL), a ?-adrenergic agonist. The test strip is made up of a sample pad, a conjugate reagent pad, a test membrane containing a control line and a test line, and an absorbent pad. CL standard

G. P. Zhang; X. N. Wang; J. F. Yang; Y. Y. Yang; G. X. Xing; Q. M. Li; D. Zhao; S. J. Chai; J. Q. Guo



Agonist–antagonist common drive during fatiguing knee extension efforts using surface electromyography  

Microsoft Academic Search

Aim. This study examined the electromyographic (EMG) activity of knee extensor agonists and a knee extensor antagonist muscle during fatiguing isometric extensions across a range of force levels. Methods. Five female subjects performed isometric knee extensions at 25%, 50%, 75% and 100% of their maximal voluntary contraction (MVC) with the knee flexed to 75°. Surface EMG (SEMG) was recorded with

Hugh Mullany; Mark O’Malley; Alan St. Clair Gibson; Christopher Vaughan



Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine ?4?2 Receptors  

PubMed Central

The ?4?2 subtype of the nicotinic acetylcholine receptor has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of ?4?2 agonists is lacking. Using binding experiments, electrophysiology and x-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at ?4?2 and the acetylcholine-binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for ?4?2 receptors. Crystal structures of five agonists with efficacies at ?4?2 from 21–76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong intersubunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong intersubunit anchoring. PMID:22170047

Rohde, Line Aagot Hede; Ahring, Philip Kiaer; Jensen, Marianne Lerbech; Nielsen, Elsebet ?stergaard; Peters, Dan; Helgstrand, Charlotte; Krintel, Christian; Harps?e, Kasper; Gajhede, Michael; Kastrup, Jette Sandholm; Balle, Thomas



Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus  

ERIC Educational Resources Information Center

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.…

Segev, Amir; Akirav, Irit



Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity*  

PubMed Central

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-? 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. PMID:22303003

Yao, Yongxue; Harrison, Kathleen A.; Al-Hassani, Mohammed; Murphy, Robert C.; Rezania, Samin; Konger, Raymond L.; Travers, Jeffrey B.



A mathematical model of the nicotinic-agonist stimulated release of dopamine from striatal  

E-print Network

Sciences 1 and Department of Biology and Biochemistry 2 , University of Bath, Bath, BA2 7AY, UK. E-mail:, using anatoxin-a (AnTx) as the agonist of choice, by virtue of its potency, stability and speci#12;city

Bath, University of


[Male-to-female agonistic support for copulation in Tibetan macaques (Macaca thibetana) at Huangshan, China].  


Biological market theory predicts that animals exchange the same commodities, or interchange different ones, to their mutual benefit. Using focal and behavioral sampling methods and continuous recording techniques, we studied Tibetan macaques (Macaca thibetana) in two study groups (YA1 and YA2) at Huangshan, China to see whether adults interchanged male-to-female agonistic support for copulation. Overall, male-to-female agonistic support was significantly correlated with copulation behaviors when data from both study groups were combined. For YA1, copulations in post-agonistic support observation (PO) was greater, but not significantly so, than random observation (RO) in the breeding season, and copulation in PO was significantly greater than RO in the non-breeding season. For YA2 copulations in PO were significantly greater than RO in both breeding and non-breeding seasons. These results suggest that a male who extends post-agonistic support to a female is significantly more likely to copulate with her. Our study provides evidence for the existence of a biological market involving interchanged social behaviors. Our study also illuminates the reproductive strategies of male competition and female choice in this species. PMID:23775987

Wang, Shuang; Li, Jin-Hua; Xia, Dong-Po; Zhu, Yong; Sun, Bing-Hua; Wang, Xi; Zhu, Lei




EPA Science Inventory

It is predicted that reciprocal crosstalk occurs between these two pathways, such that activation of each pathway will cause decreased activity in the other pathway. Accordingly, it is predicted that hypoxia and AhR agonists will exacerbate one another’s toxicity. Thi...


Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists  

PubMed Central

The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) ?, ?, and ? through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR ? agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR ? is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders. PMID:21253508

Bassaganya-Riera, Josep; Guri, Amir J.; Hontecillas, Raquel



Monoclonal Antibodies to Purified Muscarinic Receptor Display Agonist-Like Activity  

Microsoft Academic Search

Monoclonal antibody M-35, which immunoprecipitates native calf brain acetylcholine muscarinic receptor, mimics agonist stimulation of the intact guinea pig myometrium: the antibody, just like carbamoylcholine hydrochloride, causes a rise in intracellular cyclic GMP content, an inhibition of cyclic AMP accumulation due to prostacyclin, and induces uterine contractions. Another antibody, M-23, which reacts with the denatured muscarinic receptor, is devoid of

D. Leiber; S. Harbon; J.-G. Guillet; C. Andre; A. D. Strosberg



Comparative Gene Expression Profiles Induced by PPARc and PPARa/c Agonists in Human Hepatocytes  

E-print Network

Comparative Gene Expression Profiles Induced by PPARc and PPARa/c Agonists in Human Hepatocytes in human hepatocytes. Methodology/Principal Findings: Primary human hepatocytes and the well hepatocyte populations to the different compounds. Many genes involved in lipid, carbohydrate, xenobiotic

Boyer, Edmond


Fights at the Dinner Table: Agonistic Behavior in Pachydiplax longipennis (Odonata: Libellulidae) at Feeding Sites  

Microsoft Academic Search

Aggressive behavior of Pachydiplax longipennis during foraging was quantified by observing focal individuals on arrays of artificial perches. Pachydiplax apparently aggressively defend, for up to several hours at a time, one or a few feeding perches. Seventeen percent of all behaviors included agonistic actions, e.g., chasing or physical contact. The frequency of interactions was correlated positively with ambient temperature, solar

Joel M. Baird; Michael L. May



Gender differences in the intravenous self-administration of mu opiate agonists  

E-print Network

their antinociceptive activity, discriminative stimulus properties, the generation of physical dependence; Kosten et al., 1995; Lex, 1991; Rapp et al., 1995) that male and female human substance abusers may the antinociceptive activity of morphine and other mu agonists in the rat (Boyer et al., 1998; Cicero et al., 1996

Steinbach, Joe Henry


Journal of Steroid Biochemistry & Molecular Biology 77 (2001) 229238 Common phytochemicals are ecdysteroid agonists and antagonists  

E-print Network

Journal of Steroid Biochemistry & Molecular Biology 77 (2001) 229­238 Common phytochemicals of phytochemicals, including the phytoestrogens, interfere with molting and reproduction. We investigated whether in insects). None of the phytochemicals tested were ecdysone agonists in the reporter-gene assay

McLachlan, John


Agonistic Recognition in Education: On Arendt's Qualification of Political and Moral Meaning  

ERIC Educational Resources Information Center

Agonistic recognition in education has three interlinked modes of aesthetic experience and self-presentation where one is related to actions in the public realm; one is related to plurality in the way in which it comes into existence in confrontation with others; and one is related to the subject-self, disclosed by "thinking. Arendt"s conception…

Ljunggren, Carsten



The Risky Business of Dopamine Agonists in Parkinson Disease and Impulse Control Disorders  

Microsoft Academic Search

Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly dopamine agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and

Daniel O. Claassen; Wery P. M. van den Wildenberg; K. Richard Ridderinkhof; Charles K. Jessup; Madaline B. Harrison; G. Frederick Wooten; Scott A. Wylie



Impulsive smoking in a patient with Parkinson’s disease treated with dopamine agonists  

Microsoft Academic Search

Impulse control disorders, including pathological gambling, binge eating, compulsive shopping and hypersexual behaviors, have frequently been reported as a side effect of dopaminergic medications for Parkinson’s disease (PD). Here we describe a patient with PD who developed an unusual manifestation of impulsive behaviors, including cigarette smoking, associated with an increase in dopamine agonist medication. We postulate this to be related

Karina L. Bienfait; Matthew Menza; Margery H. Mark; Roseanne D. Dobkin



Unusual compulsive behaviors primarily related to dopamine agonist therapy in Parkinson's disease and multiple system atrophy  

Microsoft Academic Search

Unusual compulsive behaviors (weighing, card and video game playing, fishing, gardening, intense interest in established hobbies, locking and unlocking doors, repetitive dressing and undressing) occurred in relation to dopamine agonist therapy (six patients) and levodopa therapy (one patient) in seven patients with parkinsonism (seven Parkinson's disease, one multiple system atrophy). These behaviors occurred in tandem with pathological gambling, hypersexuality, compulsive

Andrew McKeon; Keith A. Josephs; Kevin J. Klos; Kathleen Hecksel; James H. Bower; J. Michael Bostwick; J. Eric Ahlskog



Environmental enrichment improves novel object recognition and enhances agonistic behavior in male mice.  


Environmental enrichment (EE) is an experimental paradigm in which rodents are housed in complex environments containing objects that provide stimulation, the effects of which are expected to improve the welfare of these subjects. EE has been shown to considerably improve learning and memory in rodents. However, knowledge about the effects of EE on social interaction is generally limited and rather controversial. Thus, our aim was to evaluate both novel object recognition and agonistic behavior in NMRI mice receiving EE, hypothesizing enhanced cognition and slightly enhanced agonistic interaction upon EE rearing. During a 4-week period half the mice (n = 16) were exposed to EE and the other half (n = 16) remained in a standard environment (SE). On PND 56-57, animals performed the object recognition test, in which recognition memory was measured using a discrimination index. The social interaction test consisted of an encounter between an experimental animal and a standard opponent. Results indicated that EE mice explored the new object for longer periods than SE animals (P < .05). During social encounters, EE mice devoted more time to sociability and agonistic behavior (P < .05) than their non-EE counterparts. In conclusion, EE has been shown to improve object recognition and increase agonistic behavior in adolescent/early adulthood mice. In the future we intend to extend this study on a longitudinal basis in order to assess in more depth the effect of EE and the consistency of the above-mentioned observations in NMRI mice. PMID:23588702

Mesa-Gresa, Patricia; Pérez-Martinez, Asunción; Redolat, Rosa



Structure-based design of novel human Toll-like receptor 8 agonists.  


Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds might be promising candidate vaccine adjuvants. Recently, a C2-butyl furo[2,3-c]quinoline was reported with purely TLR8 agonistic activity. This compound was successfully co-crystallized with the human TLR8 ectodomain, and the co-crystal structure revealed ligand-induced reorganization of the binding pocket of TLR8. The loss of a key hydrogen bond between the oxygen atom of the furanyl ring of the agonist and Thr 574 in TLR8 suggested that the furan ring is dispensable. Employing a disconnection strategy, 3- and 4-substituted aminoquinolines were investigated. Focused structure-based ligand design studies led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist (EC50 =0.2 ?M). Preliminary evaluation of this compound in ex vivo human blood assay systems revealed that it retains prominent cytokine-inducing activity. Together, these results indicate the suitability of this compound as a novel vaccine adjuvant, warranting further investigation. PMID:24474703

Kokatla, Hari Prasad; Sil, Diptesh; Tanji, Hiromi; Ohto, Umeharu; Malladi, Subbalakshmi S; Fox, Lauren M; Shimizu, Toshiyoki; David, Sunil A



Development of 3D-QSAR models in cyclic ureidobenzenesulfonamides: human ? 3Adrenergic receptor agonist  

Microsoft Academic Search

Pharmacophoric mapping based on 3D-QSAR studies is performed on sixteen cyclic ureidobenzenesulfonamides for their ?3-adrenergic receptor agonistic activity. The best 3D-QSAR model (with r2=0.877) which described the properties and distributions of 5-biophoric and 2-secondary biophoric sites, showed a good correlation between the observed and predicted activity both in training and test.

Sushil K. Kashaw; Lalit Rathi; Pradeep Mishra; Anil K. Saxena



Stimulants as Specific Inducers of Dopamine-Independent ? Agonist Self-Administration in Rats  

PubMed Central

A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of ? agonists mediated by their selective actions at ?1 receptors (?1Rs), 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 trained to self-administer the dopamine releaser, d-methamphetamine (0.01–0.32 mg/kg per injection), the ?-opioid receptor agonist, heroin (0.001–0.032 mg/kg per injection), and the noncompetitive N-methyl-d-aspartate receptor/channel antagonist ketamine (0.032–1.0 mg/kg per injection). As with cocaine, self-administration of d-methamphetamine induced reinforcing effects of the selective ?1R agonists PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate hydrochloride] and (+)-pentazocine (0.032–1.0 mg/kg per injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032–10 mg/kg per injection, each) self-administration. Although the ?1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g., remifentanil, 0.1–3.2 µg/kg per injection, for heroin and (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+)-MK 801; dizocilpine), 0.32–10.0 µg/kg per injection, for ketamine). The ?R antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008; 1.0–10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was affected neither by the dopamine receptor antagonist (+)-butaclamol (10–100 ?g/kg) nor by the opioid antagonist (?)-naltrexone (1.0–10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induces reinforcing effects of previously inactive ?1R agonists. It is further suggested that induced ?1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment. PMID:23908387

Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi; Kopajtic, Theresa A.



Individual calling to the feeding station can reduce agonistic interactions and lesions in group housed sows.  


In this study we used a new call feeding station, which enabled sows to learn that they have access to feed only after an individual acoustic signal was given. We tested whether this call feeding station is able to reduce agonistic interactions between sows and whether effects of call feeding can further be improved by enrichment. A total of 85 gestating sows were kept in a dynamic group in a large waiting area (207 m²) equipped with littered laying areas and an outside area. During a control treatment sows were fed in a normal electronic feeding station once a day (NF1-). Before testing the call feeding station sows had been conditioned for an acoustic signal (a trisyllabic "name") and learned that they were allowed to enter the feeding station only after their name was called. In the call feeding station sows were fed either once (CF1-) or twice a day (CF2-). In addition, we tested for effects of further enrichment such as straw in the activity area (CF2+). Agonistic behaviors and number of sows were observed by video in continuous recording from 0600 to 1800 h in an area (4 by 3.25 m) in front of the feeding station in periods of 4 d (NF1- = 7 periods, CF1- = 5 periods, CF2- = 3 periods, and CF2+ = 4 periods) and analyzed using mixed models. During each observation period sows were scored for wounds and body lesions at different body parts. From 0600 to 1100 h the proportion of agonistic interactions was much greater in the feeding mode NF1- compared with CF1- (feeding mode × time of day: P < 0.001) and in CF1- agonistic interactions were on a low level throughout the whole feeding cycle. The feeding frequency and the additional presence of straw in the activity area did not affect the proportion of agonistic interactions (all P > 0.05). The results on the number of sows in front of the feeding station mirrored the findings for agonistic interactions. In NF1- more sows were involved in agonistic interactions compared with CF1- (83.1 ± 12.9% vs. 61.5 ± 19.6%; P = 0.005) but there was no difference between the call feeding station (CF) treatments. The number of severe lesions was greater at the head (P = 0.014) and the flank (P = 0.006) but not at the shoulders (P = 0.057) and the hindquarter (P = 0.426) in NF1- compared with CF1-. The results suggest that signaling the feeding time individually increases the predictability for access to the feeding station and consequently reduces competition between sows. PMID:23372046

Kirchner, J; Manteuffel, G; Schrader, L



Behavioral effects of the novel potent cannabinoid CB1 agonist AM 4054  

PubMed Central

Due to the ubiquity of the CB1 cannabinoid receptor throughout the nervous system, as well as the many potential therapeutic uses of CB1 agonist-based interventions, it is desirable to synthesize novel probes of the CB1 receptor. Here, the acute behavioral effects of systemic (i.p.) administration of the putative novel CB1 full agonist AM 4054 were tested in rats. In Experiment 1, a dose range (0.15625 – 1.25 mg/kg) of AM 4054 produced effects consistent with CB1 agonism in the cannabinoid tetrad of tasks in rats, including induction of analgesia, catalepsy, hypothermia, and locomotor suppression. These effects were reversed with the CB1-selective inverse agonist AM 251 in Experiment 2, indicating that AM 4054 produced CB1 receptor-mediated effects. Analysis of open-field activity indicated that the reduction in locomotion is more consistent with general motor slowing than anxiogenesis. AM 4054 (0.0625 – 0.5 mg/kg) also dose-dependently reduced fixed-ratio 5 (FR5) operant responding for food in Experiment 3, and microanalysis of the timing and rate of lever pressing indicated a pattern of suppression similar to other CB1 agonists. Minimum doses of AM 4054 (0.125 – 0.3125 mg/kg) required to produce significant effects in these behavioral assays were lower than those of many CB1 agonists. It is likely that AM 4054 is a potent pharmacological tool for assessment of cannabinoid receptor function. PMID:23603029

McLaughlin, Peter J.; Thakur, Ganesh A.; McClure, Evan D.; Brown, Cara M.; Winston, Keisha M.; Wood, JodiAnne T.; Makriyannis, Alexandros; Salamone, John D.



Gender differences in the effects of presynaptic and postsynaptic dopamine agonists on latent inhibition in rats.  


The present study investigated gender differences in the effects of presynaptic and postsynaptic DA agonists on latent inhibition in the passive avoidance paradigm. During the preexposure phase, 32 male and 32 female Wistar rats were exposed to a passive avoidance box (or a different context) and received drug injections in three trials: the control group received an injection of 10% ascorbic acid in a different context. The experimental groups received injections of 10% ascorbic acid (latent inhibition [LI] group), 1mg/kg of the postsynaptic DA D(1)/D(2) agonist apomorphine (APO group), and 1.5mg/kg of the presynaptic DA agonist methamphetamine (METH group) in a passive avoidance box. All experimental groups were placed in the light compartment of the passive avoidance box and were allowed to enter into the dark compartment to receive a footshock (1mA, 2s) in five trials over 5 days. The latency to enter into the dark compartment was recorded in these five trials. The latent inhibition occurred in the female LI group but not in the male LI group. Regardless of gender, the APO group exhibited an increase in latent inhibition. Male rats in the METH group exhibited a decrease in latent inhibition, but female rats in the METH group exhibited an increase in latent inhibition, indicating that the METH group exhibited sexual dimorphism. The gender factor interacted only with the METH group and not the LI or APO group. The present paper discusses whether gender, the postsynaptic DA D(1)/D(2) agonist APO, and presynaptic DA agonist METH may be related to schizophrenia. PMID:22348862

Wang, Ying-Chou; He, Bo-Han; Chen, Chih-Chung; Huang, Andrew Chih Wei; Yeh, Yu-Chi



Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics  

PubMed Central

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V1a, V1b and V2 receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V1b receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V1a agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V2/V1a antagonist, conivaptan and the V2 antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V1a, V1b and V2 antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences. PMID:22375852

Manning, M; Misicka, A; Olma, A; Bankowski, K; Stoev, S; Chini, B; Durroux, T; Mouillac, B; Corbani, M; Guillon, G



Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor  

PubMed Central

Background and Purpose Artificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such ‘superagonism’ has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a ‘superagonist’. Experimental Approach Signalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label-free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G-protein activation, evaluation of cell surface agonist binding and computation of operational efficacies. Key Results In CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi/Gs signalling competence. In the orthosteric loss-of-function mutant M2-Y1043.33A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. ‘Superagonism’ is preserved in the physiological cellular context of MRC-5 human lung fibroblasts. Structure–signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that ‘superagonism’ of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points. Conclusion and Implications Supraphysiological agonist efficacy at muscarinic M2 ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR ‘superagonism’ is provided. We suggest that iperoxo-like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators. Linked Article This article is commented on by Langmead and Christopoulos, pp. 353–356 of this issue. To view this commentary visit PMID:23062057

Schrage, R; Seemann, WK; Klockner, J; Dallanoce, C; Racke, K; Kostenis, E; De Amici, M; Holzgrabe, U; Mohr, K



Comparative toxicity of three ecdysone agonist insecticides against the Mediterranean flour moth.  


The Mediterranean flour moth, Ephestia Kuehniella Zeller (Lepidoptera: Pyralidae), is an important pest in stored products worldwide, and is one of the major pests in flour mills in Algeria. Because environmental consideration, alternative approaches to neurotoxic insecticides, as well as safe, effective, and sound integrated pest management strategies are developed pest control agents such as the insect growth regulator (IGRs). Among these IGRs, the bisacylhydrazine derivatives are nonsteroidal ecdysterold agonists that mimic the action of moulting hormones and induce a precocious and incomplete moult in several insect orders. In topical bioassays using the pupae of E. kuehniella, three ecdysteroid agonists: RH-5849, the first bisaclhydrazine ecdysone agonist and two analogs, RH-5992 (tebufenozide) and RH-0345 (halofenozide), were evaluated on the reproduction under laboratory conditions. In a first series of experiments, the efficacy of these compounds was tested. These compounds exhibited insecticidal activity and the duration of pupal development was reduced with a dose-response relationship. Among the three tested compounds, tebufenozide (LD50 = 0.005 microg) appeared the most potent ecdysteroid agonist against E. kuehniella (RH-5849: LD50 = 0.05 microg and RH-0345: LD50 = 5.10 microg). In a second series of experiments, the effects of the ecdysone agonists (LD50) were investigated on the reproduction. Data showed that the three compounds affected growth of ovaries as evidenced by morphometric measurements of the ovaries from newly emerged adult females. In addition, the thickness of the chorion from basal oocytes was reduced only by RH-5992 and RH-0345. However, electron microscopic observations revealed that the three compounds had no significant effect on the fine structure of chorion. Finally, measurements of ovarian ecdysteroids' production by an enzyme immunoassay showed an increase in the hormonal amounts recorded in treated series compared to control series. PMID:16628915

Hami, M; Taibi, F; Smagghe, G; Soltani-Mazouni, N



Desensitization of Human CRF2(a) Receptor Signaling Governed by Agonist Potency and ?Arrestin2 Recruitment  

PubMed Central

The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and nonselective (UCN1 or sauvagine) agonists prominently desensitized CRF2(a) receptors in a rapid, concentration-dependent manner. A considerably slower rate and smaller magnitude of desensitization developed in response to the weak agonist CRF. CRF1 receptor desensitization stimulated by CRF, cortagine or stressin1-A had no effect on CRF2(a) receptor cyclic AMP signaling. Conversely, desensitization of CRF2(a) receptors by UCN2 or UCN3 did not cross-desensitize Gs-coupled CRF1 receptor signaling. In transfected HEK293 cells, activation of CRF2(a) receptors by UCN2, UCN3 or CRF resulted in receptor phosphorylation and internalization proportional to agonist potency. Neither protein kinase A nor casein kinases mediated CRF2(a) receptor phosphorylation or desensitization. Exposure of HEK293 or U2OS cells to UCN2 or UCN3 (100 nM) produced strong ?arrestin2 translocation and colocalization with membrane CRF2(a) receptors while CRF (1 µM) generated only weak ?arrestin2 recruitment. ?arrestin2 did not internalize with the receptor, however, indicating that transient CRF2(a) receptor-arrestin complexes dissociate at or near the cell membrane. Since deletion of the ?arrestin2 gene upregulated Gs-coupled CRF2(a) receptor signaling in MEF cells, a ?arrestin2 mechanism restrains Gs-coupled CRF2(a) receptor signaling activated by urocortins. We further conclude the rate and extent of homologous CRF2(a) receptor desensitization are governed by agonist-specific mechanisms affecting GRK phosphorylation, ?arrestin2 recruitment, and internalization thereby producing unique signal transduction profiles that differentially affect the stress response. PMID:23820308

Hauger, Richard L.; Olivares-Reyes, J. Alberto; Braun, Sandra; Hernandez-Aranda, Judith; Hudson, Christine C.; Gutknecht, Eric; Dautzenberg, Frank M.; Oakley, Robert H.



Desensitization of human CRF2(a) receptor signaling governed by agonist potency and ?arrestin2 recruitment.  


The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and non-selective (UCN1 or sauvagine) agonists prominently desensitized CRF2(a) receptors in a rapid, concentration-dependent manner. A considerably slower rate and smaller magnitude of desensitization developed in response to the weak agonist CRF. CRF1 receptor desensitization stimulated by CRF, cortagine or stressin1-A had no effect on CRF2(a) receptor cyclic AMP signaling. Conversely, desensitization of CRF2(a) receptors by UCN2 or UCN3 did not cross-desensitize Gs-coupled CRF1 receptor signaling. In transfected HEK293 cells, activation of CRF2(a) receptors by UCN2, UCN3 or CRF resulted in receptor phosphorylation and internalization proportional to agonist potency. Neither protein kinase A nor casein kinases mediated CRF2(a) receptor phosphorylation or desensitization. Exposure of HEK293 or U2OS cells to UCN2 or UCN3 (100nM) produced strong ?arrestin2 translocation and colocalization with membrane CRF2(a) receptors while CRF (1?M) generated only weak ?arrestin2 recruitment. ?arrestin2 did not internalize with the receptor, however, indicating that transient CRF2(a) receptor-arrestin complexes dissociate at or near the cell membrane. Since deletion of the ?arrestin2 gene upregulated Gs-coupled CRF2(a) receptor signaling in MEF cells, a ?arrestin2 mechanism restrains Gs-coupled CRF2(a) receptor signaling activated by urocortins. We further conclude that the rate and extent of homologous CRF2(a) receptor desensitization are governed by agonist-specific mechanisms affecting GRK phosphorylation, ?arrestin2 recruitment, and internalization thereby producing unique signal transduction profiles that differentially affect the stress response. PMID:23820308

Hauger, Richard L; Olivares-Reyes, J Alberto; Braun, Sandra; Hernandez-Aranda, Judith; Hudson, Christine C; Gutknecht, Eric; Dautzenberg, Frank M; Oakley, Robert H



Natural product agonists of peroxisome proliferator-activated receptor gamma (PPAR?): a review  

PubMed Central

Agonists of the nuclear receptor PPAR? are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPAR? agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPAR?-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPAR? modulators (SPPARMs), transactivating the expression of PPAR?-dependent reporter genes as partial agonists. Those natural PPAR? ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPAR? (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPAR?-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPAR? (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPAR? activation by dietary interventions or food supplements. PMID:25083916

Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M.; Heiss, Elke H.; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M.; Atanasov, Atanas G.



Effects of ??-agonists on force during and following anoxia in rat extensor digitorum longus muscle.  


Electrical stimulation of isolated muscles may lead to membrane depolarization, gain of Na(+), loss of K(+) and fatigue. These effects can be counteracted with ?(2)-agonists possibly via activation of the Na(+)-K(+) pumps. Anoxia induces loss of force; however, it is not known whether ?(2)-agonists affect force and ion homeostasis in anoxic muscles. In the present study isolated rat extensor digitorum longus (EDL) muscles exposed to anoxia showed a considerable loss of force, which was markedly reduced by the ?(2)-agonists salbutamol (10(-6) M) and terbutaline (10(-6) M). Intermittent stimulation (15-30 min) clearly increased loss of force during anoxia and reduced force recovery during reoxygenation. The ?(2)-agonists salbutamol (10(-7)-10(-5) M) and salmeterol (10(-6) M) improved force development during anoxia (25%) and force recovery during reoxygenation (55-262%). The effects of salbutamol on force recovery were prevented by blocking the Na(+)-K(+) pumps with ouabain or by blocking glycolysis with 2-deoxyglucose. Dibutyryl cAMP (1 mM) or theophylline (1 mM) also improved force recovery remarkably. In anoxic muscles, salbutamol decreased intracellular Na(+) and increased (86)Rb uptake and K(+) content, indicating stimulation of the Na(+)-K(+) pumps. In fatigued muscles salbutamol induced recovery of excitability. Thus ?(2)-agonists reduce the anoxia-induced loss of force, leading to partial force recovery. These data strongly suggest that this effect is mediated by cAMP stimulation of the Na(+)-K(+) pumps and that it is not related to recovery of energy status (PCr, ATP, lactate). PMID:22492937

Fredsted, A; Gissel, H; Ortenblad, N; Clausen, T



Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?  


In humans, mu- and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu- and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (p<0.002 for nalmefene 3 mg and p<0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefene's affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [(35)S]GTPgammaS binding studies demonstrated that nalmefene is a full antagonist at mu-opioid receptors and has partial agonist properties at kappa-opioid receptors. Elevations in serum prolactin following nalmefene are consistent with this partial agonist effect at kappa-opioid receptors. As kappa-opioid receptor activation can lower dopamine in brain regions important to the persistence of alcohol and cocaine dependence, the partial kappa agonist effect of nalmefene may enhance its therapeutic efficacy in selected addictive diseases. PMID:15988468

Bart, Gavin; Schluger, James H; Borg, Lisa; Ho, Ann; Bidlack, Jean M; Kreek, Mary Jeanne




E-print Network

LABORATOIRE DE PHYSIQUE DES SOLIDES UMR 8502 Centre Universitaire, Bât. 510 91405 Orsay cedex) 212503. #12;LABORATOIRE DE PHYSIQUE DES SOLIDES UMR 8502 Centre Universitaire, Bât. 510 91405 Orsay cedex fundamental fine particle magnetism utilizing colloidal dispersions or ferrofluids as the medium for study

Paris-Sud 11, Université de