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In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing mullerian system  

Microsoft Academic Search

Diethylstilbestrol (DES) was widely used to treat pregnant women through 1971. The reproductive tracts of their female offspring ex- posed to DES in utero are characterized by anatomic abnormalities. Here we show that DES administered to mice in utero produces changes in the expression pattern of several Hox genes that are involved in patterning of the reproductive tract. DES produces



A HOXA10 Estrogen Response Element (ERE) is Differentially Regulated by 17 Beta-estradiol and Diethylstilbestrol (DES)  

Microsoft Academic Search

The molecular mechanisms by which estrogens regulate developmental gene expression are poorly understood. While 17 beta-estradiol is normally present at high concentrations in pregnancy, exposure to the estrogen diethylstilbestrol (DES) in utero induces developmental anomalies of the female reproductive tract. HOX gene expression is altered by DES, leading to abnormal Müllerian duct differentiation. The mechanism of ligand-specific regulation of HOX

G Eda Akbas; Joon Song; Hugh S Taylor



Interactions of diethylstilbestrol (DES) and DES analogs with membrane progestin receptor-alpha and the correlation with their nongenomic progestin activities.  


Progestin induction of oocyte maturation (OM) in fish is a useful model for investigating endocrine disruption of nongenomic steroid actions. Although diethylstilbestrol (DES) analogs have been shown to mimic the actions of progestins to induce meiotic maturation of goldfish and zebrafish oocytes, their molecular mechanisms of action remain unclear. The ability of these endocrine-disrupting chemicals (EDCs) to interact with the progestin receptor mediating OM was investigated in receptor binding assays using plasma membranes from goldfish ovaries and breast cancer cells transfected with goldfish membrane progestin receptor (mPR)-alpha. Membranes prepared from both ovaries and mPRalpha-transfected cells showed high-affinity, saturable, displaceable, single binding sites specific for the goldfish maturation-inducing steroid, 17alpha,20beta-dihydroxy-4-pregnen-3-one (17,20beta-DHP). DES and DES analogs (dipropionate-DES and hexestrol), which induce OM in goldfish, bound to the receptor and caused concentration-dependent displacement of [3H]-17,20beta-DHP, whereas dimethyl ether-DES had no affinity for the receptor. Scatchard plot analysis of specific 17,20beta-DHP binding in the presence of different amounts of DES showed that DES binding is of the noncompetitive type. The activities of DES and DES analogs to induce meiotic maturation of goldfish oocytes were examined in an in vitro bioassay. Whereas a concentration-dependent induction of OM was observed in response to DES, dipropionate-DES, and hexestrol, dimethyl ether-DES did not show any OM-inducing activity. The close correspondence between binding of DES and its analogs to the mPRalpha protein and their OM-inducing activities suggests a mechanism of endocrine disruption mediated by binding to mPRalpha resulting in its activation, thereby mimicking the nongenomic action of the progestin 17,20beta-DHP. PMID:17446184

Tokumoto, Toshinobu; Tokumoto, Mika; Thomas, Peter



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.



Diethylstilbestrol (DES)-Stimulated Hormonal Toxicity is Mediated by ER? Alteration of Target Gene Methylation Patterns and Epigenetic Modifiers (DNMT3A, MBD2, and HDAC2) in the Mouse Seminal Vesicle  

PubMed Central

Background: Diethylstilbestrol (DES) is a synthetic estrogen associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by estrogen receptor ? (ER?), which alters expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes. Objectives: We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression. Methods: We used the neonatal DES exposure mouse model to examine DNA methylation patterns via bisulfite conversion sequencing in SVs of wild-type (WT) and ER?-knockout (?ERKO) mice. Results: The DNA methylation status at four specific CpGs (–160, –237, –306, and –367) in the Svs4 gene promoter changed during mouse development from methylated to unmethylated, and DES prevented this change at 10 weeks of age in WT SV. At two specific CpGs (–449 and –459) of the Ltf gene promoter, DES altered the methylation status from methylated to unmethylated. Alterations in DNA methylation of Svs4 and Ltf were not observed in ?ERKO SVs, suggesting that changes of methylation status at these CpGs are ER? dependent. The methylation status was associated with the level of gene expression. In addition, gene expression of three epigenetic modifiers—DNMT3A, MBD2, and HDAC2—increased in the SV of DES-exposed WT mice. Conclusion: DES-induced hormonal toxicity resulted from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that were mediated by ER?. Alterations in gene expression of DNMT3A, MBD2, and HDAC2 in DES-exposed male mice may be involved in mediating the changes in methylation status in the SV. Citation: Li Y, Hamilton KJ, Lai AY, Burns KA, Li L, Wade PA, Korach KS. 2014. Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ER? alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle. Environ Health Perspect 122:262–268;? PMID:24316720

Li, Yin; Hamilton, Katherine J.; Lai, Anne Y.; Burns, Katherine A.; Li, Leping; Wade, Paul A.



Fertility of female mice fed coumestrol and diethylstilbestrol  

Microsoft Academic Search

Coumestrol, a compound produced by various legumes which exerts estrogen?like activity in animals, and diethylstilbestrol (DES) were studied as chemical agents for controlling reproduction in mice. Female mice were fed control diets or diets containing 100 ppm coumestrol for eight days. Female mice were exposed to males and reproductive tracts examined 14 days later. Litter size was not affected by

Elias A. Elias; R. L. Kincaid



Diethylstilbestrol Exposure in Neonatal Mice Induces Changes in the Adulthood in the Immune Response to Taenia crassiceps without Modifications of Parasite Loads  

PubMed Central

Industrial growth has increased the exposition to endocrine disruptor compounds (EDC's), which are exogenous agents with agonist or antagonist action of endogenous steroid hormones that may affect the course of parasite infections. We wanted to determine if the exposure to diethylstilbestrol (DES), an estrogen agonist, to both male and female mice affected the immune response and their susceptibility to T. crassiceps cysticercosis. In all infected groups, females showed higher parasite loads than males, and neonatal DES administration did not modify this pattern. In the spleen, noninfected mice showed sex-related differences in the percentage of the CD8+ subpopulation, but DES decreased the percentage of CD3+, CD19+, and CD8+ subpopulations in infected mice. In the mesenteric lymphatic node (MNL), DES showed a dimorphic effect in the percentage of CD19+ cells. Regarding estrogen receptor alpha (ER-?) expression, DES treatment induced a reduction in the expression of this receptor in both noninfected female and male mice in the spleen, which was decreased only in males in CD3+ and CD8+ lymphocytes in MNL cell subpopulations. Our study is the first one to demonstrate that DES neonatal treatment in male and female mice affects the immune cell percentage, without effect on the susceptibility to T. crassiceps cysticercosis. PMID:25243144

Nava-Castro, Karen E.; Morales-Montor, Jorge; Ortega-Hernando, Alejandra; Camacho-Arroyo, Ignacio



Effects of Diethylstilbestrol in Fathead Minnows: Part 1. Effects on Reproductive Endocrine Function  

EPA Science Inventory

Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, was once widely prescribed to prevent miscarriages, and was used as a growth promoter in feed for beef and poultry production. After it was determined that DES caused significant adverse effects in the offspring of mo...


Effects of Diethylstilbestrol in Fathead Minnows: Part 2. Concentrations in Water and Tissues  

EPA Science Inventory

Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, was once widely prescribed to prevent miscarriages, and was used as a growth promoter in feed for beef and poultry production. After it was determined that DES caused significant adverse effects in the offspring of mot...


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



Histochemical and ultrastructural characteristics of the endometrial connective tissue stroma from mice continuously fed diethylstilbestrol  

Microsoft Academic Search

Summary  Histochemical and transmission electron microscopy were utilized to examine the endometrial connective tissue stroma of mice\\u000a continuously fed diethylstilbestrol (DES). Virgin female mice were continuously fed diets containing 0, 320, or 640 ppb DES\\u000a from 4 weeks of age until moribund. All animals reported on in this study were between 622 to 762 days of age when sacrificed.\\u000a Light microscopy

Robert J. Wordinger; Benjamin Highman; James W. Townsend; David L. Greenman



Neonatal exposure to diethylstilbestrol causes granulomatous orchitis via epididymal inflammation.  


Diethylstilbestrol (DES), an endocrine-disrupting chemical, is an infamous artificial estrogenic compound. Although neonatal exposure to DES has been shown to result in inflammation of the male reproductive system, it has not, to our knowledge, been reported to induce testicular inflammation. Here we report that neonatal exposure to DES caused granulomatous orchitis with spermatogenic disturbance in 4 of 17 ICR male mice at 12 weeks of age. In the animals with spermatogenic disturbance, we observed either seminiferous tubules containing only cells with Sertoli cell features (likely Sertoli cell syndrome), or tubule cells in maturation arrest that contained only spermatogonia and/or spermatocytes. Following neonatal DES exposure, 5-week-old mice exhibited inflammation in cauda epididymis; by 8 weeks, the inflammation had spread to all segments of epididymis but not the testis; by 12 weeks, inflammation of the epididymis was observed in all mice. These data indicated that cauda epididymis has increased sensitivity to neonatal DES exposure compared to other segments of epididymis and testis. The data also implied that neonatal DES exposure-induced inflammation in cauda epididymis extended gradually to the testis via corpus and caput during development. PMID:24449359

Miyaso, Hidenobu; Naito, Munekazu; Hirai, Shuichi; Matsuno, Yoshiharu; Komiyama, Masatoshi; Itoh, Masahiro; Mori, Chisato



Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats.  


The synthetic oestrogen diethylstilbestrol (DES), which is known to bind oestrogen receptors (ERs), has been reported to have adverse effects on endocrine homeostasis; however, the molecular mechanisms underlying these effects are poorly understood. In this study, we treated rats with DES and found high levels of this compound in the liver, adrenal glands and pituitary gland, as compared with other tissues. We have also detected early adverse effects of DES in the adrenal glands. The adrenal glands of rats treated with DES (340??g/kg body weight every 2 days) for 2 weeks showed increased weight and size and a decreased fat droplet size. Following 1 week of treatment with DES, the blood and adrenal corticosterone levels were substantially decreased without any histological alterations. The levels of the precursors for corticosteroid biosynthesis in the adrenal glands were also decreased, as determined using mass spectroscopy. Cholesterol, the principal material of corticosteroid biosynthesis, decreased substantially in the adrenal glands after only 1 week of treatment with DES. In conclusion, cholesterol insufficiency results in a reduction in adrenal corticosterone biosynthesis, which may lead to endocrine dysfunction, such as reproductive toxicity. PMID:24578295

Haeno, Satoko; Maeda, Naoyuki; Yagi, Takeshi; Tahata, Sachi; Sato, Michiko; Sakaguchi, Kanako; Miyasho, Taku; Ueda, Hiromi; Yokota, Hiroshi



Gender-related behavior in women exposed prenatally to diethylstilbestrol.  

PubMed Central

Accumulating evidence in experimental animals over the past three decades suggests that mammalian brain development and differentiation of the central nervous system are influenced by perinatal exposure to sex hormones. Hence, changes in human behavioral patterns may be associated with prenatal exposure to estrogenic substances such as diethylstilbestrol (DES). This paper reviews relevant studies from a series of laboratories and finds that no clear-cut differences can be demonstrated to date between unexposed and DES-exposed women in gender-related behavior, although the physical and psychological impact of the problems associated with exposure to DES are well documented. If both prenatal and postnatal influences such as social, economic, and environmental factors are taken into consideration, individual variation is more apparent than differences in gender-related behavior between unexposed and DES-exposed women. In summary, gender-related behavior is determined by a complex array of interacting factors, and prenatal influences are only one of many developmental events. More studies are needed using larger populations with carefully controlled selection criteria to suggest a direct role of prenatal DES exposure on subsequent gender-related behavior. Images p208-a PMID:8404755

Newbold, R R




E-print Network

NANCY LANGSTON REGULATINGDIETHYLSTILBESTROL (DES), ENDOCRINE DISRUPTORS, the retreat from precaution: Nancy Langston, "The Retreat from Precaution: Regulating Diethylstilbestrol (DES), Endocrine is played by endocrine disruptors--industrial pollutants that mimic hormones and alter sexual development

Langston, Nancy


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.



Early to middle gestational exposure to diethylstilbestrol impairs the development of labyrinth zone in mouse placenta.  


This study was performed to clarify the involvement of impaired labyrinth zone (LZ) of the placenta in the developmental toxicity of diethylstilbestrol (DES). DES at 10??g/kg per day was administered orally to mice on days 4 through 8 of gestation. Histological observation of the LZ and determination of blood glucose levels in dam and fetus were performed on day 13. A high frequency of embryonic death was observed in the DES group. DES induced the underdevelopment of the plexus vasculosus, extensive maternal blood space and the decreased expression of glucose transporters in the LZ, and a reduction of the glucose level in embryos. These findings suggest that impaired LZ development may be related to the embryolethality of DES. PMID:24118512

Kagawa, Nao; Saito, Yoshiaki; Nagao, Tetsuji



Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERR?  

PubMed Central

The orphan nuclear receptor ERR? is expressed in undifferentiated trophoblast stem cell lines and extraembryonic ectoderm, and genetic ablation of ERR? results in abnormal trophoblast proliferation and precocious differentiation toward the giant cell lineage. Here, we show that the synthetic estrogen diethylstilbestrol (DES) promotes coactivator release from ERR? and inhibits its transcriptional activity. Strikingly, treatment of trophoblast stem cells with DES led to their differentiation toward the polyploid giant cell lineage. In addition, DES-treated pregnant mice exhibited abnormal early placenta development associated with an overabundance of trophoblast giant cells and an absence of diploid trophoblast. These results define a novel pathway for DES action and provide evidence for steroidlike control of trophoblast development. PMID:11297507

Tremblay, Gilles B.; Kunath, Tilo; Bergeron, Denis; Lapointe, Line; Champigny, Céline; Bader, Jo-Ann; Rossant, Janet; Giguère, Vincent



Structural insights into selective agonist actions of tamoxifen on human estrogen receptor alpha.  


Tamoxifen-an anti-estrogenic ligand in breast tissues used as a first-line treatment in estrogen receptor (ER)-positive breast cancers-is associated with the development of resistance followed by resumption of tumor growth in about 30 % of cases. Whether tamoxifen assists in proliferation in such cases or whether any ligand-independent pathway to transcription exists is not fully understood; also, no ER? mutants have been detected so far that could lead to tamoxifen resistance. Using in silico conformational analysis of the ER? ligand binding domain (LBD), in the absence and presence of selective agonist (diethylstilbestrol; DES), antagonist (Faslodex; ICI), and selective estrogen receptor modulator (SERM; 4-hydroxy tamoxifen; 4-OHT) ligands, we have elucidated ligand-responsive structural modulations of the ER?-LBD dimer in its agonist and antagonist complexes to address the issue of "tamoxifen resistance". DES and ICI were found to stabilize the dimer in their agonist and antagonist conformations, respectively. The ER?-LBD dimer without the presence of any bound ligand also led to a stable structure in agonist conformation. However, binding of 4-OHT to the antagonist structure led to a flexible conformation allowing the protein to visit conformations populated by agonists as was evident from principal component analysis and radius of gyration plots. Further, the relaxed conformations of the 4-OHT bound protein exhibited a diminished size of the co-repressor binding pocket in the LBD, thus signaling a partial blockage of the co-repressor binding motif. Thus, the ability of 4-OHT-bound ER?-LBD to assume flexible conformations visited by agonists and reduced co-repressor binding surface at the LBD provide crucial structural insights into tamoxifen-resistance that complement our existing understanding. PMID:25060147

Chakraborty, Sandipan; Biswas, Pradip Kumar



Structural insights into Resveratrol’s antagonist and partial agonist actions on estrogen receptor alpha  

PubMed Central

Background Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ER?) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ER?) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ER? ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ER? monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ER? in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ER? dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ER? are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ER?. Conclusions Our Molecular Dynamics simulation of RES-ER? structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity. PMID:24160181



[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



Switched impulsive control of the endocrine disruptor diethylstilbestrol singular model  

NASA Astrophysics Data System (ADS)

In this work, a switched and impulsive controller is designed to control the Endocrine Disruptor Diethylstilbestrol mechanism which is usually modeled as a singular system. Then the exponential stabilization property of the proposed switched and impulsive singular model is discussed under matrix inequalities. A design algorithm is given and applied for the physiological process of endocrine disruptor diethylstilbestrol model to illustrate the effectiveness of the results.

Zamani, Iman; Shafiee, Masoud; Ibeas, Asier; de la Sen, M.



Prenatal diethylstilbestrol exposure and risk of uterine leiomyomata in the Nurses' Health Study II.  


Previous studies evaluating the association of prenatal exposure to diethylstilbestrol (DES), a potent endocrine disruptor, with incidence of uterine leiomyomata (UL) have had conflicting results. We evaluated the association between prenatal DES exposure and incident UL in women in the Nurses' Health Study II from 1989 to 2009. Women were aged 25-42 years at enrollment and had a prenatal exposure window corresponding to DES use. The analytical sample was larger than previous studies and included 102,164 premenopausal women with intact uteri, no prior history of UL or cancer, and prenatal DES exposure. Multivariable-adjusted Cox proportional hazard models were used to estimate the relationship between DES exposure and UL risk. During 1,273,342 person-years of follow-up, there were 11,831 incident cases of UL. Women with prenatal exposure to DES had a higher incidence of UL compared with unexposed women, with an adjusted hazard ratio of 1.12 (95% confidence interval: 0.98, 1.27). Risk was strongest for women exposed to DES in the first trimester, when exposure corresponds to early stages of fetal Müllerian development (adjusted hazard ratio = 1.21, 95% confidence interval: 1.02, 1.43). These results suggest that first-trimester DES exposure may be associated with an increased risk of UL, but they must be interpreted with concern for detection and recall biases. PMID:24142917

Mahalingaiah, Shruthi; Hart, Jaime E; Wise, Lauren A; Terry, Kathryn L; Boynton-Jarrett, Renée; Missmer, Stacey A



Diallyl sulfide inhibits diethylstilbestrol induced DNA damage in human breast epithelial cells (MCF-10A).  


Breast cancer is the second leading cause of cancer deaths in women in the United States. Diethylstilbestrol (DES) is a synthetic estrogen that has been shown to cause cancer in animals and humans, altering cell viability as well as inducing DNA damage. Diallyl sulfide (DAS) is a garlic organosulfide that has been shown to inhibit both the initiation and promotion phases of cancer in vivo and in vitro, as well as reduce the risk of cancer in epidemiological studies. MCF-10A cells, regarded as a normal breast epithelial cell line, were treated with varying concentrations of DES, DAS or various dose combinations of DES and DAS concomitantly, and assessed for cell viability, DNA strand breaks, and lipid peroxidation. DES (10?M) in combination with 1, 10, or 100?M DAS resulted in a 31%, 34%, or 36% respective increase in cell viability compared to the DES treatment alone, after 24h. At the same time point, 1, 10, and 100?M DAS were all effective in significantly reducing DES (100?M)-induced strand breaks to near that of the vehicle control. Additionally, 1?M DAS was effective in significantly reducing DES (100?M)-induced lipid peroxidation after 3h. The results of this research suggest that DAS is effective in recovering cell viability, attenuating DNA strand breaks, and decreasing lipid peroxidation in MCF-10A cells. PMID:25278253

McCaskill, Michael L; Rogan, Eleanor; Thomas, Ronald D



Timing and recovery of postweaning exposure to diethylstilbestrol on early pregnancy in CD-1 mice.  


Exposure timing could play an important role in the effects of estrogenic endocrine disrupting chemicals (EEDCs) on early pregnancy. This study examined the sensitivity of different exposure periods from weaning to gestation day 4.5 (D4.5) to 50ppb diethylstilbestrol (DES, a test EEDC) diet on embryo implantation and potential recovery upon temporary cessation of DES exposure in CD-1 mice. Peripubertal (3-5 weeks old) DES exposure reduced the numbers of corpora lutea and implantation sites. Postpubertal (5-7 weeks old) DES exposure did not have significant effects on early pregnancy. Postmating (D0.5-D4.5) DES exposure affected postovulation events leading to impaired embryo implantation. A 5-day premating rest from 5-week DES exposure (3-8 weeks old) resulted in recovery of early pregnancy rate. These data demonstrate that peripubertal and postmating periods are sensitive windows to endocrine disruption of early pregnancy and temporary cessation of exposure could partially alleviate adverse effects of DES on early pregnancy. PMID:25062584

Zhao, Fei; Zhou, Jun; El Zowalaty, Ahmed E; Li, Rong; Dudley, Elizabeth A; Ye, Xiaoqin



Model ecosystem evaluation of the environmental impacts of the veterinary drugs phenothiazine, sulfamethazine, clopidol, and diethylstilbestrol.  

PubMed Central

Four veterinary drugs of dissimilar chemical structures were evaluated for environmental stability and penchant for bioaccumulation. The techniques used were (1) a model aquatic ecosystem (3 days) and (2) a model feedlot ecosystem (33 days) in which the drugs were introduced via the excreta of chicks or mice. The model feedlot ecosystem was supported by metabolism cage studies to determine the amount and the form of the drug excreted by the chicks or mice. Considerable quantities of all the drugs were excreted intact or as environmentally short-lived conjugates. Diethylstilbestrol (DES) and Clopidol were the most persistent molecules, but only DES bioaccumulated to any appreciable degree. Phenothiazine was very biodegradable; sulfamethazine was relatively biodegradable and only accumulated in the organisms to very low levels. Data from the aquatic model ecosystem demonstrated a good correlation between the partition coefficients of the drugs and their accumulation in the fish. Images FIGURE 1. PMID:1037611

Coats, J R; Metcalf, R L; Lu, P Y; Brown, D D; Williams, J F; Hansen, L G



Involvement of insulin-like factor 3 (Insl3) in diethylstilbestrol-induced cryptorchidism.  


Recently, it has been shown that targeted inactivation of the Insl3 gene in male mice results in cryptorchidism. The Insl3 gene encodes insulin-like factor 3 (Insl3), which is expressed in fetal Leydig cells. The testicular factor Insl3 appears to play an important role in the transabdominal phase of testis descent, which involves development of the gubernaculum. Other studies have demonstrated that in utero exposure to diethylstilbestrol (DES), a synthetic estrogen, can lead to cryptorchidism both in humans and in animal models. The present study was undertaken to investigate whether prenatal DES-exposure might interfere with testicular Insl3 mRNA expression. Furthermore, the effect of DES on steroidogenic factor 1 (SF-1) mRNA expression level was determined, since it has been shown that SF-1 plays an essential role in transcriptional activation of the Insl3 gene promoter. Timed pregnant mice were treated with DES (100 microg/kg body weight) or vehicle alone on days E9 (gestational day 9) through E17. Control and DES-exposed mouse fetuses were collected at E16, E17 and E18, when transabdominal testis descent is taking place. Lack of gubernaculum development in DES-exposed animals was confirmed by histological analyses at E17. Expression of Insl3 and SF-1 mRNAs was studied in testes of control and DES-exposed fetuses at E16 and E18 by RNase protection assay. Prenatal DES-exposure resulted in a three-fold decrease in Insl3 mRNA expression level (P<0.005), at both E16 and E18. In contrast, DES treatment had no effect on the expression of SF-1 mRNA. These results support our hypothesis that DES may interfere with gubernaculum development by altering Insl3 mRNA expression, providing a possible mechanism by which DES may cause cryptorchidism. PMID:10650968

Emmen, J M; McLuskey, A; Adham, I M; Engel, W; Verhoef-Post, M; Themmen, A P; Grootegoed, J A; Brinkmann, A O



Physiological and biochemical perturbations in Daphnia magna following exposure to the model environmental estrogen diethylstilbestrol  

SciTech Connect

The estrogenic properties of many environmental contaminants, such as DDE and PCBs, have been associated with reproductive failure in a variety of vertebrate species. While estrogens have been measured in many invertebrate species, the function of this hormone in invertebrates is controversial. The objective of the present study was to identify possible physiological and biochemical target sites for the estrogenic effects of some xenobiotics on the freshwater crustacean Daphnia magna using the model environmental estrogen diethylstilbestrol (DES). Chronic exposure of daphnids to 0.50 mg/L DES reduced molting frequency among first-generation juveniles and decreased fecundity of second-generation daphnids. Adult first-generation daphnids chronically exposed to DES, as well as adult daphnids acutely exposed to DES for only 48 h, were examined for steroid hormone metabolic capabilities using testosterone as the model steroid. The rate of elimination of two major hydroxylated metabolites of testosterone was significantly reduced, and elimination of glucose conjugates of testosterone was significantly elevated from exposure to 0.50 mg/L DES. These results demonstrate that multigeneration exposure of daphnids to DES results in reduced fecundity and altered steroid metabolic capabilities. Thus, some arthropods, like vertebrates, are sensitive to the effects of endocrine-disrupting chemicals.

Baldwin, W.S.; Milam, D.L.; LeBlanc, G.A. [North Carolina State Univ., Raleigh, NC (United States). Dept. of Toxicology



Cloperastine rescues impairment of passive avoidance response in mice prenatally exposed to diethylstilbestrol.  


We previously reported that prenatal exposure to diethylstilbestrol (DES) impaired passive avoidance responses in mice. Apart from the above, we also found that cloperastine, a centrally acting antitussive, ameliorated depression-like and anxiety-like behaviors in rodents at antitussive-effective doses. In this study, we investigated whether or not cloperastine rescues impairment of passive avoidance responses in mice prenatally exposed to DES. Male DES-exposed mice were subcutaneously administered cloperastine at 10 or 30 mg/kg twice a day from 32 to 41 days after birth and subjected to behavioral testing 42 to 46 days after birth. Cloperastine at 10 and 30 mg/kg ameliorated DES-induced impairment of passive avoidance responses. In addition, cloperastine affected the levels of 5-HT1A receptors, GIRK and BDNF in the hippocampus of DES-exposed mice. However, the number of BrdU-positive cells in the hippocampus of DES-exposed mice was not changed by chronic administration of cloperastine. These findings suggest that the action of endocrine disruptors in the brain may not always be irreversible, and that the symptoms caused by endocrine disruptors might be curable with drugs such as cloperastine. PMID:22223406

Soeda, Fumio; Hirakawa, Emi; Inoue, Masako; Shirasaki, Tetsuya; Takahama, Kazuo



Urogenital teratogenicity of synthetic and natural estrogens in the rat: diethylstilbestrol and estradiol  

SciTech Connect

Diethylstilbestrol (DES), a synthetic estrogen and a carcinogen, is a potent urogenital teratogen in humans and rodents. The natural estrogen, estradiol (E/sub 2/), induces malformations in rats only at a maternal toxic dose. This difference in potency could result from differences in fetal sensitivity, or in the distribution and/or metabolism of the two compounds. The current studies tested the hypothesis that the teratogenicity of DES is mediated by its estrogenic activity (rather than its metabolic activation). The two estrogens were directly compared by injecting them into day 19 fetuses, bypassing any maternal modifying factors. Both DES (0.1, 1 or 10 and E/sub 2/ (10 or 100 caused dose-related incidences of urogenital malformations (diagnosed at 6-7 weeks), but DES was 10- to 100-fold more potent. Between 24 h and 9 days after DES or E/sub 2/ exposure, histologic evidence of estrogenic stimulation was observed, including premature myometrial growth and differentiation, and vaginal epithelial thickening. Thus, DES and E/sub 2/ act directly in the fetus, to produce similar teratogenic effects, without maternal mediation. Following both maternal and fetal administration of /sup 14/C-DES or /sup 3/H-E/sub 2/, the /sup 14/C (from DES) was concentrated in fetal tissues, whereas /sup 3/H (from E/sub 2/) was retained in fetal plasma (protein-bound). Fetal genital tract contained the largest proportion of unchanged E/sub 2/ (74%) or DES (86%). It was concluded that (1) the teratogenicity of DES reflects its estrogenic activity in the fetus; (2) the fetus is sensitive to a brief exposure to estrogens, including LY and (3) the synthetic estrogen is more potent that estradiol because of its greater availability to fetal genital tissues: protein binding and rapid metabolism reduce the teratogenicity of the natural estrogen.

Henry, E.C.



Liver X receptors interfere with the deleterious effect of diethylstilbestrol on testicular physiology.  


Liver X receptors LXR? (NR1H3) and LXR? (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ER? (NR3A1) and ER? (NR3A2), and Lxr?/?. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 ?g DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxr?/?; those whose accumulation is repressed by the absence of Lxr?/?. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxr?/?. Altogether, our study shows that both nuclear receptors Lxr? and Lxr? are not only basally important for testicular physiology but could also have a preventive effect against estrogen-like endocrine disruptors. PMID:24333430

Oumeddour, Abdelkader; Viennois, Emilie; Caira, Françoise; Decourbey, Clélia; Maqdasy, Salwan; Tahraoui, Abdelkrim; Baron, Silvère; Volle, David H; Lobaccaro, Jean-Marc A



Estrogen Receptor-? Mediates Diethylstilbestrol-Induced Feminization of the Seminal Vesicle in Male Mice  

PubMed Central

Background: Studies have shown that perinatal exposure to the synthetic estrogen diethylstilbestrol (DES) leads to feminization of the seminal vesicle (SV) in male mice, as illustrated by tissue hyperplasia, ectopic expression of the major estrogen-inducible uterine secretory protein lactoferrin (LF), and reduced expression of SV secretory protein IV (SVS IV). Objectives: The present study was designed to evaluate the role of the estrogen receptor (ER) in this action by using ER-knockout (ERKO) mice. Methods: Wild-type (WT), ER?-null (?ERKO), and ER?-null (?ERKO) male mice were treated with either vehicle or DES (2 ?g/day) on neonatal days 1–5. These mice were divided into two groups: In the first group, intact mice were sacrificed at 10 weeks of age; in the second group, mice were castrated at 10 weeks of age, allowed to recover for 10 days, treated with dihydrotestosterone (DHT) or placebo, and sacrificed 2 weeks later. Body weights and SV weights were recorded, and mRNA expression levels of Ltf (lactoferrin), Svs4, and androgen receptor (Ar) were assessed. Results: In DES-treated intact mice, SV weights were reduced in WT and ?ERKO mice but not in ?ERKO mice. DES-treated WT and ?ERKO males, but not ?ERKO males, exhibited ectopic expression of LF in the SV. DES treatment resulted in decreased SVS IV protein and mRNA expression in WT males, but no effect was seen in ?ERKO mice. In addition, DES-treated ?ERKO mice exhibited reduced Svs4 mRNA expression but maintained control levels of SVS IV protein. In DES-treated castrated mice, DHT implants restored SV weights to normal levels in ?ERKO mice but not in WT mice, suggesting full androgen responsiveness in ?ERKO mice. Conclusions: These data suggest that DES-induced SV toxicity and feminization are primarily mediated by ER?; however, some aspects of androgen response may require the action of ER?. PMID:22275727

Walker, Vickie R.; Jefferson, Wendy N.; Couse, John F.



Effects of In Utero Exposure to Bisphenol A or Diethylstilbestrol on the Adult Male Reproductive System  

PubMed Central

The objective of this study was to determine if in utero exposure to Bisphenol A (BPA) induced reproductive tract abnormalities in the adult male testis. Using the C57/Bl6 mouse, we examined sex-organ weights, anogenital distance (AGD), and testis histopathology in adult males exposed in utero via oral gavage to sesame oil, 50 ?g/kg BPA, 1,000 ?g/kg BPA, or 2 ?g/kg diethylstilbestrol (DES) as a positive control from gestational days 10–16. No changes in sperm production or germ cell apoptosis were observed in adult testes following exposure to either chemical. Adult mRNA levels of genes associated with sexual maturation and differentiation, GATA4 and ID2, were significantly lower only in DES-exposed testes. In summary, the data indicate no gross alterations in spermatogenesis following in utero exposure to BPA or DES. At the molecular level, in utero exposure to DES, but not BPA, leads to decreased mRNA expression of genes associated with Sertoli cell differentiation. PMID:21922642

LaRocca, Jessica; Boyajian, Alanna; Brown, Caitlin; Smith, Stuart Duncan; Hixon, Mary



In utero exposure to the oestrogen mimic diethylstilbestrol disrupts gonadal development in a viviparous reptile.  


The ubiquitous presence of endocrine-disrupting chemicals (EDCs) in the environment is of major concern. Studies on oviparous reptiles have significantly advanced knowledge in this field; however, 30% of reptilian species are viviparous (live-bearing), a parity mode in which both yolk and a placenta support embryonic development, thus exposure to EDCs may occur via multiple routes. In this first study of endocrine disruption in a viviparous lizard (Niveoscincus metallicus), we aimed to identify effects of the oestrogen mimic diethylstilbestrol (DES) on gonadal development. At the initiation of sexual differentiation, pregnant N. metallicus were treated with a single dose of DES at 100 or 10µgkg--1, a vehicle solvent or received no treatment. There was no dose-response effect, but the testes of male neonates born to DES-exposed mothers showed reduced organisation of seminiferous tubules and a lack of germ cells compared with those from control groups. The ovaries of female neonates born to DES-exposed mothers exhibited phenotypic abnormalities of ovarian structure, oocytes and follicles compared with controls. The results indicate that, in viviparous lizards, maternal exposure to oestrogenic EDCs during gestation may have profound consequences for offspring reproductive fitness. PMID:24718097

Parsley, Laura M; Wapstra, Erik; Jones, Susan M



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



Comparative effects of neonatal diethylstilbestrol on external genitalia development in adult males of two mouse strains with differential estrogen sensitivity.  


The effect of neonatal exposure to diethylstilbestrol (DES), a potent synthetic estrogen, was examined to evaluate whether the CD-1 (estrogen insensitive, outbred) and C57 (estrogen sensitive, inbred) mouse strains differ in their response to estrogen disruption of male ExG differentiation. CD-1 and C57BL/6 litters were injected with sesame oil or DES (200 ng/g/5 ?l in sesame oil vehicle) every other day from birth to day 10. Animals were sacrificed at the following time points: birth, 5, 10 and 60 days postnatal. Neonatally DES-treated mice from both strains had many ExG abnormalities that included the following: (a) severe truncation of the prepuce and glans penis, (b) an abnormal urethral meatus, (c) ventral tethering of the penis, (d) reduced os penis length and glans width, (e) impaired differentiation of cartilage, (f) absence of urethral flaps, and (g) impaired differentiation of erectile bodies. Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues. While the effects of DES were similar in the more estrogen-sensitive C57BL/6 mice versus the less estrogen-sensitive CD-1 mice, the severity of DES effects was consistently greater in C57BL/6 mice. We suggest that many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development. PMID:25449353

Mahawong, Phitsanu; Sinclair, Adriane; Li, Yi; Schlomer, Bruce; Rodriguez, Esequiel; Ferretti, Max M; Liu, Baomai; Baskin, Laurence S; Cunha, Gerald R



Effects of diethylstilbestrol on luteinizing hormone-producing cells in the mouse anterior pituitary.  


Gonadotrophs in the anterior pituitary secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Neonatal diethylstilbestrol (neoDES) treatment affects reproductive function of male and female mice, but the effect of this treatment on the development as well as direct effects on pituitary gonadotrophs have not been ascertained. We investigated LH-secreting gonadotropes and the expression of genes involved in the synthesis and secretion of gonadotropins in the anterior pituitary of neoDES mice using immunohistochemistry and real-time reverse transcription-polymerase chain reaction (RT-PCR). The percentage of LH-secreting gonadotropes in 90-day-old female mice treated neonatally with an oil vehicle (neoOil) was significantly lower than in 30-day-old neoOil females but not in males, indicating a significant reduction after reproductive maturation in females. The percentage of LH-secreting gonadotropes in the medial area of 90-day-old neoDES females was significantly lower than that of 90-day-old neoOil females, ovariectomized neoOil females, and neoOil and neoDES males. The expression of the LH beta (Lhb) subunit in the anterior pituitary of 90-day-old neoDES females was similar to that in neoOil females, but it was significantly lower than that observed in 90-day-old males. Ovariectomy increased the expression of the alpha subunit of glycoprotein hormones, FSH beta (Fshb) subunit and Lhb subunit both in neoOil and neoDES females, suggesting that the anterior pituitary of neoDES female mice is regulated by ovarian hormones via negative feedback. In organ-cultured, anterior pituitaries exposed to DES exhibited no change in the number of LH-secreting gonadotropes but did reduced gene expression. These results suggest that LH-secreting gonadotropes in the female mice are not only directly affected by neoDES but also are influenced by the masculinization of the hypothalamus. That is, neonatal DES exposure can masculinize or defeminize the hypothalamus of female mice. However, the regulation of the pituitary gonadotropins by the hypothalamus could be different from that in intact male mice. PMID:24521563

Ishikawa, Machiko; Murai, Erina; Hashiguchi, Yuka; Iguchi, Taisen; Sato, Tomomi



Ovarian dysfunction, obesity and pituitary tumors in female mice following neonatal exposure to low-dose diethylstilbestrol.  


In a previous study, we found that early life exposure to low-dose diethylstilbestrol (DES) induced early onset of spontaneous abnormalities in estrus cycle and shortened survival in female Sprague-Dawley rats. In order to confirm the repeatability of the previous study, neonates of C57BL/6J mice were orally administered DES at doses of 0.005, 0.05, 0.5 and 5 ?g/kg/day, and the aging of their reproductive function was observed. As a result, delayed toxicity on ovarian function was found in females treated with 0.5 ?g/kg/day of DES. Concomitantly, the females in the 0.05 ?g/kg/day of DES, or greater, groups, had increased body weights and, in the 0.5 ?g/kg/day of DES, or greater, groups, had developed pituitary tumors, which were causal factors in their accelerated mortality. Thus, we found that early life exposure to low-dose DES induced early onset of spontaneous abnormalities in estrus cycle not only in female rats but also in female mice. PMID:25450423

Ohta, Ryo; Ohmukai, Hideo; Toyoizumi, Tomoyasu; Shindo, Tomoko; Marumo, Hideki; Ono, Hiroshi



Liquid-phase exfoliated graphene as highly-sensitive sensor for simultaneous determination of endocrine disruptors: Diethylstilbestrol and estradiol.  


It is quite important to develop convenient and rapid analytical methods for trace levels of endocrine disruptors because they heavily affect health and reproduction of humans and animals. Herein, graphene was easily prepared via one-step exfoliation using N-methyl-2-pyrrolidone as solvent, and then used to construct an electrochemical sensor for highly-sensitive detection of diethylstilbestrol (DES) and estradiol (E2). On the surface of prepared graphene film, two independent and greatly-increased oxidation waves were observed at 0.28V and 0.49V for DES and E2. The remarkable signal enlargements indicated that the detection sensitivity was improved significantly. The influences of pH value, amount of graphene and accumulation time on the oxidation signals of DES and E2 were discussed. As a result, a highly-sensitive and rapid electrochemical method was newly developed for simultaneous detection of DES and E2. The values of detection limit were evaluated to be 10.87nM and 4.9nM for DES and E2. Additionally, this new method was successfully used in lake water samples and the accuracy was satisfactory. PMID:25265595

Hu, Lintong; Cheng, Qin; Chen, Danchao; Ma, Ming; Wu, Kangbing



Pubertal timing after neonatal diethylstilbestrol exposure in female rats: neuroendocrine vs peripheral effects and additive role of prenatal food restriction.  


We studied the effects of neonatal exposure to diethylstilbestrol (DES) on pubertal timing in female rats. We examined associated neuroendocrine changes and effects of prenatal food restriction. Age at vaginal opening was advanced after exposure to 10 ?g/kg/d of DES and delayed after 1 ?g/kg/d (subcutaneous injections). Using this lower dose, pulsatile GnRH secretion was slower at 25 days of age. Both doses reduced KiSS1 mRNA levels at 15 days of age. Using functional Kisspeptin promoter assay, 1 or 10 ?M DES reduced or increased KISS1 transcription, respectively. Leptin stimulatory effect on GnRH secretion in vitro (15 days of age) was reduced after prenatal food restriction and neonatal DES exposure (higher dose), both effects being cumulative. Thus, alterations in pubertal timing by DES neonatally are not unequivocally toward precocity, the level of exposure being critical. We provide evidence of neuroendocrine disruption and interaction with prenatal food availability. PMID:24316331

Franssen, Delphine; Ioannou, Yiannis S; Alvarez-real, Alexandra; Gerard, Arlette; Mueller, Johanna K; Heger, Sabine; Bourguignon, Jean-Pierre; Parent, Anne-Simone



Demonstration of estrogen receptors and of estrogen responsiveness in the HKT-1097 cell line derived from diethylstilbestrol-induced kidney tumors  

Microsoft Academic Search

Summary  This study was undertaken in order to examine the estrogen sensitivity of HKT-1097, an established cell line recently derived\\u000a from diethylstilbestrol (DES)-induced kidney tumors in Syrian hamsters. Estrogen receptor (ER) level in HKT-1097, determined\\u000a by enzyme-linked immunoassay, was 67 fmol\\/mg protein, i.e., a value approx. 30% lower than that found in Syrian hamster kidney\\u000a tumors. ER immunostaining in cells fixed

R. Brohée; D. Nonclercq; F. Journé; G. Toubeau; P. Falmagne; G. Leclercq; J.-A. Heuson-Stiennon; G. Laurent



Differential Effects of Bisphenol A and Diethylstilbestrol on Human, Rat and Mouse Fetal Leydig Cell Function  

PubMed Central

Endocrine disruptors (ED) have been incriminated in the current increase of male reproductive alterations. Bisphenol A (BPA) is a widely used weak estrogenic environmental ED and it is debated whether BPA concentrations within the average internal exposure are toxic. In the present study we investigated the effects of 10?12 to 10?5 M BPA concentrations on fetal Leydig cell function, as fetal life is a critical period of sensitivity to ED effects on male reproductive function. To this aim, fetal testes from human at 6.5–10.5 gestational weeks (GW) or from rat and mouse at a comparable critical period of development (14.5 days post-coitum (dpc) for rat and 12.5 dpc for mouse) were explanted and cultured using our validated organotypic culture system in the presence or absence of BPA for 1–3 days. BPA concentrations as low as 10?8 M reduced testosterone secretion by human testes from day 1 of culture onwards, but not by mouse and rat testes where concentrations equal to 10?5 M BPA were required. Similarly, 10?8 M BPA reduced INSL3 mRNA levels only in human cultured testes. On the contrary, 10?5 and 10?6 M diethylstilbestrol (DES), a classical estrogenic compound, affected testosterone secretion only in rat and mouse testis cultures, but not in human testis cultures. Lastly, contrarily to the DES effect, the negative effect of BPA on testosterone produced by the mouse fetal testis was maintained after invalidation of estrogen receptor ? (ER?). In conclusion, these results evidenced i) a deleterious effect of BPA on fetal Leydig cells function in human for concentrations from 10?8 M upwards, ii) species-specific differences raising concerns about extrapolation of data from rodent studies to human risk assessment, iii) a specific signaling pathway for BPA which differs from the DES one and which does not involve ER?. PMID:23284716

N’Tumba-Byn, Thierry; Moison, Delphine; Lacroix, Marlène; Lecureuil, Charlotte; Lesage, Laëtitia; Prud’homme, Sophie M.; Pozzi-Gaudin, Stéphanie; Frydman, René; Benachi, Alexandra; Livera, Gabriel



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



Inhibition of XO or NOX attenuates diethylstilbestrol-induced endothelial nitric oxide deficiency without affecting its effects on LNCaP cell invasion and apoptosis  

PubMed Central

Oestrogen protects cardiovascular health partially via an up-regulation of NO• (NO radical) production. Its synthetic analogue DES (diethylstilbestrol), used as a potent androgen deprivation therapy for patients with prostate cancer, is however associated with high incidence of thromboembolic events. Exposure of BAECs (bovine aortic endothelial cells) to pharmacologically relevant dosage (12.5 ?mol/l, 24 h) of DES resulted in a marked reduction in endothelial NO• bioavailability determined by ESR (electron spin resonance), while 17?-oestradiol instead increased NO• production as expected. Intriguingly, endothelial O2•? (superoxide anion) production was up-regulated by DES in vitro and in vivo, which was, however, attenuated by the ER (oestrogen receptor) antagonist ICI 182780, the XO (xanthine oxidase) inhibitor oxypurinol or the NOX (NADPH oxidase) inhibitor NSC23766. These agents also restored NO• production. DES alone in a cell-free system did not produce any ESR-sound O2•? signal. Of note, eNOS (endothelial NO synthase) mRNA and protein remained unchanged in response to DES. These results suggest that receptor-dependent activation of XO or NOX, and subsequent production of O2•?, mediate DES-induced NO• deficiency. This could represent a previously unrecognized mechanism that is responsible for cardiovascular complications of DES administration. Importantly, DES-induced suppression of LNCaP cell invasion and apoptosis were not affected by XO or NOX inhibitor. Therefore combinatorial therapy of DES and XO/NOX inhibitor may prove to be an innovative and useful therapeutic option in eliminating cardiovascular complications of DES, while preserving its anti-cancer effects, benefiting patients with advanced cancer who do not respond well to any other treatments but DES. PMID:22568671

YOUN, Ji-Youn; NGUYEN, Andrew; CAI, Hua



Inhibition of XO or NOX attenuates diethylstilbestrol-induced endothelial nitric oxide deficiency without affecting its effects on LNCaP cell invasion and apoptosis.  


Oestrogen protects cardiovascular health partially via an up-regulation of NO• (NO radical) production. Its synthetic analogue DES (diethylstilbestrol), used as a potent androgen deprivation therapy for patients with prostate cancer, is however associated with high incidence of thromboembolic events. Exposure of BAECs (bovine aortic endothelial cells) to pharmacologically relevant dosage (12.5 ?mol/l, 24 h) of DES resulted in a marked reduction in endothelial NO• bioavailability determined by ESR (electron spin resonance), while 17?-oestradiol instead increased NO• production as expected. Intriguingly, endothelial O(2)•- (superoxide anion) production was up-regulated by DES in vitro and in vivo, which was, however, attenuated by the ER (oestrogen receptor) antagonist ICI 182780, the XO (xanthine oxidase) inhibitor oxypurinol or the NOX (NADPH oxidase) inhibitor NSC23766. These agents also restored NO• production. DES alone in a cell-free system did not produce any ESR-sound O(2)•- signal. Of note, eNOS (endothelial NO synthase) mRNA and protein remained unchanged in response to DES. These results suggest that receptor-dependent activation of XO or NOX, and subsequent production of O(2)•-, mediate DES-induced NO• deficiency. This could represent a previously unrecognized mechanism that is responsible for cardiovascular complications of DES administration. Importantly, DES-induced suppression of LNCaP cell invasion and apoptosis were not affected by XO or NOX inhibitor. Therefore combinatorial therapy of DES and XO/NOX inhibitor may prove to be an innovative and useful therapeutic option in eliminating cardiovascular complications of DES, while preserving its anti-cancer effects, benefiting patients with advanced cancer who do not respond well to any other treatments but DES. PMID:22568671

Youn, Ji-Youn; Nguyen, Andrew; Cai, Hua



G protein-coupled estrogen receptor-protein kinase A-ERK-CREB signaling pathway is involved in the regulation of mouse gubernaculum testis cells by diethylstilbestrol.  


The etiology of testicular dysgenesis syndrome is multifactorial and involves environmental factors, such as environmental estrogens. Several studies have shown that hormonal effects on the gubernaculum may affect testicular descent. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the morphology and proliferation of gubernacular cells, but the underlying mechanisms remain elusive. In this study, we aimed to determine whether DES may regulate the function of gubernaculum testis cells by way of nongenomic effects mediated by G protein-coupled estrogen receptor (GPER). We used cultured mouse gubernacular testis cells to demonstrate that GPER is expressed in gubernaculum testis cells. Erk1/2 inhibitor PD98059, PKA inhibitor H89, and Src inhibitor PP2 relieved DES-induced inhibition of gubernaculum testis cell proliferation, but ER inhibitor ICI 182780 had no effects on DES-induced inhibition of gubernaculum testis cell proliferation. In addition, we found that DES induced the activation of CREB downstream of PKA, Src, and ERK1/2 in these cells. These data suggest that the effects of DES on mouse gubernaculum testis cells are mediated at least partially by GPER-protein kinase A-ERK-CREB signaling pathway. PMID:24306628

Zhang, Xuan; Li, Jian-hong; Duan, Shou-xing; Lin, Qing-Jun; Ke, Song; Ma, Lian; Huang, Tian-hua; Jiang, Xue-wu



Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo.  


Antisense transcript, long non-coding RNA HOTAIR is a key player in gene silencing and breast cancer and is transcriptionally regulated by estradiol. Here, we have investigated if HOTAIR expression is misregulated by bisphenol-A (BPA) and diethylstilbestrol (DES). Our findings demonstrate BPA and DES induce HOTAIR expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of rat. Luciferase assay showed that HOTAIR promoter estrogen-response-elements (EREs) are induced by BPA and DES. Estrogen-receptors (ERs) and ER-coregulators such as MLL-histone methylases (MLL1 and MLL3) bind to the HOTAIR promoter EREs in the presence of BPA and DES, modify chromatin (histone methylation and acetylation) and lead to gene activation. Knockdown of ERs down-regulated the BPA and DES-induced expression of HOTAIR. In summary, our results demonstrate that BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters leading to its endocrine disruption in vitro and in vivo. PMID:24533973

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



Non-diethylstilbestrol-associated primary clear cell carcinoma of the vagina: two case reports with immunohistochemical studies and literature review.  


Primary clear cell adenocarcinomas most commonly involve the genitourinary system, including the vagina. Previously, primary clear cell adenocarcinomas of the vagina have been discussed within the context of prenatal exposure to diethylstilbestrol. Due to its widely proven role in the development of this carcinoma, administration of diethylstilbestrol is prohibited. We present two cases of non-diethylstilbestrol-associated primary clear cell adenocarcinoma of the vagina from the archives of the Anatomical Pathology Department at King Abdulaziz University in order to improve our understanding of its biological behavior. Our findings suggest that primary clear cell adenocarcinoma of the vagina may be unrelated to diethylstilbestrol exposure and that non-diethylstilbestrol-associated primary clear cell adenocarcinoma of the vagina, when present at a younger age, may have a worse prognosis. PMID:24850989

Mufti, Shagufta T; Ali, Hiba Hassan



Diethylstilbestrol can effectively accelerate estradiol-17-O-glucuronidation, while potently inhibiting estradiol-3-O-glucuronidation.  


This in vitro study investigates the effects of diethylstilbestrol (DES), a widely used toxic synthetic estrogen, on estradiol-3- and 17-O- (E2-3/17-O) glucuronidation, via culturing human liver microsomes (HLMs) or recombinant UDP-glucuronosyltransferases (UGTs) with DES and E2. DES can potently inhibit E2-3-O-glucuronidation in HLM, a probe reaction for UGT1A1. Kinetic assays indicate that the inhibition follows a competitive inhibition mechanism, with the Ki value of 2.1±0.3?M, which is less than the possible in vivo level. In contrast to the inhibition on E2-3-O-glucuronidation, the acceleration is observed on E2-17-O-glucuronidation in HLM, in which cholestatic E2-17-O-glucuronide is generated. In the presence of DES (0-6.25?M), Km values for E2-17-O-glucuronidation are located in the range of 7.2-7.4?M, while Vmax values range from 0.38 to 1.54nmol/min/mg. The mechanism behind the activation in HLM is further demonstrated by the fact that DES can efficiently elevate the activity of UGT1A4 in catalyzing E2-17-O-glucuronidation. The presence of DES (2?M) can elevate Vmax from 0.016 to 0.81nmol/min/mg, while lifting Km in a much lesser extent from 4.4 to 11?M. Activation of E2-17-O-glucuronidation is well described by a two binding site model, with KA, ?, and ? values of 0.077±0.18?M, 3.3±1.1 and 104±56, respectively. However, diverse effects of DES towards E2-3/17-O-glucuronidation are not observed in liver microsomes from several common experimental animals. In summary, this study issues new potential toxic mechanisms for DES: potently inhibiting the activity of UGT1A1 and powerfully accelerating the formation of cholestatic E2-17-O-glucuronide by UGT1A4. PMID:25596428

Zhu, Liangliang; Xiao, Ling; Xia, Yangliu; Zhou, Kun; Wang, Huili; Huang, Minyi; Ge, Guangbo; Wu, Yan; Wu, Ganlin; Yang, Ling



Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains.  


Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5-120 days postnatal to evaluate ExG malformations. Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation. PMID:25449352

Mahawong, Phitsanu; Sinclair, Adriane; Li, Yi; Schlomer, Bruce; Rodriguez, Esequiel; Ferretti, Max M; Liu, Baomei; Baskin, Laurence S; Cunha, Gerald R



Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-?B Motifs  

PubMed Central

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 effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor ?B (NF-?B), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-?B, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-?B2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions. PMID:22888145

Singh, Narendra P.; Singh, Udai P.; Nagarkatti, Prakash S.



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



Persistent Hypomethylation in the Promoter of Nucleosomal Binding Protein 1 (Nsbp1) Correlates with Overexpression of Nsbp1 in Mouse Uteri Neonatally Exposed to Diethylstilbestrol or Genistein  

PubMed Central

Neonatal exposure of CD-1 mice to diethylstilbestrol (DES) or genistein (GEN) induces uterine adenocarcinoma in aging animals. Uterine carcinogenesis in this model is ovarian dependent because its evolution is blocked by prepubertal ovariectomy. This study seeks to discover novel uterine genes whose expression is altered by such early endocrine disruption via an epigenetic mechanism. Neonatal mice were treated with 1 or 1000 ?g/kg DES, 50 mg/kg GEN, or oil (control) on d 1–5. One group of treated mice was killed before puberty on d 19. Others were ovariectomized or left intact, and killed at 6 and 18 months of age. Methylation-sensitive restriction fingerprinting was performed to identify differentially methylated sequences associated with neonatal exposure to DES/GEN. Among 14 candidates, nucleosomal binding protein 1 (Nsbp1), the gene for a nucleosome-core-particle binding protein, was selected for further study because of its central role in chromatin remodeling. In uteri of immature control mice, Nsbp1 promoter CpG island (CGI) was minimally methylated. Once control mice reached puberty, the Nsbp1 CGI became hypermethylated, and gene expression declined further. In contrast, in neonatal DES/GEN-treated mice, the Nsbp1 CGI stayed anomalously hypomethylated, and the gene exhibited persistent overexpression throughout life. However, if neonatal DES/GEN-treated mice were ovariectomized before puberty, the CGI remained minimally to moderately methylated, and gene expression was subdued except in the group treated with 1000 ?g/kg DES. Thus, the life reprogramming of uterine Nsbp1 expression by neonatal DES/GEN exposure appears to be mediated by an epigenetic mechanism that interacts with ovarian hormones in adulthood. PMID:18669593

Tang, Wan-Yee; Newbold, Retha; Mardilovich, Katerina; Jefferson, Wendy; Cheng, Robert Y. S.; Medvedovic, Mario; Ho, Shuk-Mei



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

. 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... from 2 pounds less to 29 pounds more than the unimplanted calves on the ,:same ranch durilig the 4 years. Implanting appeared to be most effective ill ~ummary increasing weaning weight when range feed conditions were best. Half to all...

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



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.


Simultaneous Determination of Diethylstilbestrol, Testosterone, and 17?-Estradiol Residues in Meat and Meat Products Using Gas–Liquid Chromatography  

Microsoft Academic Search

A gas-chromatographic procedure was developed for the simultaneous determination of hormones (diethylstilbestrol, testosterone, and 17ß-estradiol) as heptafluorobutyric anhydride derivatives. A mid-polarity HP-50 capillary column (silicone liquid phase containing 50% phenyl groups) and an electron-capture detector were used. The detection limits were 0.3–0.6 mg in a sample of 2 µL. The applicability of this procedure for the determination of hormone residues

E. N. Barkatina; S. V. Volkovich; O. N. Venger; V. I. Murokh; N. D. Kolomiets; O. V. Shulyakovskaya




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



Diethylstilbestrol 1?mg in the Treatment of Acute Urinary Retention due to Prostatic Obstruction in the Elderly: A Preliminary Study.  


Patients who failed a catheter-free trial after acute urinary retention and one week of full dose alpha-blocker and 5-alpha-reductase inhibitor were offered Diethylstilbestrol 1?mg plus Aspirin 100?mg over 4 weeks. Prostate volume, age, serum creatinine, and initial retention drained urine volume were recorded. After excluding cardiovascular morbidity (n = 7), upper urinary tract dilation (n = 3), compromised renal function (n = 2), urinary tract infection (n = 2), neurological diagnosis (n = 2), or preferred immediate channel transurethral resection of prostate (n = 5), 48 of 69 consecutive patients ?70 years were included. Mean age was 76.6 years (70-84), mean prostate volume 90?cm(3) (42-128), and mean follow-up 204 days; 58% (28/48) were passing urine and 42% (20/48) were catheter dependent after 4 weeks Diethylstilbestrol trial. Mean age and drained urine volume of catheter dependent patients were 82.4 years and 850?mL compared with 74.6 years and 530?mL in catheter-free men, respectively. Age and drained urine volume were independent predictors of catheter-free trial (both P < 0.01). Seventy-five percent (6/8) of patients 80 years and older were catheter dependent. Transient nipple/breast tenderness and gynecomastia were the only adverse effects reported by 21% (10/48) and 4% (2/48), respectively. No patient presented severe complications. PMID:24575128

Reis, Leonardo Oliveira; De Mendonça, Gustavo Borges; Carneiro, Bruno D; Schneider, Edson; Gewehr, Eduardo Varella; Meirelles, André; Denardi, Fernandes; Gugliotta, Antonio



Diethylstilbestrol 1?mg in the Treatment of Acute Urinary Retention due to Prostatic Obstruction in the Elderly: A Preliminary Study  

PubMed Central

Patients who failed a catheter-free trial after acute urinary retention and one week of full dose alpha-blocker and 5-alpha-reductase inhibitor were offered Diethylstilbestrol 1?mg plus Aspirin 100?mg over 4 weeks. Prostate volume, age, serum creatinine, and initial retention drained urine volume were recorded. After excluding cardiovascular morbidity (n = 7), upper urinary tract dilation (n = 3), compromised renal function (n = 2), urinary tract infection (n = 2), neurological diagnosis (n = 2), or preferred immediate channel transurethral resection of prostate (n = 5), 48 of 69 consecutive patients ?70 years were included. Mean age was 76.6 years (70–84), mean prostate volume 90?cm3 (42–128), and mean follow-up 204 days; 58% (28/48) were passing urine and 42% (20/48) were catheter dependent after 4 weeks Diethylstilbestrol trial. Mean age and drained urine volume of catheter dependent patients were 82.4 years and 850?mL compared with 74.6 years and 530?mL in catheter-free men, respectively. Age and drained urine volume were independent predictors of catheter-free trial (both P < 0.01). Seventy-five percent (6/8) of patients 80 years and older were catheter dependent. Transient nipple/breast tenderness and gynecomastia were the only adverse effects reported by 21% (10/48) and 4% (2/48), respectively. No patient presented severe complications. PMID:24575128

Reis, Leonardo Oliveira; De Mendonça, Gustavo Borges; Carneiro, Bruno D.; Schneider, Edson; Gewehr, Eduardo Varella; Meirelles, André; Denardi, Fernandes; Gugliotta, Antonio



Beta-Adrenergic Agonists  

PubMed Central

Inhaled ?2-adrenoceptor (?2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the ?2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of ?2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and ?-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled ?2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

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



Cloning and Expression of the Delayed-Rectifier IsK Channel from Neonatal Rat Heart and Diethylstilbestrol-Primed Rat Uterus  

Microsoft Academic Search

cDNAs encoding a delayed-rectifier-type K^+ channel were cloned from both neonatal rat heart and ovariectomized, diethylstilbestrol-primed rat uterus by using the polymerase chain reaction. Both clones have nucleotide sequences identical to that encoding the rat kidney IsK channel [Takumi, T., Ohkubo, H. & Nakanishi, S. (1988) Science 242, 1042-1045] and encode a putative protein of 130 amino acids. Injection of

Kimberly Folander; Jeffrey S. Smith; Joanne Antanavage; Carl Bennett; Robert B. Stein; Richard Swanson



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.


Histamine H3 receptor agonists.  


The SAR of H3 ligands has been difficult to evaluate because of species differences, multiple isoforms and constitutive activity, among other complicating factors. A review is given of the sometimes-conflicting affinity, activity and efficacy data of H3 agonists that has been described in literature to date. PMID:15544556

De Esch, I J P; Belzar, K J



An optimised method for the accurate determination of zeranol and diethylstilbestrol in animal tissues using isotope dilution-liquid chromatography/mass spectrometry.  


Isotope dilution-liquid chromatography/mass spectrometry (ID-LC/MS) has been established as a candidate reference method for the accurate determination of growth promoters (zeranol, taleranol, and diethylstilbesterol) in raw meat samples. Sample preparation processes including an enzymatic hydrolysis, extraction, and SPE clean-up were optimised. The sensitivity difference of trans- and cis-diethylstilbestrol (isomerizing in sample preparation processes) by the LC/MS was measured by running a trans/cis mixture (ratio measured by a quantitative NMR) with and without sample matrices, and applied for the determination of total diethylstilbestrol. Validity, repeatability, and reproducibility of the analytical method were tested by measuring gravimetrically fortified samples (chicken breast, bovine muscles, and porcine muscle) in a number of different time periods. Measurement results agreed with the fortified values within their uncertainties. The method provided accurate results of the target analytes in the range of 0.05-15 ?g/kg with the relative expanded uncertainty of 2-15%. PMID:23578613

Han, Hyesun; Kim, Byungjoo; Lee, Sueg Geun; Kim, Jeongkwon



Kappa Opioid Receptor Agonist and Brain Ischemia  

PubMed Central

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

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



The Structural Basis of Estrogen Receptor\\/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen  

Microsoft Academic Search

Ligand-dependent activation of transcription by nuclear receptors (NRs) is mediated by interactions with coactivators. Receptor agonists promote coactivator binding, and antagonists block coactivator binding. Here we report the crystal structure of the human estrogen receptor ? (hER?) ligand-binding domain (LBD) bound to both the agonist diethylstilbestrol (DES) and a peptide derived from the NR box II region of the coactivator

Andrew K. Shiau; Danielle Barstad; Paula M. Loria; Lin Cheng; Peter J. Kushner; David A. Agard; Geoffrey L. Greene



PPAR? Agonist Beyond Glucose Lowering Effect  

PubMed Central

The nuclear hormone receptor PPAR? is activated by several agonists, including members of the thiazolidinedione group of insulin sensitizers. Pleiotropic beneficial effects of these agonists, independent of their blood glucose-lowering effects, have recently been demonstrated in the vasculature. PPAR? agonists have been shown to lower blood pressure in animals and humans, perhaps by suppressing the renin-angiotensin (Ang)-aldosterone system (RAAS), including the inhibition of Ang II type 1 receptor expression, Ang-II-mediated signaling pathways, and Ang-II-induced adrenal aldosterone synthesis/secretion. PPAR? agonists also inhibit the progression of atherosclerosis in animals and humans, possibly through a pathway involving the suppression of RAAS and the thromboxane A2 system, as well as the protection of endothelial function. Moreover, PPAR?-agonist-mediated renal protection, especially the reduction of albuminuria, has been observed in diabetic nephropathy, including animal models of the disease, and in non-diabetic renal dysfunction. The renal protective activities may reflect, at least in part, the ability of PPAR? agonists to lower blood pressure, protect endothelial function, and cause vasodilation of the glomerular efferent arterioles. Additionally, anti-neoplastic effects of PPAR? agonists have recently been described. Based on the multiple therapeutic actions of PPAR? agonists, they will no doubt lead to novel approaches in the treatment of lifestyle-related and other diseases. PMID:21437157

Uruno, Akira; Kudo, Masataka; Matsuda, Ken; Yang, Chul Woo; Ito, Sadayoshi



The cannabinoid receptor inverse agonist AM251 regulates the expression of the EGF receptor and its ligands via destabilization of oestrogen-related receptor ? protein  

PubMed Central

BACKGROUND AND PURPOSE AM251 is an inverse agonist of the cannabinoid 1 receptor (CB1R) that can exert ‘off-target’ effects in vitro and in CB1R knock-out mice. AM251 is also potent at modulating tumour cell growth, suggesting that growth factor-mediated oncogenic signalling could be regulated by AM251. Since dysregulation of the EGF receptor has been associated with carcinogenesis, we examined AM251 regulation of EGF receptor (EGFR) expression and function. EXPERIMENTAL APPROACH The various biological functions of AM251 were measured in CB1R-negative human cancer cells. Pharmacological and genetic approaches were used to validate the data. KEY RESULTS The mRNA levels for EGFR and its associated ligands, including HB-EGF, were induced several fold in PANC-1 and HCT116 cells in response to AM251. This event was associated with enhanced expression of EGFR on the cell surface with concomitant increase in EGF-induced cellular responses in AM251-treated cells. Exposure to XCT790, a synthetic inverse agonist of the orphan nuclear oestrogen-related receptor ? (ERR?), also induced EGFR and HB-EGF expression to the same extent as AM251, whereas pretreatment with the ERR?-selective agonist, biochanin A, blunted AM251 actions. AM251 promoted the degradation of ERR? protein without loss of the corresponding mRNA. Knock-down of ERR? by siRNA-based approach led to constitutive induction of EGFR and HB-EGF levels, and eliminated the biological responses of AM251 and XCT790. Finally, AM251 displaced diethylstilbestrol prebound to the ligand-binding domain of ERR?. CONCLUSIONS AND IMPLICATIONS AM251 up-regulates EGFR expression and signalling via a novel non-CB1R-mediated pathway involving destabilization of ERR? protein in selected cancer cell lines. PMID:21449913

Fiori, JL; Sanghvi, M; O'Connell, MP; Krzysik-Walker, SM; Moaddel, R; Bernier, M



Purine Receptors: GPCR Structure and Agonist Design  

PubMed Central

An integrated approach to the study of drug-receptor interactions has been applied to adenosine receptors (ARs) and P2Y nucleotide receptors. This approach includes probing the receptor structure through site-directed mutagenesis and molecular modeling, in concert with altering the structure of the agonist ligands. Goals of this structural approach are to generate a testable hypothesis for location of the binding site and subsequently to enable the rational design of new agonists and antagonists. In this manner, receptor subtype selectivity has been increased, and agonists have been converted into partial agonists and antagonists. An approach to receptor engineering (neoceptors) has been explored, in which synthetic small molecule agonists (neoligands) are specifically tailored to activate only receptors in which the putative binding sites have been modified. This orthogonal approach to receptor activation, intended for eventual gene therapy, has been demonstrated for A3 and A2A ARs. PMID:15616163

Jacobson, Kenneth A.; Kim, Soo-Kyung; Costanzi, Stefano; Gao, Zhan-Guo



Monoterpenoid agonists of TRPV3  

PubMed Central

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

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



Hollow-fiber-supported liquid-phase microextraction using an ionic liquid as the extractant for the pre-concentration of bisphenol A, 17-?-estradiol, estrone and diethylstilbestrol from water samples with HPLC detection.  


A new method for the determination of four endocrine disrupting compounds (EDCs) (bisphenol A, 17-?-estradiol, estrone and diethylstilbestrol) in water samples has been developed using polypropylene hollow-fiber-supported ionic liquid (IL, 1-Octyl-3-methylimidazolium hexafluorophosphate, [C8MIM][PF6]) microextraction [HF-liquid-phase microextraction (LPME)] combined with high-performance liquid chromatography (HPLC)/UV. This method was used to investigate pollutants in surface water, on the Neijiang River, located at Zhenjiang, Jiangsu Province. Several parameters (sample pH, volume of accepter phase, ionic strength) were investigated. Under the optimum extraction conditions (sample pH, 2.0; volume of extraction solvent, 2.5 ?L; ionic strength, 2.57) the proposed method offered: good linearity range, 0.15-100 ?g L(-1), with the correlation coefficients (r(2)) of 0.9996, 0.9994, 0.9990 and 0.9984, respectively; low limits of detection, 0.03, 0.05, 0.10, 0.05 ?g L(-1) (S/N = 3) for bisphenol A, 17-?-estradiol, estrone and diethylstilbestrol, respectively; good reproducibility (relative standard deviation (RSD), 8.41, 7.61, 9.00, 7.22%, respectively, n = 5); satisfactory recoveries (80.2-107.1%, n = 5); and high enrichment factors, 5,240, 3,693, 2,425 and 2,086, were achieved, for the four chemicals, respectively. Using the proposed HF-LPME, among 15 sampling sites along Neijiang River, bisphenol A, diethylstilbestrol and 17-?-estradiol were detected in some sites, all of which were the near suburban sampling sites. The results indicate that the role of municipal sewage is an important source of EDC contamination. PMID:24622552

Zou, Yanmin; Zhang, Zhen; Shao, Xiaoling; Chen, Yao; Wu, Xiangyang; Yang, Liuqing; Zhu, Jingjing; Zhang, Dongmei



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



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.


Multiple tyrosine metabolites are GPR35 agonists  

PubMed Central

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

Deng, Huayun; Hu, Haibei; Fang, Ye



Thrombopoietin Receptor Agonists in Primary ITP  

PubMed Central

Thrombopoietin (TPO) regulates thrombopoiesis through activation of TPO receptors on the megakaryocyte cell surface, resulting in increased platelet production. The TPO receptor agonists are novel treatments for patients with chronic ITP aimed at increasing platelet production through interactions with the TPO receptor on megakaryocytes. Two TPO receptor agonists, romiplostim and eltrombopag, have received regulatory approval. In patients with chronic ITP who remain at risk of bleeding following treatment with first-line therapies, these agents have been shown to increase platelet counts, decrease bleeding events and reduce the need for adjunctive or rescue treatments. The TPO receptor agonists are well-tolerated, though uncertainty remains regarding the risk of thromboembolism and bone marrow fibrosis. Comparative clinical trial data addressing the efficacy, safety, cost-effectiveness, and impact on health-related quality of life of TPO receptor agonists relative to other second-line treatment options are needed to guide treatment decisions in chronic ITP patients who fail first-line therapies. PMID:23664510

Siegal, Deborah; Crowther, Mark; Cuker, Adam



Histrionicotoxin enhances agonist-induced desensitization of acetylcholine receptor.  

PubMed Central

Dihydroisohistrionicotoxin inhibits acetylcholine receptor-dependent 22Na+ uptake of cultured chick muscle cells with a KI of 0.2 micrometer. The inhibition is noncompetitive with respect to agonists. The toxin enhances desensitization of the receptor by agonists which is accompanied by a 10-fold increase in receptor affinity for agonists. Dihydroisohistrionicotoxin increases the affinity of the desensitized form of the receptor for agonists but not antagonists. The results suggest that dihydroisohistrionicotoxin inhibits the acetylcholine receptor by causing an increase in the affinity of the desensitized form of the receptor for agonists and thereby stabilizing the desensitized state. PMID:272000

Burgermeister, W; Catterall, W A; Witkop, B



Anti-nociception mediated by a ? opioid receptor agonist is blocked by a ? receptor agonist  

PubMed Central

BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the ? (MOP), ? (DOP), ? (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg?1), unmasked etorphine (3 mg·kg?1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg?1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg?1) and diazepam (1 mg·kg?1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit PMID:24923251

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



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

SciTech Connect

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 have shown in rats that PCB (Arochlor) causes liver adenofibrosis, thyroid dysfunction, atypical mitochondria, and dilation of both smooth and rough endoplasmic reticulum. Matthews et al. (1978) also reported that 4, 4{prime} chlorinated biphenyl was the most potent inducer of monooxygenases, irrespective of chlorination at other sites. Although these compounds have been studied extensively in mammals, there is a paucity of data examining their effects when non-fetotoxic amounts are administered chronically and orally during gestation. The present study is part of a larger effort designed to establish a protocol for testing the developmental effects of xenobiotics such as DES and PCB. Levels of acetylcholinesterase (AChE) were measured as an indicator of the integrity of nerve transmission in the central nervous system. Monoamine oxidase (MAO) is a marker for the outer mitochondrial membrane and is an important amine metabolizing enzyme. Testosterone and estradiol are important sex steroids in mammals, and effects upon levels of the two hormones may signal anomalies in development of sex characteristics. 35 refs., 3 figs., 1 tab.

Vincent, D.R.; Bradshaw, W.S.; Booth, G.M.; Seegmiller, R.E. [Brigham Young Univ., Provo, UT (United States); Allen, S.D. [Utah State Univ., Logan, UT (United States)



Binding ability of impromidine, a potent H2 agonist of histamine  

NASA Astrophysics Data System (ADS)

Impromidine (fig.1) is a potent and selective histamine H2 receptor agonist and its structure comprises a strongly basic guanidine group containing two different imidazole-containing side chains. The present work deals with the study of coordination equilibria between impromidine and Cu(II) and Ni(II) in aqueous solution at 25 circC. Potentiometric, UV-Visible and EPR studies on Cu(II) complexes with impromidine have shown that this anti-ulcerogenic drug is a very potent chelating agent. This drug is found to be a very effective ligand for Ni(II) ions also. The effective coordination of impromidine to metal ions may have significant biological implications. L'impromidine est un agoniste H2 de l'histamine, sa structure possède un groupement guanidinique de forte basicité et dont l'environne ment des deux groupements imidazoliques est différent. Le présent travail consiste en l'étude de la coordination de l'impromidine avec le Cu(II) et le Ni(II) en milieu aqueux à 25 circC. La potentiométrie, LíUV-Visible et la RPE montrent que le cuivre se coordine très fortement avec l'impromidine. Nous avons trouvé que ce médicament se coordine aussi fortement avec le nickel(II). La coordination de l'impromidine avec les métaux pourrait avoir des applications importantes en médecine.

Anouar, A.; Lhadi, E.; Decock, P.; Kozlowskyinst4, H.



Mixed Kappa/Mu Opioid Receptor Agonists: The 6?-Naltrexamines  

PubMed Central

Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6?-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, non-selective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo, with 12a acting as a KOR agonist, and therefore somewhat similar to the previously evaluated analogues 3–6, while 12b displayed predominant MOR agonist activity. PMID:19253970

Cami-Kobeci, Gerta; Neal, Adrian P.; Bradbury, Faye A.; Purington, Lauren C.; Aceto, Mario D.; Harris, Louis S.; Lewis, John W.; Traynor, John R.; Husbands, Stephen M.



Pyrimidine benzamide-based thrombopoietin receptor agonists  

Microsoft Academic Search

A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series

Lawrence A. Reiter; Chakrapani Subramanyam; Emilio J. Mangual; Christopher S. Jones; Marc I. Smeets; William H. Brissette; Sandra P. McCurdy; Paul D. Lira; Robert G. Linde; Qifang Li; Fangning Zhang; Amy S. Antipas; Laura C. Blumberg; Jonathan L. Doty; James P. Driscoll; Michael J. Munchhof; Sharon L. Ripp; Andrei Shavnya; Richard M. Shepard; Diana Sperger; Lisa M. Thomasco; Kristen A. Trevena; Lilli A. Wolf-Gouveia; Liling Zhang



Photolabelling the urotensin II receptor reveals distinct agonist- and partial-agonist-binding sites  

PubMed Central

The mechanism by which GPCRs (G-protein-coupled receptors) undergo activation is believed to involve conformational changes following agonist binding. We have used photoaffinity labelling to identify domains within GPCRs that make contact with various photoreactive ligands in order to better understand the activation mechanism. Here, a series of four agonist {[Bpa1]U-II (Bpa is p-benzoyl-L-phenylalanine), [Bpa2]U-II, [Bpa3]U-II and [Bpa4]U-II} and three partial agonist {[Bpa1Pen5D-Trp7Orn8]U-II (Pen is penicillamine), [Bpa2Pen5D-Trp7Orn8]U-II and [Pen5Bpa6D-Trp7Orn8]U-II} photoreactive urotensin II (U-II) analogues were used to identify ligand-binding sites on the UT receptor (U-II receptor). All peptides bound the UT receptor expressed in COS-7 cells with high affinity (Kd of 0.3–17.7 nM). Proteolytic mapping and mutational analysis led to the identification of Met288 of the third extracellular loop of the UT receptor as a binding site for all four agonist peptides. Both partial agonists containing the photoreactive group in positions 1 and 2 also cross-linked to Met288. We found that photolabelling with the partial agonist containing the photoreactive group in position 6 led to the detection of transmembrane domain 5 as a binding site for that ligand. Interestingly, this differs from Met184/Met185 of the fourth transmembrane domain that had been identified previously as a contact site for the full agonist [Bpa6]U-II. These results enable us to better map the binding pocket of the UT receptor. Moreover, the data also suggest that, although structurally related agonists or partial agonists may dock in the same general binding pocket, conformational changes induced by various states of activation may result in slight differences in spatial proximity within the cyclic portion of U-II analogues. PMID:17064254

Holleran, Brian J.; Beaulieu, Marie-Eve; Proulx, Christophe D.; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard



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



Structure-activity relationships of dimeric PPAR agonists.  


A series of dimeric PPAR agonists were designed and tested for PPAR activity in vitro. The SAR showed that dimeric ligands with a common group or full dimeric ligands had retained or even increased PPARgamma potency. The dimeric agonist concept can be used to fine tune the subtype selectivity of PPAR agonists. The PPARgamma potency could, at least partly, be explained using molecular modeling. PMID:15713415

Sauerberg, Per; Mogensen, John P; Jeppesen, Lone; Svensson, L Anders; Fleckner, Jan; Nehlin, Jan; Wulff, Erik M; Pettersson, Ingrid



Indacaterol, A Novel Once Daily Inhaled ?2-Adrenoreceptor Agonist  

PubMed Central

In this article we will review the role of long acting ?2-adrenoreceptor agonists and long-acting muscarinic agents in the management of airflow obstruction. We will then focus our attention on indacaterol, one of the new once daily inhaled ?2-adrenoreceptor agonists. Pharmacologically this drug is a nearly full ?2-agonist without loss of efficacy after prolonged administration. We will also discuss its dosing, safety and tolerability. PMID:19452036

Roig, Jorge; Hernando, Rosana; Mora, Ramon



Compulsive eating and weight gain related to dopamine agonist use  

Microsoft Academic Search

Dopamine agonists have been implicated in causing compulsive behaviors in patients with Parkinson's disease (PD). These have included gambling, hypersexuality, hobby- ism, and other repetitive, purposeless behaviors (\\

Melissa J. Nirenberg; Cheryl Waters



TO901317, a potent LXR agonist, is an inverse agonist of CAR.  


The basal transcriptional activity of unliganded human constitutive androstane receptor (hCAR) was shown to be repressed by the potent liver X receptor (LXR) agonist, TO901317, in a concentration-dependent manner using a reporter assay in cultured cells. TO901317 also repressed the basal transcriptional activity of both mouse and rat CAR. The certified hCAR agonist, CITCO, partially reversed this repressive effect of TO901317 on hCAR basal activity. Unlike hCAR, a three alanine insertion mutant and the splice variant 2 of hCAR require agonists, such as CITCO, to become transcriptionally active and the CITCO-induced reporter activity was repressed by TO901317. As has been previously shown for the typical hCAR inverse agonist, PK11195, TO901317 blocked the interaction of hCAR with steroid receptor co-activator 1 (SRC1). In contrast, the interaction between hCAR and nuclear receptor corepressor 1 (NCoR1) was promoted by PK11195 and TO901317. Furthermore, the hCAR-mediated basal induction of endogenous cytochrome P450 2B6 (CYP2B6) mRNA was adversely affected by co-treatment with TO901317. PMID:23665929

Kanno, Yuichiro; Tanuma, Nobuaki; Takahashi, Ami; Inouye, Yoshio



Radiolabelled D2 agonists as prolactinoma imaging agents  

SciTech Connect

During the past year, further studies on mAChR were conducted. These studies included verification of the difference in pituitary distribution based on ligand charge. The pituitary localization of TRB. A neutral mAChR ligand, was verified. The lack of QNB blockade of TRB uptake was tested by blockage with scopolamine, another mAChR antagonist and by testing the effect in a different strain of rat. Neither scopolamine or change of rat strain had any effect. We concluded that TRB uptake in pituitary is not a receptor-mediated process. Further studies were conducted with an additional quaternized mAChR ligand: MQNB. Pituitary localization of MQNB, like MTRB, could be blocked by pretreatment with QNB. We have tentatively concluded that permanent charge on a mAChR antagonist changes the mechanism of uptake in the pituitary. Time course studies and the effects of DES on myocardial uptake are reported. A brief report on preliminary results of evaluation of quaternized mAChR ligands in the heart is included. In a limited series of such ligands, we have observed a single binding site and a difference in B{sub max} values: QNB competition studies yield larger B{sub max} values than studies with {sup 3}H-NMS. Progress in the synthesis of D{sub 2} agonists includes solving a synthetic problem and preparation of the cold'' analogue of N-0437 using procedures applicable to eventual synthesis with {sup 11}C-CH{sub 3}I. 2 refs., 5 figs., 1 tab.

Otto, C.A.



Further characterization of the direct inhibitory effect of LHRH agonists at the testicular level in the rat.  


To further clarify the relative importance of the pituitary and gonadal sites of LHRH action, intact and hypophysectomized adult male rats were treated with hCG for 7 days, in the presence or absence of simultaneous treatment with increasing doses of the LHRH agonist [D-Ser(TBU)6des-Gly-NH2(10)]LHRH ethylamide, Buserelin (0.025, 0.25, 2.5 or 25 micrograms/rat, twice daily). Daily treatment of intact adult rats with hCG (25 IU) markedly increased ventral prostate and seminal vesicle weight, while a dose-dependent inhibition of the effect was observed following combined administration of Buserelin. In hypophysectomized rats, treatment with hCG resulted in a partial restoration of ventral prostate and seminal vesicle weight, while combined treatment with a high dose of the LHRH agonist (25 micrograms, twice daily) partially (P less than 0.05) inhibited the stimulatory effect of hCG. LH/hCG receptors were almost completely inhibited after hCG injection alone and a further decrease was observed in the presence of simultaneous LHRH agonist treatment. The hCG-induced stimulation of GH/PRL receptors was counteracted by Buserelin treatment in hypophysectomized animals. The present data demonstrate that although LHRH-induced LH release has been shown to play a major role in the loss of testicular functions induced by low doses of LHRH agonists in the rat, a direct inhibitory action of LHRH agonists can be exerted at the testicular level at high doses of the peptide. PMID:6323867

Marchetti, B; Labrie, F



Chimpanzees Extract Social Information from Agonistic Screams  

PubMed Central

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

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



[Melatoninergic receptor agonists and antagonists: therapeutic perspectives].  


The chronobiotic neurohormone melatonin, synthetized in the pineal gland during darkness periods governs the circadian and seasonal biological rhythms. Physiologically, melatonin regulates the sleep/activity alternance, together with the circadian cycle of body temperature and cortisol secretion, and influences various immune, endocrine and metabolic functions. Dysfunction of the endogenous melatonin secretion is associated with mood and behavioral disorders including body weight. Patients with severe depression exhibit desynchronized and reduced melatonin secretion, in parallel with marked sleep disturbances whereas exogenous melatonin administration and antidepressive drugs restore melatonin secretion. A dysregulated melatonin secretion is also observed in obese subjects. Implication of melatonin in these disorders stimulated the search for melatonin analogues with enhanced antidepressive and body weight control effects. The melatoninergic agonist S 20098, or agomelatin, disclosed a potent antidepressive and anxiolytic activity in preclinical studies, which was confirmed in clinical trials in patients with major depression. The antagonist S 20928 was shown to limit seasonal weight gain in an hibernating rodent model. Thus, development of melatoninergic agonists and antagonists appear as an innovative approach in the treatment of depression and obesity, two major public health problems. PMID:17762830

Guardiola-Lemaitre, Béatrice



Early exposure of 17?-ethynylestradiol and diethylstilbestrol induces morphological changes and alters ovarian steroidogenic pathway enzyme gene expression in catfish, Clarias gariepinus.  


Environmental estrogens are major cause of endocrine disruption in vertebrates, including aquatic organisms. Teleosts are valuable and popular models for studying the effects of endocrine disrupting chemicals (EDCs) in the environment. In the present study, we investigated the changes caused by exposure to the synthetic estrogens 17?-ethynylestradiol (EE2 ) and diethylstilbesterol (DES) during early stages of growth and sex differentiation of air-breathing catfish, Clarias gariepinus, at the morphological, histological, and molecular levels. Catfish hatchlings, 0 day post hatch (dph) were exposed continuously to sublethal doses of EE2 (50 ng/L) and DES (10 ng/L) until 50 dph and subsequently monitored for ovarian structural changes and alteration in the gene expression of steroidogenic enzymes till adulthood. Treated fish exhibited morphological deformities such as spinal curvature, stunted growth, and yolk-sac fluid retention. In addition to ovarian atrophy, DES-treated fish showed either rudimentary or malformed ovaries. Detailed histological studies revealed precocious oocyte development as well as follicular atresia. Further, transcript levels of various steroidogenic enzyme and transcription factor genes were altered in response to EE2 and DES. Activity of the rate-limiting enzyme of estrogen biosynthesis, aromatase, in the ovary as well as the brain of treated fish was in accordance with transcript level changes. These developmental and molecular effects imparted by EE2 and DES during early life stages of catfish could demonstrate the deleterious effects of estrogen exposure and provide reliable markers for estrogenic EDCs exposure in the environment. © 2013 Wiley Periodicals, Inc. Environ Toxicol, 2013. PMID:24273110

Sridevi, P; Chaitanya, R K; Prathibha, Y; Balakrishna, S L; Dutta-Gupta, A; Senthilkumaran, B



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.




Microsoft Academic Search

A tradition stretching back to early Greek philosophy has described the mind as a field of struggle or even battle. This comparison has been termed the agonistic metaphor, based on the Hellenistic notion of athletic contests. Today, it is not uncommon for psychotherapists and the general public to seek solutions to mental health problems agonistically. Examples of this are cited




Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration.  


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

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



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




EPA Science Inventory

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


Inhaled ?2 agonists and performance in competitive athletes  

PubMed Central

Objectives To provide an overview of the current literature on the use of inhaled ?2 agonists in non?asthmatic competitive athletes, and to assess the performance enhancing effect of inhaled ?2 agonists. Methods Review of the literature. Results Twenty randomised, placebo controlled studies (19 double blind, one single blind) were located. Only three studies reported a performance enhancing effect of inhaled ?2 agonists. However, methodological shortcomings were most likely responsible for these findings (for example, non?elite athletes, inconsistent results in different tests, subgroups with above?average responsiveness). Conclusions This review reveals that there is no ergogenic potential of inhaled ?2 agonists in non?asthmatic athletes. In view of the epidemiology of asthma in athletes and the considerable workload involved in provision of therapeutic use exemptions the inclusion of inhaled ?2 agonists on the list of prohibited substances should be reconsidered. PMID:16799103

Kindermann, W; Meyer, T



Des Moines.  

ERIC Educational Resources Information Center

This document, intended for elementary students, contains articles and activities designed to acquaint young people with the history of Des Moines, Iowa. The articles are short, and new or difficult words are highlighted and defined for young readers. "The Raccoon River Indian Agency" discusses the archeological exploration of the indian…

Gore, Deborah, Ed.



Mixed ?/? 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



Toll-like receptor 2 agonists inhibit human fibrocyte differentiation  

PubMed Central

Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF)-? accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC) class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN)-?, IFN-?, interleukin (IL)-12, aggregated immunoglobulin G (IgG) or serum amyloid P (SAP), factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-?, IFN-?, granulocyte colony-stimulating factor and tumor growth factor ?1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure. PMID:21106092



Dopamine agonist withdrawal syndrome: implications for patient care.  


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

Nirenberg, Melissa J




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



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


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

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



Predictors of Impulsivity and Reward Seeking Behavior With Dopamine Agonists  

E-print Network

., Dejian Lai, PhD2 1Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, sexuality) in subjects taking dopamine agonists for Parkinson's disease and restless legs syndrome. Methods

Lichtarge, Olivier


Unique agonist-bound cannabinoid CB1 receptor conformations indicate agonist specificity in signaling  

PubMed Central

Cannabinoid drugs differ in their rank order of potency to produce analgesia versus other central nervous system effects. We propose that these differences are due to unique agonist-bound cannabinoid CB1 receptor conformations that exhibit different affinities for individual subsets of intracellular signal transduction pathways. In order to test this hypothesis, we have used plasmon-waveguide resonance (PWR) spectroscopy, a sensitive method that can provide direct information about ligand-protein and protein-protein interactions, and can detect conformational changes in lipid-embedded proteins. A recombinant epitope-tagged human cannabinoid CB1 receptor was expressed in insect Sf9 cells, solubilized and purified using two-step affinity chromatography. The purified receptor was incorporated into a lipid bilayer on the surface of the PWR resonator. PWR spectroscopy demonstrated that cannabinoid agonists exhibit high affinity (KD = 0.2 ± 0.03 nM and 2 ± 0.4 nM for CP 55,940 and WIN 55,212-2, respectively) for the purified epitope tagged hCB1 receptor. Interestingly however, these structurally different cannabinoid agonists shifted the PWR spectra in opposite directions, indicating that CP 55,940 and WIN 55,212-2 binding leads to different hCB1 receptor conformations. Furthermore, PWR experiments also indicated that these CP 55,940- and WIN 55,212 - bound hCB1 receptor conformations exhibit slightly different affinities to an inhibitory G protein heterotrimer, Gi1 (KD = 27 ± 8 nM and KD = 10.7 ± 4.7 nM, respectively), whereas they strikingly differ in their ability to activate this G protein type. PMID:18162180

Georgieva, Teodora; Devanathan, Savitha; Stropova, Dagmar; Park, Chad K.; Salamon, Zdzislaw; Tollin, Gordon; Hruby, Victor J.; Roeske, William R.; Yamamura, Henry I.; Varga, Eva



Xamoterol, a ?1-adrenoceptor partial agonist  

PubMed Central

1 Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587), a ?1-adrenoceptor partial agonist, improves both systolic and diastolic function in heart failure patients. 2 Double-blind, randomised studies comparing xamoterol with placebo showed that the beneficial haemodynamic effects of xamoterol produced significant improvements in exercise capacity and symptoms in patients with mild to moderate heart failure. These studies formed the basis for a large European multicentre study programme which recruited over 1000 patients, randomised to xamoterol (200 mg twice daily, n = 617), digoxin (0.125 mg twice daily, n = 135) or placebo (n = 300) for 3 months. 3 Efficacy was assessed by measuring exercise capacity and symptoms. The xamoterol group improved exercise capacity by 37% compared with an 18% improvement in the placebo group. Differences in the symptom scores measured by visual analogue scales and Likert scores indicated significant improvements by xamoterol in the cardinal symptoms of heart failure, dyspnoea and fatigue. 4 Analyses of data from subsets of patients in the study showed that elderly patients, patients on no other heart failure therapy and patients with cardiomegaly all had similar improvements in exercise and symptoms to those seen in the whole study population. In the subset which included digoxin treatment, xamoterol produced significantly greater improvements in exercise capacity than digoxin (33% vs 17%, P < 0.05) and was associated with fewer side-effects. 5 Xamoterol is therefore a promising addition to heart failure therapies currently available. PMID:2572251

Marlow, H. F.



Use of ?2-Agonists in Neuroanesthesia: An Overview  

PubMed Central

?2-Agonists are a novel class of drugs with mechanisms of action that differ from other commonly used anesthetic drugs. They have neuroprotective, cardioprotective, and sedative effects. These unique characteristics make them potentially useful during neuroanesthesia and intensive care. We review the effects of dexmedetomidine on cerebral blood flow and cerebral metabolism, along with recent advances in using ?2-agonists in neuroanesthesia and neurointensive care. PMID:21603337

Farag, Ehab; Argalious, Maged; Sessler, Daniel I.; Kurz, Andrea; Ebrahim, Zeyd Y.; Schubert, Armin



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



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

Microsoft Academic Search

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

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



Highly Potent, Chemically Stable Quorum Sensing Agonists for Vibrio Cholerae.  


In the Vibrio cholerae pathogen, initiation of bacterial quorum sensing pathways serves to suppress virulence. We describe herein a potent and chemically stable small molecule agonist of V. cholerae quorum sensing, which was identified through rational drug design based on the native quorum sensing signal. This novel agonist may serve as a useful lead compound for the control of virulence in V. cholerae. PMID:24436778

Perez, Lark J; Karagounis, Theodora K; Hurley, Amanda; Bassler, Bonnie L; Semmelhack, Martin F



Toll-like receptor 2 agonists inhibit human fibrocyte differentiation  

Microsoft Academic Search

BACKGROUND: In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and\\/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. RESULTS: When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8

Anu S Maharjan; Darrell Pilling; Richard H Gomer



Recurrent laryngeal nerve activation by ? 2 adrenergic agonists in goats  

Microsoft Academic Search

The purpose of this study was to test the hypothesis that respiratory arrhythmias and apneas induced by ?2 agonists in anesthetized goats are associated with an increase of upper airway expiratory-related activity, rather than a general depression of breathing. Activities of phrenic (Phr) and recurrent laryngeal nerves (RLN) were recorded in response to the ?2 agonists clonidine (0.5–3.0 ?g ·

M. S. Hedrick; M. L. Ryan; G. E. Bisgard



AMG 837: A Potent, Orally Bioavailable GPR40 Agonist  

Microsoft Academic Search

The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of ?-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4’-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of

Jonathan B. Houze; Liusheng Zhu; Ying Sun; Michelle Akerman; Wei Qiu; Alex J. Zhang; Rajiv Sharma; Michael Schmitt; Yingcai Wang; Jiwen Liu; Jinqian Liu; Julio C. Medina; Jeff D. Reagan; Jian Luo; George Tonn; Jane Zhang; Jenny Ying-Lin Lu; Michael Chen; Edwin Lopez; Kathy Nguyen; Li Yang; Liang Tang; Hui Tian; Steven J. Shuttleworth; Daniel C.-H. Lin


Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists  

Microsoft Academic Search

Toll-like receptor 9 (TLR9) agonists have demonstrated substantial potential as vaccine adjuvants, and as mono- or combination therapies for the treatment of cancer and infectious and allergic diseases. Commonly referred to as CpG oligodeoxynucleotides (ODN), TLR9 agonists directly induce the activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early

Jörg Vollmer; Arthur M. Krieg



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



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



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))



Agonists and antagonists for P2 receptors  

PubMed Central

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

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



Rat Urinary Bladder Carcinogenesis by Dual-Acting PPAR? + ? Agonists  

PubMed Central

Despite clinical promise, dual-acting activators of PPAR? and ? (here termed PPAR?+? agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPAR? is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPAR? can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPAR? as well as PPAR?, making it plausible that the urothelial carcinogenicity of PPAR?+? agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPAR?+? agonist ragaglitazar, and the available literature about the role of PPAR? and ? in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPAR?+? agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds. PMID:19197366

Oleksiewicz, Martin B.; Southgate, Jennifer; Iversen, Lars; Egerod, Frederikke L.



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.



Sound production during agonistic behavior of male Drosophila melanogaster.  


Male Drosophila fruit flies acquire and defend territories in order to attract females for reproduction. Both, male-directed agonistic behavior and female-directed courtship consist of series of recurrent stereotypical components. Various studies demonstrated the importance of species-specific sound patterns generated by wing vibration as being critical for male courtship success. In this study we analyzed the patterns and importance of sound signals generated during agonistic interactions of male Drosophila melanogaster. In contrast to acoustic courtship signals that consist of sine and pulse patterns and are generated by one extended wing, agonistic signals lack sine-like components and are generally produced by simultaneous movements of both wings. Though intra-pulse oscillation frequencies (carrier frequency) are identical, inter-pulse intervals are twice as long and more variable in aggression signals than in courtship songs, where their precise temporal pattern serves species recognition. Acoustic signals accompany male agonistic interactions over their entire course but occur particularly often after tapping behavior which is a major way to identify the gender of the interaction partner. Since similar wing movements may either be silent or generate sound and wing movements with sound have a greater impact on the subsequent behavior of a receiver, sound producing wing movements seem to be generated intentionally to serve as a specific signal during fruit fly agonistic encounters. PMID:20953152

Jonsson, Thorin; Kravitz, Edward A; Heinrich, Ralf



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.



Principles of agonist recognition in Cys-loop receptors  

PubMed Central

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

Lynagh, Timothy; Pless, Stephan A.



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

PubMed Central

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

Langmead, Christopher J; Christopoulos, Arthur



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



A reversed sulfonamide series of selective RORc inverse agonists.  


The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series. PMID:25453817

van Niel, Monique B; Fauber, Benjamin P; Cartwright, Matthew; Gaines, Simon; Killen, Jonathan C; René, Olivier; Ward, Stuart I; de Leon Boenig, Gladys; Deng, Yuzhong; Eidenschenk, Céline; Everett, Christine; Gancia, Emanuela; Ganguli, Arunima; Gobbi, Alberto; Hawkins, Julie; Johnson, Adam R; Kiefer, James R; La, Hank; Lockey, Peter; Norman, Maxine; Ouyang, Wenjun; Qin, Ann; Wakes, Nicole; Waszkowycz, Bohdan; Wong, Harvey



Amino acid conjugates as kappa opioid receptor agonists.  


A novel series of kappa (kappa) opioid receptor agonists were synthesized by incorporating the key structural features of known kappa opioid agonists while replacing the aryl acetamide portion with substituted amino acid conjugates. Compounds 3j (Ki = 6.7 nM), 3k (Ki = 3.6 nM), 3l (Ki = 4.6 nM), 3m (Ki = 0.83 nM) and 3o (Ki = 2 nM) possessed potent affinities for the kappa opioid receptor in vitro with reasonable selectivity over other opioid receptors. PMID:15713370

Kumar, Virendra; Guo, Deqi; Daubert, Jeffrey D; Cassel, Joel A; DeHaven, Robert N; Mansson, Erik; DeHaven-Hudkins, Diane L; Maycock, Alan L



Beta2-agonist extraction procedures for chromatographic analysis.  


Normally, different procedures were necessary to prepare sample matrices for chromatographic determination of beta2-agonists. The present review includes sampling, pre-treatment and extraction/purification for urine, plasma, liver, meat, feeds, hair and milk powder, as previous steps for chromatographic analysis of beta2-agonists. Six methodologies were especially revised for extraction/purification namely, liquid-liquid extraction, solid-phase extraction (SPE), matrix solid-phase dispersion, immunoaffinity chromatography, dialysis and supercritical fluid extraction. SPE was discussed in detail and five mechanisms were described: adsorption, apolar, polar, ion-exchange and mixed phase. A brief conclusion in this field was also outlined. PMID:10890511

dos Ramos, F J



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



Structure des ADN complmentaires des lactoprotines : application la recherche des gnes et leur localisation chromosomique  

E-print Network

Structure des ADN complémentaires des lactoprotéines : application à la recherche des gènes et à entrepris. 1) Construction de banques ovine et bovine d ADN complémentaires !ADNcJ. Sélection et identification des clones recombinants contenant les ADN complé- mentaires des ARNm des 6 principales

Paris-Sud XI, Université de


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


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

E-print Network

ACCELERATED COMMUNICATION Di(2-ethylhexyl) phthalate Is a Highly Potent Agonist for the Human the common plasticizer, di(2- ethylhexyl) phthalate (DEHP), as a highly potent and uniquely selective agonist

Omiecinski, Curtis


Estradiol and ER? agonists enhance recognition memory, and DPN, an ER? agonist, alters brain monoamines.  


Effects of estradiol benzoate (EB), ER?-selective agonist, propyl pyrazole triol (PPT) and ER?-selective agonists, diarylpropionitrile (DPN) and Compound 19 (C-19) on memory were investigated in OVX rats using object recognition (OR) and placement (OP) memory tasks. Treatments were acute (behavior 4h later) or sub chronic (daily injections for 2 days with behavior 48 h later). Objects were explored in sample trials (T1), and discrimination between sample (old) and new object/location in recognition trials (T2) was examined after 2-4h inter-trial delays. Subjects treated sub chronically with EB, DPN, and C-19, but not PPT, discriminated between old and new objects and objects in old and new locations, suggesting that, at these doses and duration of treatments, estrogenic interactions with ER? contribute to enhancements in recognition memory. Acute injections of DPN, but not PPT, immediately after T1, also enhanced discrimination for both tasks (C19 was not investigated). Effects of EB, DPN and PPT on anxiety and locomotion, measured on elevated plus maze and open field, did not appear to account for the mnemonic enhancements. Monoamines and metabolites were measured following DPN treatment in subjects that did not receive behavioral testing. DPN was associated with alterations in monoamines in several brain areas: indexed by the metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the MHPG/norepinephrine (NE) ratio, NE activity was increased by 60-130% in the prefrontal cortex (PFC) and ventral hippocampus, and NE activity was decreased by 40-80% in the v. diagonal bands and CA1. Levels of the dopamine (DA) metabolite, homovanillic acid (HVA), increased 100% in the PFC and decreased by 50% in the dentate gyrus following DPN treatment. The metabolite of serotonin, 5-hydroxyindole acetic acid (5-HIAA), was increased in the PFC and CA3, by approximately 20%. No monoaminergic changes were noted in striatum or medial septum. Results suggest that ER? mediates sub chronic and acute effects of estrogens on recognition memory and that memory enhancements by DPN may occur, in part, through alterations in monoaminergic containing systems primarily in PFC and hippocampus. PMID:20828630

Jacome, Luis F; Gautreaux, Claris; Inagaki, Tomoko; Mohan, Govini; Alves, Stephen; Lubbers, Laura S; Luine, Victoria



Radiolabelled D/sub 2/ agonists as prolactinoma imaging agents: Progress report for period February 1, 1987-January 31, 1988  

SciTech Connect

Three D/sub 2/ agonists, /sup 3/H-DHEC, /sup 3/H-BrCr and /sup 3/H-ADTN, were evaluated with /sup 3/H-DHEC showing the most promise as a potential prolactinoma imaging agent. Concentration vs time plots for all three compounds in normal and in DES-treated pituitary tissue are reported. The exceptional D/sub 2/ receptor affinity of N-0437 has prompted synthetic efforts towards preparation of iodo-N-0437 in spite of a lack of preliminary tissue distribution data. An evaluation of /sup 18/F-FDG uptake in the prolactinoma model and as a muscarinic ligand in control animals were evaluated. 2 refs., 3 figs.

Otto, C.A.



Innate Immune Responses to TLR2 and TLR4 Agonists Differ between Baboons, Chimpanzees and Humans  

PubMed Central

Background African catarrhine primates differ in bacterial disease susceptibility. Methods Human, chimpanzee, and baboon blood was stimulated with TLR-detected bacterial agonists and cytokine/chemokine induction assessed by real-time pcr. Results Humans and chimpanzees shared similar cytokine/chemokine responses, while baboon cytokine/chemokine induction differed. Generally, responses were agonist-independent. Conclusions These primates tend to generate species rather than agonist–specific responses to bacterial agonists. PMID:22978822

Brinkworth, Jessica F.; Pechenkina, Ekaterina A.; Silver, Jack; Goyert, Sanna M.



Discovery of Tertiary Amine and Indole Derivatives as Potent ROR?t Inverse Agonists.  


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

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



Captive female gorilla agonistic relationships with clumped defendable food resources  

Microsoft Academic Search

Minimal feeding competition among female mountain gorillas (Gorilla gorilla beringei) has resulted in egalitarian social relationships with poorly defined agonistic dominance hierarchies. Thus, gorillas are generally viewed as non-competitive egalitarian folivores that have had little need to develop effective competitive strategies to access food resources. However, this generalization is inconsistent with more recent research indicating that most gorillas are frugivorous,

Jennifer Scott; Joan S. Lockard



Agonistic behavioral interactions between introduced western mosquitofish and native topminnows  

Microsoft Academic Search

The stocking of western mosquitofish Gambusia affinis for mosquito control negatively impacts native fishes with similar ecological requirements. In this study, a series of laboratory microcosm experiments was used to examine intra and interspecific agonistic behavioral interactions (e.g., chases and nips) between western mosquitofish and northern starhead topminnow Fundulus dispar, northern studfish F. catenatus, blackstripe topminnow F. notatus, and banded

Trent M. Sutton; Rebecca A. Zeiber; Brant E. Fisher



Identification of tertiary sulfonamides as RORc inverse agonists.  


Screening a nuclear receptor compound subset in a RORc biochemical binding assay revealed a benzylic tertiary sulfonamide hit. Herein, we describe the identification of compounds with improved RORc biochemical inverse agonist activity and cellular potencies. These improved compounds also possessed appreciable selectivity for RORc over other nuclear receptors. PMID:24685544

Fauber, Benjamin P; René, Olivier; Burton, Brenda; Everett, Christine; Gobbi, Alberto; Hawkins, Julie; Johnson, Adam R; Liimatta, Marya; Lockey, Peter; Norman, Maxine; Wong, Harvey



Dopamine agonists in prevention of ovarian hyperstimulation syndrome.  


Abstract The aim of this review is to analyze the efficacy of different dopamine agonists in the prevention of ovarian hyperstimulation syndrome (OHSS). Cabergoline, quinagolide and bromocriptine are the most common dopamine agonists used. There are wide clinical variations among the trials in the starting time (from the day of human chorionic gonadotrophin (hCG) to the day following oocyte retrieval); the duration of the treatment (4-21 days), the dose of cabergoline (0.5?mg or 0.25?mg orally) and in the regimens used. At present, the best known effective regimen is 0.5?mg of cabergoline for 8 days or rectal bromocriptine at a daily dose of 2.5?mg for 16 days. Dopamine agonists have shown significant evidences of their efficacy in the prevention of moderate and early-onset OHSS (9.41%), compared with a placebo (21.45%), which cannot be confirmed for the treatment of late OHSS. It would be advisable to start with the treatment on the day of hCG injection or preferably a few hours earlier. The use of dopamine agonists should be indicated in patients at high risk of OHSS, as well as in patients with a history of previous OHSS even without evident signs of the syndrome. PMID:25093428

Kasum, Miro; Vr?i?, Hrvoje; Stani?, Patrik; Ježek, Davor; Oreškovi?, Slavko; Beketi?-Oreškovi?, Lidija; Pekez, Marijeta



The discovery of long acting ? 2-adrenoreceptor agonists  

Microsoft Academic Search

The design and profile of a series of saligenin containing long acting ?2-adrenoreceptor agonists is described. Evaluation of these analogues using a guinea-pig tissue model demonstrates that analogues within this series have significantly longer durations of action than salmeterol and have the potential for a once daily profile in human.

Alan D. Brown; Mark E. Bunnage; Paul A. Glossop; Kim James; Rhys Jones; Russell A. Lewthwaite; Simon Mantell; Christelle Perros-Huguet; David A. Price; Mike Trevethick; Rob Webster



The discovery of long acting beta2-adrenoreceptor agonists.  


The design and profile of a series of saligenin containing long acting beta(2)-adrenoreceptor agonists is described. Evaluation of these analogues using a guinea-pig tissue model demonstrates that analogues within this series have significantly longer durations of action than salmeterol and have the potential for a once daily profile in human. PMID:17498952

Brown, Alan D; Bunnage, Mark E; Glossop, Paul A; James, Kim; Jones, Rhys; Lane, Charlotte A L; Lewthwaite, Russell A; Mantell, Simon; Perros-Huguet, Christelle; Price, David A; Trevethick, Mike; Webster, Rob



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



Chemotype-selective Modes of Action of ?-Opioid Receptor Agonists*  

PubMed Central

The crystal structures of opioid receptors provide a novel platform for inquiry into opioid receptor function. The molecular determinants for activation of the ?-opioid receptor (KOR) were studied using a combination of agonist docking, functional assays, and site-directed mutagenesis. Eighteen positions in the putative agonist binding site of KOR were selected and evaluated for their effects on receptor binding and activation by ligands representing four distinct chemotypes: the peptide dynorphin A(1–17), the arylacetamide U-69593, and the non-charged ligands salvinorin A and the octahydroisoquinolinone carboxamide 1xx. Minimally biased docking of the tested ligands into the antagonist-bound KOR structure generated distinct binding modes, which were then evaluated biochemically and pharmacologically. Our analysis identified two types of mutations: those that affect receptor function primarily via ligand binding and those that primarily affect function. The shared and differential mechanisms of agonist binding and activation in KOR are further discussed. Usually, mutations affecting function more than binding were located at the periphery of the binding site and did not interact strongly with the various ligands. Analysis of the crystal structure along with the present results provide fundamental insights into the activation mechanism of the KOR and suggest that “functional” residues, along with water molecules detected in the crystal structure, may be directly involved in transduction of the agonist binding event into structural changes at the conserved rotamer switches, thus leading to receptor activation. PMID:24121503

Vardy, Eyal; Mosier, Philip D.; Frankowski, Kevin J.; Wu, Huixian; Katritch, Vsevolod; Westkaemper, Richard B.; Aubé, Jeffrey; Stevens, Raymond C.; Roth, Bryan L.



Arylacetamides as peripherally restricted kappa opioid receptor agonists  

Microsoft Academic Search

Analogues of the kappa (?) opioid receptor agonist, ICI 199441, were prepared. Ki values for these analogues at the cloned human ? opioid receptor ranged from 0.058 to 25nM. Trifluoromethylaryl derivatives were potent analgesics when administered subcutaneously in the rat and were more peripherally restricted than the parent compound, ICI 199441.

Virendra Kumar; Michael A. Marella; Luz Cortes-Burgos; An-Chih Chang; Joel A. Cassel; Jeffrey D. Daubert; Robert N. DeHaven; Diane L. DeHaven-Hudkins; Susan L. Gottshall; Erik Mansson; Alan L. Maycock



ARCHIVAL REPORT 2 Adrenergic and Imidazoline Receptor Agonists  

E-print Network

moxonidine seems to have substantial potential for treating addictive disorders. Key Words: Cocaine is a primary goal of addiction recovery. Understanding the neural mechanisms involved in relapse facilitatesARCHIVAL REPORT 2 Adrenergic and Imidazoline Receptor Agonists Prevent Cue-Induced Cocaine Seeking

Aston-Jones, Gary


Antiproliferative Effects of Cannabinoid Agonists on Deep Infiltrating Endometriosis  

PubMed Central

Deep infiltrating endometriosis (DIE) is characterized by chronic pain, hyperproliferation of endometriotic cells and fibrosis. Since cannabinoids are endowed with antiproliferative and antifibrotic properties, in addition to their psychogenic and analgesic effects, cannabinoid agonists have been evaluated in DIE both in vitro and in vivo. The in vitro effects of the cannabinoid agonist WIN 55212-2 were evaluated on primary endometriotic and endometrial stromal and epithelial cell lines extracted from patients with or without DIE. Cell proliferation was determined by thymidine incorporation and production of reactive oxygen species by spectrofluorometry. ERK and Akt pathways were studied by immunoblotting. Immunoblotting of ?-smooth muscle actin was studied as evidence of myofibroblastic transformation. The in vivo effects of WIN 55212-2 were evaluated on Nude mice implanted with human deep infiltrating endometriotic nodules. The in vitro treatment of stromal endometriotic cells by WIN 55212-2 decreased cell proliferation, reactive oxygen species production, and ?-smooth muscle actin expression. The decrease in cell proliferation induced by WIN 55212-2 was not associated with a decrease in ERK activation, but was associated with the inhibition of Akt activation. WIN 55212-2 abrogated the growth of endometriotic tissue implanted in Nude mice. Cannabinoid agonists exert anti-proliferative effects on stromal endometriotic cells linked to the inhibition of the Akt pathway. These beneficial effects of cannabinoid agonists on DIE have been confirmed in vivo. PMID:21057002

Leconte, Mahaut; Nicco, Carole; Ngô, Charlotte; Arkwright, Sylviane; Chéreau, Christiane; Guibourdenche, Jean; Weill, Bernard; Chapron, Charles; Dousset, Bertrand; Batteux, Frédéric



RESEARCH Open Access Long acting b2-agonist and corticosteroid restore  

E-print Network

was to determine whether a long-acting b2 adrenergic receptor agonist (salmeterol hydroxynaphthoate, Sal) combined-acting b2 adrenergic receptor agonist after bacterial infection restores the airway glandular cell function with a combination of b2 adrenergic receptor agonist and glucocorticoid. Background The epithelial lining

Paris-Sud XI, Université de


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)



Effects of Dopamine Agonists on Neuropsychiatric Symptoms of Parkinson’s Disease  

Microsoft Academic Search

The efficacy of dopamine (DA) agonists in the treatment of motor symptoms of Parkinson’s disease (PD) has been clearly demonstrated. It has also been documented that DA agonists may have both a positive and a negative impact on neuropsychiatric symptoms in PD patients. This paper will focus on the effects of DA agonists on depressive and cognitive symptoms of PD.

Irena Rektorová



Cost-Effectiveness Analysis of Dopamine Agonists in the Treatment of Parkinson's Disease in Japan  

Microsoft Academic Search

Background: Dopamine agonists such as bromocriptine or pergolide are often used in Japan to treat Parkinson's disease. Dopamine agonists are relatively expensive drugs; economic evaluations are required. Objective: To evaluate the cost effectiveness of dopamine agonists for the treatment of Parkinson's disease in Japan. Design and setting: We used a Markov model to simulate the course of Parkinson's disease and

Takuro Shimbo; Kenji Hira; Manabu Takemura; Tsuguya Fukui



The ?2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis.  


Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the ?-adrenoceptor (?-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple ?-AR agonists: isoproterenol (nonselective ?-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective ?(3)-AR agonist), and formoterol (selective ?(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the ?-AR antagonist propranolol and the ?(2)-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor ? coactivator 1?, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1? subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of ?(2)-AR ligands for therapeutic MB. PMID:22490378

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



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


The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT? or MT? subtype-selective compounds are available up to now. Administration of the MT?-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT? receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT? or MT? receptors are expected in coming years. PMID:21554566

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



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



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

PubMed Central

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

Moreau, J. L.; Pieri, L.



Topographical amino acid substitution in position 10 of glucagon leads to antagonists/partial agonists with greater binding differences.  


The role of position 10 in the beta-turn region of glucagon was investigated by substituting chiral constrained amino acids and other modifications in the N-terminal region. A series of glucagon analogues have been designed and synthesized by incorporating beta-methylphenylalanine isomers (2S,3S, 2S,3R, 2R,3R, and 2R,3S) at position 10 in order to explore the structural and topographical requirements of the glucagon receptor, and, in addition, utilizing previous studies which indicated that antagonism could be enhanced by modifications (des-His1, Glu9) and a bulky group at position 5. The structures of the new analogues are as follows: [des-His1,-Tyr5,Glu9]glucagon-NH2 (II), [des-His1,Tyr5,Glu9,Phe10]glucagon-NH2 (III), [des-His1,Tyr5,Glu9,-Ala10]glucagon-NH2 (IV), [des-His1,Tyr5,Glu9,(2S,3R)-beta-MePhe10]glucagon-NH2 (V), [des-His1,-Tyr5,Glu9,(2S,3S)-beta-MePhe10]glucagon-NH2 (VI), [des-His1,Tyr5,Glu9,D-Tyr10]glucagon-NH2 (VII), [des-His1,Tyr5,Glu9,D-Phe10]glucagon-NH2 (VIII), [des-His1,Tyr5,Glu9,D-Ala10]glucagon-NH2 (IX), [des-His1,Tyr5,Glu9,(2R,3R)-beta-MePhe10]glucagon-NH2 (X), and [des-His1,Tyr5,Glu9,(2R,3S)-beta-MePhe10]glucagon-NH2 (XI). These analogues led to dramatically different changes in in vitro binding affinities for glucagon receptors. Their receptor binding potencies IC50 values (nM) are 2.3 (II), 4.1 (III), 395.0 (IV), 10.0 (V), 170.0 (VI), 74.0 (VII), 34.5 (VIII), 510.0 (IX), 120.0 (X), and 180.0 (XI). Analogues II, III, V, VI, and XI were found to be weak partial agonists/partial antagonists with maximum stimulation between 5%-9%, while the other compounds (IV and VII-X) were antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10(-5) M. In competition experiments, all of the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose-response curve. The pA2 values were 6.60 (II), 6.85 (III), 6.20 (IV), 6.20 (V), 6.10 (VI), 6.50 (VII), 6.20 (VIII), 5.85 (IX), 6.20 (X), and 6.00 (XI). Putative topographical requirements of the glucagon receptor for the aromatic side chain conformation in position 10 of glucagon antagonists are discussed. PMID:8691441

Azizeh, B Y; Shenderovich, M D; Trivedi, D; Li, G; Sturm, N S; Hruby, V J



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



Expression des constantes de distorsion centrifuge des hexafluorures en fonction des frquences harmoniques.  

E-print Network

L-55 Expression des constantes de distorsion centrifuge des hexafluorures en fonction des de distorsion centrifuge des molécules XY6 en fonc- tion des fréquences harmoniques ; l for the centrifugal distortion constants as a function of harmonic frequencies ; application is made to SF6 and UF6. 4

Paris-Sud XI, Université de


Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity  

PubMed Central

Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [35S]GTP?S assay are predictive of the in vivo profile. PMID:23438330



Courtship and agonistic sounds by the cichlid fish Pseudotropheus zebra.  


Courtship and agonistic interactions in an African cichlid species present a richer diversity of acoustic stimuli than previously reported. Male cichlids, including those from the genus Pseudotropheus (P.), produce low frequency short pulsed sounds during courtship. Sounds emitted by P. zebra males in the early stages of courtship (during quiver) were found to be significantly longer and with a higher number of pulses than sounds produced in later stages. During agonistic intrasexual quiver displays, males produced significantly longer sounds with more pulses than females. Also, male sounds had a shorter duration and pulse period in courtship than in male-male interactions. Taken together, these results show that the acoustic repertoire of this species is larger than what was previously known and emphasize the importance of further research exploiting the role of acoustic stimuli in intra- and interspecific communication in African cichlids. PMID:18681618

Miguel Simões, J; Duarte, Ine S G; Fonseca, Paulo J; Turner, George F; Clara Amorim, M



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



Modification of peptide interaction with MHC creates TCR partial agonists  

Microsoft Academic Search

We report the creation of TCR partial agonists by the novel approach of manipulating the interaction between immunogenic peptide and MHC. Amino acids at MHC anchor positions of the I-Ek-restricted hemoglobin (64–76) and moth cytochrome c (88–103) peptides were exchanged with MHC anchor residues from the low affinity class II invariant chain peptide (CLIP), resulting in antigenic peptides with altered

Kelli R. Ryan; Lisa K. McNeil; Chinh Dao; Peter E. Jensen; Brian D. Evavold



Improving the developability profile of pyrrolidine progesterone receptor partial agonists  

SciTech Connect

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

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



Alpha-2 agonists to reduce vasopressor requirements in septic shock?  


One of the unsolved problems of septic shock is the poor responsiveness, or reduced vascular reactivity, to vasopressors used to increase blood pressure (BP). Attempts to restore vascular reactivity with NO inhibitors or low dose steroids have met with little success. Low vascular reactivity, which may lead to refractory shock and death, is linked to desensitization or down-regulation of alpha-1 adrenergic receptors. Our working hypothesis is that the use of alpha-2 agonists (e.g. clonidine or dexmedetomidine) in septic shock, in addition to the state-of-the-art treatment (including volume load and vasopressors), will reduce the vasopressor requirements needed to restore adequate BP. This counter-intuitive proposal is based on the fact that alpha-2 agonists will reduce the massive release of endogenous catecholamines. A decrease in plasma endogenous catecholamine concentrations will be followed by reduced down-regulation of alpha-1 receptors and/or a gradual re-sensitization of alpha-1 adrenergic receptors. In turn, this will lead to lowered vasopressor requirement, with respect to dose and duration. Our hypothesis, based on a reverse "denervation hypersensitivity", is at variance with accepted treatments, which rest only on volume load and vasopressors and emphasizes restoration of blood pressure per se. Several observations in the cardiology and anesthesia setting have shown increased vascular reactivity following alpha-2 agonist administration. Our preliminary observations in the setting of septic shock again suggest such increased vascular reactivity. Improved outcome was also observed. Rigorous work is warranted to verify reduced vasopressor requirement and improved outcome, when an alpha-2 agonist is combined with state-of -the-art treatment of septic shock. PMID:20817367

Pichot, C; Géloën, A; Ghignone, M; Quintin, L



Octopaminergic agonists for the cockroach neuronal octopamine receptor  

PubMed Central

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

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



Vasoactive Intestinal Peptide Inhaled Agonists: Potential Role in Respiratory Therapeutics  

PubMed Central

Purpose of review: Vasoactive Intestinal Peptide (VIP) is a neuropeptide, expressed by lymphoid as well as neural cells, which has diverse effects on the cellular mediators of inflammation and immunity and is also a potent neurotransmitter. VIP seems to have a major role in the homeostasis of the respiratory system, while several studies, including clinical trials, suggest that VIP-inhaled agonists could be used in respiratory therapeutics. In this review, we provide an introduction to the field of VIP research geared to clinical and research pulmonologists. Recent Findings: As a neurotransmitter, VIP exerts a potent bronchodilatory and vasodilatory effect and also is supposed to induce the house-keeping mucus secretion by submucosal glands. On the other hand, it has immunomodulatory functions which include humoral immune response suppression, inhibition of vascular and bronchial remodeling and inflammation and attenuation of the cigarette smoke extract-induced apoptotic death of alveolar L2 cells. Recent research on a wide spectrum of lung diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary hypertension, and sarcoidosis indicates a potential therapeutic role of a VIP agonist. Simultaneously, novel stabilized inhaled VIP agonists and drug delivery systems have been proposed as a promising candidate alternative drug with minimized side effects. These data are supported by the results of certain, limited clinical trials which have already been conducted. Conclusion: Ongoing research continues to clarify the immunomodulatory effects of VIP and to confirm animal findings with human studies. A major challenge for investigators will be to determine whether stabilized inhaled-VIP agonists could be used in respiratory therapeutics. PMID:23935337

Mathioudakis, AG; Chatzimavridou-Grigoriadou, V; Evangelopoulou, E; Mathioudakis, GA



Cytokine-Induced Loss of Glucocorticoid Function: Effect of Kinase Inhibitors, Long-Acting ?2-Adrenoceptor Agonist and Glucocorticoid Receptor Ligands  

PubMed Central

Acting on the glucocorticoid receptor (NR3C1), glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2×glucocorticoid response element (GRE) reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-? (TNF) or interleukin-1? inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h) was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2×GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK) inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2×GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2×GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3 expression by TNF. Finally, formoterol-enhanced 2×GRE reporter activity was also proportional to agonist efficacy and functionally reversed repression by TNF. As similar effects were apparent on glucocorticoid-induced gene expression, the most effective strategy to overcome glucocorticoid resistance in this model was addition of formoterol to high efficacy NR3C1 agonists. PMID:25625944

Rider, Christopher F.; Shah, Suharsh; Miller-Larsson, Anna; Giembycz, Mark A.; Newton, Robert



Cytokine-Induced Loss of Glucocorticoid Function: Effect of Kinase Inhibitors, Long-Acting ?2-Adrenoceptor Agonist and Glucocorticoid Receptor Ligands.  


Acting on the glucocorticoid receptor (NR3C1), glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2×glucocorticoid response element (GRE) reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-? (TNF) or interleukin-1? inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h) was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2×GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK) inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2×GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2×GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3 expression by TNF. Finally, formoterol-enhanced 2×GRE reporter activity was also proportional to agonist efficacy and functionally reversed repression by TNF. As similar effects were apparent on glucocorticoid-induced gene expression, the most effective strategy to overcome glucocorticoid resistance in this model was addition of formoterol to high efficacy NR3C1 agonists. PMID:25625944

Rider, Christopher F; Shah, Suharsh; Miller-Larsson, Anna; Giembycz, Mark A; Newton, Robert



DES Supernova Results  

NASA Astrophysics Data System (ADS)

The Dark Energy Survey Supernova program (DES SN) will discover approximately 3500 Type Ia supernovae with well-sampled multi-color light curves in the redshift range 0.2 < z < 1.2 over its five year duration. The large field of view and high z-band sensitivity of the Dark Energy Camera, combined with the precision photometry of DES and an improved handling of systematic uncertainties will allow DES SN to provide the strongest constraints on supernova cosmology to date. One of the main challenges for DES SN will be accurate classification of such a large number of faint transients. I will describe the unique spectroscopic follow-up strategy that we are employing, with emphasis on the 100 night, survey-status program at AAT which began in September. I will present preliminary supernova results obtained from the DES Science Verification period and the beginning of DES Year 1.

D'Andrea, Christopher; Dark Energy Survey, The



Structure of the agonist-bound neurotensin receptor  

PubMed Central

Summary Neurotensin (NT) is a 13 amino acid peptide that functions as both a neurotransmitter and a hormone through activation of the neurotensin receptor NTS1, a G protein-coupled receptor (GPCR). In the brain, NT modulates activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake, and in the gut NT regulates a range of digestive processes. Here we present the structure at 2.8 Å resolution of NTS1 in an active-like state, bound to NT8-13, the C terminal portion of NT responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTS1 in an extended conformation nearly perpendicular to the membrane plane with the C-terminus oriented towards the receptor core. Our findings provide the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity. PMID:23051748

White, Jim F.; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G.; Grisshammer, Reinhard



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; Hübner, Harald; Kobilka, Brian K.; Gmeiner, Peter



Rational design of humanized dual-agonist antibodies.  


The ultralong heavy chain complementarity determining region 3 (CDR3H) of bovine antibody BLV1H12 folds into a novel "stalk-knob" structural motif and has been exploited to generate novel agonist antibodies through replacement of the "knob" domain with cytokines and growth factors. By translating this unique "stalk-knob" architecture to the humanized antibody trastuzumab (referred to hereafter by its trade name, Herceptin, Genentech USA), we have developed a versatile approach to the generation of human antibody agonists. Human erythropoietin (hEPO) or granulocyte colony-stimulating factor (hGCSF) was independently fused into CDR3H, CDR2H, or CDR3L of Herceptin using an engineered "stalk" motif. The fusion proteins express in mammalian cells in good yields and have similar in vitro biological activities compared to hEPO and hGCSF. On the basis of these results we then generated a bi-functional Herceptin-CDR fusion protein in which both hEPO and hGCSF were grafted into the heavy- and light-chain CDR3 loops, respectively. This bi-functional antibody fusion exhibited potent EPO and GCSF agonist activities. This work demonstrates the versatility of the CDR-fusion strategy for generating functional human antibody chimeras and provides a novel approach to the development of multi-functional antibody-based therapeutics. PMID:25494484

Zhang, Yong; Liu, Yan; Wang, Ying; Schultz, Peter G; Wang, Feng



Lipopolysaccharide is a Direct Agonist for Platelet RNA Splicing  

PubMed Central

Platelets express TLR4 receptors, but its ligand lipopolysaccharide (LPS) does not directly activate thrombotic functions nor, obviously, transcription by these anucleate cells. Platelets, however, store information that changes their phenotype over a few hours in the form of unprocessed RNA transcripts. We show even low concentrations of LPS in the presence of soluble CD14 initiated splicing of unprocessed IL-1? RNA, with translation and accumulation of IL-1? protein. LPS was a more robust agonist for this response than thrombin. Platelets also contained cyclooxygenase-2 pre-mRNA, which also was spliced and translated after LPS stimulation. Flow cytometry and immunocytochemistry of platelets extensively purified by negative immunodepletion showed platelets contained IL-1?, and quantitative assessment of white blood cell contamination by CD14 real time PCR confirms that leukocytes were not the IL-1? source, nor were they required for platelet stimulation. LPS did not initiate rapid platelet responses, but over time did prime platelet aggregation to soluble agonists, induced actin rearrangement, and initiated granule secretion with P-selectin expression that resulted the coating of quiescent leukocytes with activated platelets. LPS is a direct agonist for platelets that allows these cells to directly participate in the innate immune response to bacteria. PMID:18714022

Shashkin, Pavel N.; Brown, G. Thomas; Ghosh, Arundhati; Marathe, Gopal K.; McIntyre, Thomas M.



Médecine des voyages  

PubMed Central

Résumé Objectif Définir la pratique de la médecine des voyages, présenter les éléments fondamentaux d’une consultation complète préalable aux voyages à des voyageurs internationaux et aider à identifier les patients qu’il vaudrait mieux envoyer en consultation auprès de professionnels de la médecine des voyages. Sources des données Les lignes directrices et les recommandations sur la médecine des voyages et les maladies liées aux voyages publiées par les autorités sanitaires nationales et internationales ont fait l’objet d’un examen. Une recension des ouvrages connexes dans MEDLINE et EMBASE a aussi été effectuée. Message principal La médecine des voyages est une spécialité très dynamique qui se concentre sur les soins préventifs avant un voyage. Une évaluation exhaustive du risque pour chaque voyageur est essentielle pour mesurer avec exactitude les risques particuliers au voyageur, à son itinéraire et à sa destination et pour offrir des conseils sur les interventions les plus appropriées en gestion du risque afin de promouvoir la santé et prévenir les problèmes médicaux indésirables durant le voyage. Des vaccins peuvent aussi être nécessaires et doivent être personnalisés en fonction des antécédents d’immunisation du voyageur, de son itinéraire et du temps qu’il reste avant son départ. Conclusion La santé et la sécurité d’un voyageur dépendent du degré d’expertise du médecin qui offre le counseling préalable à son voyage et les vaccins, au besoin. On recommande à ceux qui donnent des conseils aux voyageurs d’être conscients de l’ampleur de cette responsabilité et de demander si possible une consultation auprès de professionnels de la médecine des voyages pour tous les voyageurs à risque élevé.

Aw, Brian; Boraston, Suni; Botten, David; Cherniwchan, Darin; Fazal, Hyder; Kelton, Timothy; Libman, Michael; Saldanha, Colin; Scappatura, Philip; Stowe, Brian



EVALUATION DE LA DETECTION DES EMOTIONS, OPINONS OU SENTIMENTS Evaluation de la dtection des motions, des opinions ou des sentiments  

E-print Network

EVALUATION DE LA DETECTION DES EMOTIONS, OPINONS OU SENTIMENTS Evaluation de la détection des émotions, des opinions ou des sentiments : dictature de la majorité ou respect de la diversité d'opinion et analyse des sentiments sont généralement évalués par comparaison des réponses du système concerné

Paris-Sud XI, Université de


Amputation des quatre membres  

PubMed Central

Les auteurs présentent les cas d'amputation des quatre membres réalisée chez trois patients différents. Ce sont des amputations réalisées pour chaque patient au cours d'une seule hospitalisation et en un seul temps opératoire. Deux patients pour gangrène sèche infectée et un pour amputation traumatique des quatre membres. L'amputation d'urgence a été pratiquée en premier temps suivie de remodelage des moignons d'amputation en second temps. L’évolution de tous les patients a été bonne. PMID:25469177

Feruzi, Maruis Kitembo; Milindi, Cédrick Sangwa; Zabibu, Mireille Kakinga; Mulefu, Jules Panda; Katombe, Francois Tshilombo



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, Björn I; Obrant, Karl J; Nordsletten, Lars; Berge, Rolf; Thommesen, Liv; Reseland, Janne E



Pharmacological characterization and therapeutic potential for the treatment of opioid abuse with ATPM-ET, an N-ethyl substituted aminothiazolomorphinan with ? agonist and ? agonist/antagonist activity.  


We previously reported that the ? agonists with mixed ? activity could attenuate heroin self-administration with less potential to develop tolerance. The present study further investigated the effects of (-)-3-N-Ethylamino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride (ATPM-ET), a ? agonist and ? agonist/antagonist, on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP), heroin self-administration and heroin-primed reinstatement of drug-seeking behavior. We found that ATPM-ET produced a longer duration of potent antinociceptive effects with less side effect of sedation. More importantly, ATPM-ET attenuated the acquisition of morphine-induced CPP, without affecting the reinstatement of morphine CPP. Furthermore, ATPM-ET significantly inhibited heroin self-administration and the reinstatement of heroin primed drug-seeking behavior. Taken together, ATPM-ET, a novel ? agonist and ? agonist/antagonist may have utility for the treatment of drug dependence. PMID:24998879

Sun, Jian-Feng; Wang, Yu-Hua; Chai, Jing-Rui; Li, Fu-Ying; Hang, Ai; Lu, Gang; Tao, Yi-Min; Cheng, Yun; Chi, Zhi-Qiang; Neumeyer, John L; Zhang, Ao; Liu, Jing-Gen; Wang, Yu-Jun



The treatment of Parkinson's disease with dopamine agonists  

PubMed Central

Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body. The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system. A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen. Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors), monoaminoxydase-inhibitors (MAO-inhibitors) and NMDA-antagonists (N-Methyl-d-aspartat-antagonists). In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia. The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine agonists the reduce dyskinesia and this differences are statistically significant. The effect of dopamine agonists is weaker then levodopa generally. The initial therapy with dopamine agonists can postpone the use of levodopa medication or keep the dose small for a longer period of time. There are more other side effects to levodopa, these are not statistically significant. The idea, which strategy for the treatment should be chosen is dependent of several factors and has to be evaluated with the individual patient. An important criterion is the age of the patient at the beginning of the treatment. For younger patients (under 65 years) the risk of developing motoric fluctuation and dyskinesia is much higher and therefore it is proposed to use levodopa at later stages. The evidence of the evaluated studies show a good effectiveness with the therapy of Parkinson disease as monotherapy of younger patients or as additional medication to levodopa as well as older patients with progressive stages of this disease. In these groups of patients there is a positive cost-benefit ratio. PMID:21289911

Konta, Brigitte; Frank, Wilhelm



Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy  

PubMed Central

Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine < morphine < methadone). Clomipramine and each mu agonist were studied alone and in fixed-proportion mixtures in assays of schedule-controlled responding, thermal nociception, and capsaicin-induced thermal allodynia. In the assay of schedule-controlled responding, all mu agonists dose-dependently decreased response rates. Clomipramine was inactive alone and did not alter the effects of mu agonists. In the assay of thermal nociception, all mu agonists produced dose-dependent antinociception. Clomipramine was inactive alone but produced a proportion-dependent enhancement of the antinociceptive effects of nalbuphine > morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine. PMID:20675432

Banks, Matthew L.; Rice, Kenner C.



[Conformation-activity relations of des-Arg9-bradykinin. I. Conformation of molecules in solution].  


The spatial structure of [des-Arg9]bradykinin, a selective agonist of the B1 type kinin receptors, was studied by means of theoretical conformational analysis. In order to restrict the number of conformations under consideration, we used available data on 1H NMR in (CD3)2SO solution indicating the C-terminal carboxyl group to interact with the guanidine group of Arg1 and the hydroxyl group of Ser6. The calculated set of [des-Arg9]bradykinin low-energy conformations was compared with the 1H NMR data. Four types of conformations were selected, which are consistent with experimental data and serve as sterically reliable models for the preferable three-dimensional structure of [des-Arg9]bradykinin in solution. PMID:2590252

Shenderovich, M D



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


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

Saitoh, Akiyoshi; Yamada, Mitsuhiko



Antidepressant-like Effects of ? Opioid Receptor Agonists in Animal Models  

PubMed Central

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

Saitoh, Akiyoshi; Yamada, Mitsuhiko



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


Rpertoire des emplois en janvier 2011 des diplms de Master  

E-print Network

Répertoire des emplois en janvier 2011 des diplômés de Master Promotion 2008 Le répertoire des (CTU / UFR SLHS) - Education et promotion sanitaires et sociales, prévention des risques (CTU normes (UFR SLHS) - Sports et sociétés (UPFR sports) OFVE, 2011 - Page 2 #12;- Domaine Sciences, Santé

Jeanjean, Louis


Plan de cours Facult des arts et des sciences  

E-print Network

familiarisé avec les structures et les types d'organisation des Protistes, des Mycètes, des Algues et des eucaryotes Stramenopila (algues brunes, diatomées et oomycètes) 13 mai 3 Les protozoaires 14 mai 4 Les champignons, Les Lichens et Mycorhizes 20 mai 5 Myxomycota, Dyctiosteliomycota, Algues rouges et vertes 21 mai

Parrott, Lael


Politique de gestion des documents administratifs et des archives  

E-print Network

Politique de gestion des documents administratifs et des archives Préparation : Division de la gestion des documents administratifs et des archives Révision : Bureau du secrétaire général Entrée en vigueur : 15 février 2012 Approbation : (CA-2012-6) Cadre juridique : Loi sur les archives (L


Des cartographies de connaissances pour un pilotage des ressources humaines  

E-print Network

Des cartographies de connaissances pour un pilotage des ressources humaines et des processus RH'apport de la prospective : Mélanges en l'honneur de Luc Boyer (2010) xx-xxi" #12;Des cartographies de'organisation. Les cartographies de connaissances, parce qu'elles permettent l'identification et la représentation de

Paris-Sud XI, Université de


Design, synthesis and evaluation of dual pharmacology ?2-adrenoceptor agonists and PDE4 inhibitors.  


A novel series of formoterol-phthalazinone hybrids were synthesised and evaluated as dual pharmacology ?2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high ?2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50=1.05nM, pEC50=9.0) and potent PDE4B2 inhibitory activities (IC50=0.092?M). PMID:24300734

Huang, Ling; Shan, Wenjun; Zhou, Qi; Xie, Jiaxing; Lai, Kefang; Li, Xingshu



Effect of pindolol on hormone secretion and body temperature: Partial agonist effects  

Microsoft Academic Search

Summary Pindolol has been shown to be a partial agonist at 5-HT1a receptors in preclinical studies. It has also been reported to inhibit the effects of other 5-HT1a partial agonists such as ipsapirone and buspirone on hormone secretion and body temperature in man, indicating its antagonist action at 5-HT1a receptors in man. To determine if pindolol has 5-HT1a agonist as

H. Y. Meltzer; M. Maes



Toll-like receptor 9 (TLR9) agonists in the treatment of cancer  

Microsoft Academic Search

Although still early in clinical development, agonists of Toll-like receptor 9 (TLR9) have demonstrated potential for the treatment of cancer. TLR9 agonists directly induce activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early clinical data support the use of TLR9 agonists in patients with solid tumors and hematologic malignancies.

A M Krieg



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

SciTech Connect

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

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



Agonists cause endocytosis of nicotinic acetylcholine receptors on cultured myotubes.  


Regulated trafficking of neurotransmitter receptors in excitable cells may play an important role in synaptic plasticity. In addition, agonist-induced endocytosis of nicotinic acetylcholine receptors (nAChRs) in particular might be involved in nicotine tolerance and addiction. The existing evidence concerning regulated internalization of cell-surface nAChRs is indirect and equivocal, however. In the present study, radioligand binding and fluorescence microscopy were used to show that agonists cause substantial endocytosis of nAChRs on cultured myotubes. Exposure to carbachol or nicotine caused a decrease in the intensity of fluorescent labeling of clusters of cell-surface nAChRs that was blocked by low temperature. Overall, myotubes exposed to carbachol or nicotine bound 50-70% less [(125)I]-alpha-bungarotoxin on the cell surface than untreated cells. The effect of carbachol was significant within 5 min, increased progressively for at least 4 h, and had a sensitivity of 100 nM or less. Exposure to carbachol caused the appearance or dramatic expansion of an intracellular pool of nAChRs, which were localized to discrete, largely perinuclear structures. A pulse-chase labeling protocol allowed the selective labeling and localization of nAChRs that had been internalized from the cell surface. In untreated cells, very little internalization of nAChRs occurred over a period of 3 h, indicating that constitutive endocytosis of receptors over this period was minimal. Exposure to carbachol, however, caused a dramatic increase in the endocytosis of nAChRs. These results provide direct evidence that agonists, including the tobacco alkaloid nicotine, can cause substantial endocytosis of cell-surface nAChRs. PMID:11745659

St John, P A; Gordon, H



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.



Adenosine receptor agonists: from basic medicinal chemistry to clinical development.  


Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A(1), A(2A), A(2B) and A(3). Adenosine plays an important role in many (patho)physiological conditions in the CNS as well as in peripheral organs and tissues. Adenosine receptors are present on virtually every cell. However, receptor subtype distribution and densities vary greatly. Adenosine itself is used as a therapeutic agent for the treatment of supraventricular paroxysmal tachycardia and arrhythmias and as a vasodilatatory agent in cardiac imaging. During the past 20 years, a number of selective agonists for A(1), A(2A) and A(3) adenosine receptors have been developed, all of them structurally derived from adenosine. Several such compounds are currently undergoing clinical trials for the treatment of cardiovascular diseases (A(1)and A(2A)), pain (A(1)), wound healing (A(2A)), diabetic foot ulcers (A(2A)), colorectal cancer (A(3)) and rheumatoid arthritis (A(3)). Clinical evaluation of some A(1) and A(2A) adenosine receptor agonists has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors; low brain penetration, which is important for the targeting of CNS diseases; short half-lifes of compounds; or a lack of effects, in some cases perhaps due to receptor desensitisation or to low receptor density in the targeted tissue. Partial agonists, inhibitors of adenosine metabolism (adenosine kinase and deaminase inhibitors) or allosteric activators of adenosine receptors may be advantageous for certain indications, as they may exhibit fewer side effects. PMID:14662005

Yan, Luo; Burbiel, Joachim C; Maass, Astrid; Müller, Christa E



Eléments de comparaison internationale des patrimoines des ménages  

Microsoft Academic Search

[fre] A partir des bribes d'information existant sur les patrimoines de divers pays européens et des USA, une comparaison de la structure des patrimoines des inégalités de répartition et de leur évolution est tentée. Actifs financiers et actifs réels figurent de façon variable dans les patrimoines des différents pays. La Grande-Bretagne, avec une forte part d'actifs financiers, notamment de valeurs

Dominique Strauss-Kahn



Narrow SAR in odorant sensing Orco receptor agonists.  


The systematic exploration of a series of triazole-based agonists of the cation channel insect odorant receptor is reported. The structure-activity relationships of independent sections of the molecules are examined. Very small changes to the compound structure were found to exert a large impact on compound activity. Optimal substitutions were combined using a 'mix-and-match' strategy to produce best-in-class compounds that are capable of potently agonizing odorant receptor activity and may form the basis for the identification of a new mode of insect behavior modification. PMID:24813736

Romaine, Ian M; Taylor, Robert W; Saidu, Samsudeen P; Kim, Kwangho; Sulikowski, Gary A; Zwiebel, Laurence J; Waterson, Alex G



Discriminative stimulus effects of spiradoline, a kappa-opioid agonist  

Microsoft Academic Search

This study represents the initial step in assessing the discriminative effects of spiradoline (U62,066), a potent congener of the selective kappa-opioid agonist, U50,488. Separate groups of rats were trained to discriminate between SC injections of saline and either 3.0 mg\\/kg spiradoline or 3.0 mg\\/kg morphine in a discrete-trial shock-avoidance\\/escape procedure. Spiradoline-trained rats generalized completely to U50,488 (ED50s for spiradoline and

Stephen G. Holtzman; Leonard Cook; George F. Steinfels



Archives participatives Au milieu des ralisations remarquables de mdiation numrique des bibliothques et des  

E-print Network

Archives participatives Au milieu des réalisations remarquables de médiation numérique des bibliothèques et des musées sur les médias sociaux, les services d'archives ont un positionnement relativement en revanche des projets ambitieux de crowdsourcing, d'« archives participatives » (voir encart

Paris-Sud XI, Université de


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))



Small-molecule Bax agonists for cancer therapy.  


Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here we used the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK programme suite. Three compounds, small-molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumour growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anticancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies. PMID:25230299

Xin, Meiguo; Li, Rui; Xie, Maohua; Park, Dongkyoo; Owonikoko, Taofeek K; Sica, Gabriel L; Corsino, Patrick E; Zhou, Jia; Ding, Chunyong; White, Mark A; Magis, Andrew T; Ramalingam, Suresh S; Curran, Walter J; Khuri, Fadlo R; Deng, Xingming



Computational Study of Synthetic Agonist Ligands of Ionotropic Glutamate Receptors  

PubMed Central

Neurological glutamate receptors are among the most important and intensely studied protein ligand binding systems in humans. They are crucial for the functioning of the central nervous system and involved in a variety of pathologies. Apart from the neurotransmitter glutamate, several artificial, agonistic and antagonistic ligands are known. Of particular interest here are novel photoswitchable agonists that would open the field of optogenetics to glutamate receptors. The receptor proteins are complex, membrane-bound multidomain oligomers that undergo large scale functional conformational changes, making detailed studies of their atomic structure challenging. Therefore, a thorough understanding of the microscopic details of ligand binding and receptor activation remains elusive in many cases. This topic has been successfully addressed by theoretical studies in the past and in this paper, we present extensive molecular dynamics simulation and free energy calculation results on the binding of AMPA and an AMPA derivative, which is the basis for designing light-sensitive ligands. We provide a two-step model for ligand binding domain activation and predict binding free energies for novel compounds in good agreement to experimental observations. PMID:23536824

Wolter, Tino; Steinbrecher, Thomas; Elstner, Marcus



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



Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets  

SciTech Connect

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

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



A Sphingosine 1-phosphate receptor 2 selective allosteric agonist  

PubMed Central

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

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



In Vitro Evaluation of TLR4 Agonist Activity: Formulation Effects  

PubMed Central

Effective in vitro evaluation of vaccine adjuvants would allow higher throughput screening compared to in vivo studies. However, vaccine adjuvants comprise a wide range of structures and formulations ranging from soluble TLR agonists to complex lipid-based formulations. The effects of formulation parameters on in vitro bioactivity assays and the correlations with in vivo adjuvant activity is not well understood. In the present work, we employ the Limulus amebocyte lysate assay and a human macrophage cellular cytokine production assay to demonstrate the differences in in vitro bioactivity of four distinct formulations of the synthetic TLR4 agonist GLA: an aqueous nanosuspension (GLA-AF), an oil-in-water emulsion (GLA-SE), a liposome (GLA-LS), and an alum-adsorbed formulation (GLA-Alum). Furthermore, we demonstrate the importance of the localization of GLA on in vitro potency. By comparing to previous published reports on the in vivo bioactivity of these GLA-containing formulations, we conclude that the most potent activators of the in vitro systems may not be the most potent in vivo adjuvant formulations. Furthermore, we discuss the formulation considerations which should be taken into account when interpreting data from in vitro adjuvant activity assays. PMID:24121074

Misquith, Ayesha; Millie Fung, H. W.; Dowling, Quinton M.; Guderian, Jeffrey A.; Vedvick, Thomas S.; Fox, Christopher B.



Effects of ?-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of ?-Agonist Efficacy and Noxious Stimulus Intensity  

PubMed Central

Pain is associated with stimulation of some behaviors and depression of others, and ?-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six ?-agonists that varied in efficacy at ?-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All ?-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All ?-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy ?-agonist nalbuphine, but not the high-efficacy ?-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective ?-opioid analgesics and reveal distinctions between opioids based on efficacy at the ?-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs. PMID:25406170

Rice, Kenner C.; Negus, S. Stevens



Effects of ?-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of ?-Agonist Efficacy and Noxious Stimulus Intensity.  


Pain is associated with stimulation of some behaviors and depression of others, and ?-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six ?-agonists that varied in efficacy at ?-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All ?-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All ?-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy ?-agonist nalbuphine, but not the high-efficacy ?-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective ?-opioid analgesics and reveal distinctions between opioids based on efficacy at the ?-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs. PMID:25406170

Altarifi, Ahmad A; Rice, Kenner C; Negus, S Stevens



A Quantitative Analysis of Agonistic Behavior in Juvenile American Lobsters (Homarus americanus L.)  

Microsoft Academic Search

In these studies a quantitative analysis of agonistic (fighting) behavior in lobsters is presented as a first step in our attempt to relate patterns of behavior to underlying neurobiological mechanisms. The agonistic behavior of juvenile American lobsters (Homarus americanus L.) was studied in laboratory tanks at the New England Aquarium. Using video analyses and statistical techniques: (1) an ethogram of

R. Huber; E. A. Kravitz



Glucocorticoids and the Development of Agonistic Behaviour during Puberty in Male Golden Hamsters  

E-print Network

early in puberty accelerates this transition. The present study investigated the possible role of glucocorticoids on the maturation of agonistic behaviour. First, we compared serum cortisol levels following a 20 investigated the effects of stress hormones on the matur- ation of agonistic behaviour. Male hamsters were

Delville, Yvon


Agonist-induced platelet procoagulant activity requires shear and a Rac1-dependent signaling mechanism.  


Activated platelets facilitate blood coagulation by exposing phosphatidylserine (PS) and releasing microvesicles (MVs). However, the potent physiological agonists thrombin and collagen poorly induce PS exposure when a single agonist is used. To obtain a greater procoagulant response, thrombin is commonly used in combination with glycoprotein VI agonists. However, even under these conditions, only a percentage of platelets express procoagulant activity. To date, it remains unclear why platelets poorly expose PS even when stimulated with multiple agonists and what the signaling pathways are of soluble agonist-induced platelet procoagulant activity. Here we show that physiological levels of shear present in blood significantly enhance agonist-induced platelet PS exposure and MV release, enabling low doses of a single agonist to induce full-scale platelet procoagulant activity. PS exposed on the platelet surface was immediately released as MVs, revealing a tight coupling between the 2 processes under shear. Using platelet-specific Rac1(-/-) mice, we discovered that Rac1 plays a common role in mediating the low-dose agonist-induced procoagulant response independent of platelet aggregation, secretion, and the apoptosis pathway. Platelet-specific Rac1 function was not only important for coagulation in vitro but also for fibrin accumulation in vivo following laser-induced arteriolar injury. PMID:25079357

Delaney, Michael Keegan; Liu, Junling; Kim, Kyungho; Shen, Bo; Stojanovic-Terpo, Aleksandra; Zheng, Yi; Cho, Jaehyung; Du, Xiaoping



Functional desensitization of the ?2 adrenoceptor is not dependent on agonist efficacy  

PubMed Central

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

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



Clinical review and treatment of select adverse effects of dopamine receptor agonists in Parkinson's disease.  


Dopamine receptor agonists provide a viable alternative or adjunct to levodopa therapy in Parkinson's disease and are associated with fewer motor complications and dyskinesia. However, all available dopamine agonists may cause profound adverse effects in some patients. In many cases, these adverse effects amplify non-motor symptoms that people with Parkinson's disease may already be experiencing. Nausea from dopamine agonists generally lessens with time and may be responsive to both antiemetic therapy and complementary remedies, such as ginger, peppermint and chamomile. Unfortunately, compulsive behaviours, as well as peripheral oedema caused by dopamine agonists, are poorly responsive to pharmacological therapy and require a reduction or discontinuation of agonist therapy. Somnolence and associated sleep attacks generally require elimination of the agonist or the use of a stimulating agent. The necessity of treatment for hallucinations and psychosis associated with dopamine agonists must be thoroughly evaluated prior to initiating therapy. If a medication is initiated for hallucinations or psychosis, quetiapine or clozapine are agents of choice. Orthostatic hypotension, though not always symptomatic, responds well to nonpharmacological strategies and medications, including indometacin, midodrine and fludrocortisone. Care must be taken to educate patients with Parkinson's disease about the common adverse effects of dopamine agonists and what can be done to lessen them. PMID:20359261

Wood, Lindy D



Agonists at mu-opioid receptors spin the wheels to keep the action going.  


A study in this issue of Molecular Pharmacology on agonist-induced internalization of mu-opioid receptors during long-term opiate drug exposure is discussed. The study demonstrates the critical role of re-cycling of reactivated mu receptors back to the plasma membrane for the maintenance of agonist signaling during long-term opiate exposure. PMID:15496509

Cox, Brian M



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



PROOF COPY 052808JAS Courtship and agonistic sounds by the cichlid fish  

E-print Network

PROOF COPY 052808JAS PROOF COPY 052808JAS Courtship and agonistic sounds by the cichlid fish Courtship and agonistic interactions in an African cichlid species present a richer diversity of acoustic stimuli than previously reported. Male cichlids, including those from the genus Pseudotropheus (P


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



Free energy calculations of A2A adenosine receptor mutation effects on agonist binding.  


A general computational scheme to evaluate the effects of single point mutations on ligand binding is reported. This scheme is applied to characterize agonist binding to the A2A adenosine receptor, and is found to accurately explain how point mutations of different nature affect the binding affinity of a potent agonist. PMID:25633558

Keränen, Henrik; Åqvist, Johan; Gutiérrez-de-Terán, Hugo




E-print Network

Regular article AN INVERSE AGONIST OF THE HISTAMINE H3-RECEPTOR IMPROVES WAKEFULNESS IN NARCOLEPSY, 75002-Paris, France. Running title: H3-RECEPTOR INVERSE AGONIST & NARCOLEPSY Correspondence should,version1 #12;Abstract Narcolepsy is characterized by excessive daytime sleepiness(EDS), cataplexy, direct

Paris-Sud XI, Université de


un cristal, des rseaux  

E-print Network

décrypter les matériaux du patrimoine. Le jaune chrome/plomb des tournesols de Van Gogh Certaines parties du tableau de van Gogh, « Fleurs dans un vase bleu » peint en 1887, ont changé de couleur au cours du temps/Université d'Anvers - Musée Van Gogh un cristal, des réseaux à l'upmc Voir l'article en ligne Site du

Arleo, Angelo


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


Enemy attraction: bacterial agonists for leukocyte chemotaxis receptors.  


The innate immune system recognizes conserved microorganism-associated molecular patterns (MAMPs), some of which are sensed by G protein-coupled receptors (GPCRs), and this leads to chemotactic leukocyte influx. Recent studies have indicated that these processes are crucial for host defence and rely on a larger set of chemotactic MAMPs and corresponding GPCRs than was previously thought. Agonists, such as bacterial formyl peptides, enterococcal pheromone peptides, staphylococcal peptide toxins, bacterial fermentation products and the Helicobacter pylori peptide HP(2-20), stimulate specific GPCRs. The importance of leukocyte chemotaxis in host defence is highlighted by the fact that some bacterial pathogens produce chemotaxis inhibitors. How the various chemoattractants, receptors and antagonists shape antibacterial host defence represents an important topic for future research. PMID:25534805

Bloes, Dominik Alexander; Kretschmer, Dorothee; Peschel, Andreas



Therapeutic potential of ?-arrestin- and G protein-biased agonists  

PubMed Central

Members of the seven-transmembrane receptor (7TMR), or G protein-coupled receptor (GPCR), superfamily represent some of the most successful targets of modern drug therapy, with proven efficacy in the treatment of a broad range of human conditions and disease processes. It is now appreciated that ?-arrestins, once viewed simply as negative regulators of traditional 7TMR-stimulated G protein signaling, act as multifunctional adapter proteins that regulate 7TMR desensitization and trafficking and promote distinct intracellular signals in their own right. Moreover, several 7TMR biased agonists, which selectively activate these divergent signaling pathways, have been identified. Here we highlight the diversity of G protein- and ?-arrestin-mediated functions and the therapeutic potential of selective targeting of these in disease states. PMID:21183406

Whalen, Erin J.; Rajagopal, Sudarshan; Lefkowitz, Robert J.



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.



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


Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. PMID:25326842

Soldevila, Berta; Puig-Domingo, Manel



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


Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. PMID:25437464

Soldevila, Berta; Puig-Domingo, Manel



TRPM8 agonists modulate contraction of the pig urinary bladder.  


The transient receptor potential melastin-8 (TRPM8) channel is activated by the "cooling" compounds menthol and icilin. Pathophysiologically, it is implicated in the overactive bladder and bladder cooling reflex, but the activity of TRPM8 in normal bladder physiology is poorly understood. We investigated the distribution of TRPM8 channels and the effect of TRPM8 agonists on the contractile function of pig bladder (n = 35) strips and whole bladders. The distribution of TRPM8 was examined by immunohistochemistry. The effect of vesical or intravascular menthol (0.1-0.3 mmol/L) or icilin (50 ?mol/L) on carbachol-induced isolated whole bladder contractions was monitored by recording vesical pressure. Strips of denuded detrusor or mucosa were mounted in organ baths to study the effect of TRPM8 agonists on the contractile responses to 10 ?mol/L carbachol. TRPM8-like immunoreactivity was detected on pig urothelium. Intravascular menthol (0.3 mmol/L) and icilin (50 ?mol/L) significantly decreased the magnitude of carbachol-induced whole bladder contraction, whereas vesical administration significantly increased the response. In detrusor and mucosal strips, both menthol (0.3 mmol/L) and icilin (50 ?mol/L) inhibited carbachol-induced contractions. We conclude that the TRPM8 channel is expressed on the urothelium of pig bladder. In the whole organ, exposure of the urothelium to menthol or icilin increases the contractile response to carbachol. Where detrusor muscle is exposed directly to these compounds, the contractile response to carbachol is reduced. PMID:23826977

Vahabi, Bahareh; Parsons, Brian A; Doran, Olena; Rhodes, Anthony; Dean, Sarah; Drake, Marcus J



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


The roots of licorice (Glycyrrhiza glabra) are a rich source of flavonoids, in particular, prenylated flavonoids, such as the isoflavan glabridin and the isoflavene glabrene. Fractionation of an ethyl acetate extract from licorice root by centrifugal partitioning chromatography yielded 51 fractions, which were characterized by liquid chromatography-mass spectrometry and screened for activity in yeast estrogen bioassays. One third of the fractions displayed estrogenic activity towards either one or both estrogen receptors (ERs; ER? and ER?). Glabrene-rich fractions displayed an estrogenic response, predominantly to the ER?. Surprisingly, glabridin did not exert agonistic activity to both ER subtypes. Several fractions displayed higher responses than the maximum response obtained with the reference compound, the natural hormone 17?-estradiol (E(2)). The estrogenic activities of all fractions, including this so-called superinduction, were clearly ER-mediated, as the estrogenic response was inhibited by 20-60% by known ER antagonists, and no activity was found in yeast cells that did not express the ER? or ER? subtype. Prolonged exposure of the yeast to the estrogenic fractions that showed superinduction did, contrary to E(2), not result in a decrease of the fluorescent response. Therefore, the superinduction was most likely the result of stabilization of the ER, yeast-enhanced green fluorescent protein, or a combination of both. Most fractions displaying superinduction were rich in flavonoids with single prenylation. Glabridin displayed ER?-selective antagonism, similar to the ER?-selective antagonist RU 58668. Whereas glabridin was able to reduce the estrogenic response of E(2) by approximately 80% at 6?×?10(-6) M, glabrene-rich fractions only exhibited agonistic responses, preferentially on ER?. PMID:21573846

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



Behavioral characterization of the new potent nonselective dopamine agonist pergolide.  


Pergolide (LY127809, CAS 66104-23-2), a non-selective dopamine agonist, was evaluated for broad behavioral properties in a wide range of pharmacological tests. The selective dopamine2(D2) agonist, bromocriptine, served as a reference standard for those tests where behavioral activity was noted with pergolide. Pergolide and bromocriptine were administered orally to mice at doses of 0.3-30 and 3-300 mg/kg, respectively. Both compounds produced biphasic effects on spontaneous activity, increased hexobarbital-induced sleep time, and lowered mouse body temperature. Qualitative changes with pergolide were observed with some mice showing hyporeactiveness, ptosis, slowed respiration and placing loss. Reserpine-induced hypothermia was reversed by pergolide with significant increases in the body temperature of reserpine-treated mice. However, a further reduction in the body temperature of reserpinized hypothermic mice was seen following bromocriptine administration. Acetic acid-induced writhing and performance on the rotarod were both impaired by higher doses of pergolide. Bromocriptine administration also reduced writhing at higher doses but did not alter performance on the rotarod. Pergolide had no effect on seizure activity as evaluated by electroshock, pentylenetetrazol (pentetrazol) or strychnine. Oxotremorine-induced tremors and salivation, grip strength, and tail-flick were not affected by pergolide. Neither pergolide nor bromocriptine altered established shuttle-avoidance behavior in rats at oral doses of 0.1 to 30 mg/kg. Behavioral assessment of pergolide in dogs was complicated by severe emetic responses at clinically relevant doses greater than 0.003 mg/kg. In summary, these data suggest that pergolide produces a behavioral profile which is characteristic of dopaminergics.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1418051

Helton, D R; Modlin, D L; Williams, P D



Recent advances in the development of farnesoid X receptor agonists  

PubMed Central

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

Carey, Elizabeth J.; Lindor, Keith D.



Immobilized thrombin receptor agonist peptide accelerates wound healing in mice.  


To accelerate the healing processes in wound repair, attempts have been repeatedly made to use growth factors including thrombin and its peptide fragments. Unfortunately, the employment of thrombin is limited because of its high liability and pro-inflammatory actions at high concentrations. Some cellular effects of thrombin in wound healing are mediated by the activation of protease activated receptor-1 (PAR-1). The thrombin receptor agonist peptide (TRAP:SFLLRN) activates this receptor and mimics the effects of thrombin, but TRAP is a relatively weak agonist. We speculated that the encapsulated peptide may be more effective for PAR-1 activation than nonimmobilized peptide and developed a novel method for TRAP encapsulation in hydrogel films based on natural and synthetic polymers. The effects of an encapsulated TRAP in composite poly(N-vinyl caprolactam)-calcium alginate (PVCL) hydrogel films were investigated in a mouse model of wound healing. On day 7 the wound sizes decreased by about 60% under TRAP-chitosan-containing PVCL films, as compared with control films without TRAP. In the case of TRAP-polylysine-containing films no significant decrease in wound sizes was found. The fibroblast/macrophage ratio increased under TRAP-containing films on day 3 and on day 7. The number of proliferating fibroblasts increased to 150% under TRAP-chitosan films on day 7 as compared with control films. The number of [3H]-thymidine labeled endothelial and epithelial cells in granulation tissues was also enhanced. Thus, the immobilized TRAP to PVCL-chitosan hydrogel films were found to promote wound healing following the stimulation of fibroblast and epithelial cell proliferation and neovascularization. Furthermore, TRAP was shown to inhibit the secretion of the inflammatory mediator PAF from stimulated rat peritoneal mast cells due to augmentation of NO release from the mast cells. The encapsulated TRAP is suggested to accelerate wound healing due to the anti-inflammatory effects and earlier development of the proliferative phase of wound healing. PMID:11697718

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



The efficiency of electrical stimulation to counteract the negative effects of ?-agonists on meat tenderness of feedlot cattle  

Microsoft Academic Search

Beta agonists used as growth enhancers are known to affect the aging potential of beef muscle negatively. On the other hand, procedures like electrical stimulation could accelerate rigor and the aging process. In this study, 20 out of 40 young steers received no beta agonist (C), the remaining twenty steers received a beta agonist (zilpaterol hydrochloride) (Z) for the 30days

M. Hope-Jones; P. E. Strydom; L. Frylinck; E. C. Webb



A review of shark agonistic displays: comparison of display features and implications for shark–human interactions  

Microsoft Academic Search

Agonistic displays in 23 species of sharks of six families are described and illustrated. These displays are reviewed in terms of ethological concepts and shark hydrodynamic models. Shark agonistic displays feature many common elements rendering them readily distinguishable from normal swimming and pseudodisplays caused by sharksucker irritation. Shark agonistic displays are most readily elicited by rapid, direct diver approach when

R. Aidan Martin



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




Early Life Stress in Depressive Patients: HPA Axis Response to GR and MR Agonist  

PubMed Central

Background: Evidence indicates that early life stress (ELS) can induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress in the adult life that leads to depression. These appear to be related to the impairment of HPA hormones through binding to glucocorticoid (GR) and mineralocorticoid receptors (MR). The aim of this study was to evaluate the impact of ELS in HPA axis response to challenges with GR and MR agonists in depressed patients. Methods: We included 30 subjects, 20 patients with current major depression (HAM-D21???17). Patients were recruited into two groups according to ELS history assessed by the Childhood Trauma Questionnaire (CTQ). The cortisol measures in the saliva and plasma were evaluated after using (at 10:00 p.m.) placebo, fludrocortisone (MR agonist), or dexamethasone (GR agonist). Results: Depressed patients showed a significantly lower salivary cortisol upon waking after placebo compared with controls. Moreover, cortisol awakening responses (CAR) after MR agonist were found to be lower in depressed patients than in controls. With CTQ scores, HAM-D21, body mass index and CAR after placebo, GR agonist, MR agonist we found in a Linear Regression model that depressive patients with ELS (p?=?0.028) show differences between placebo vs. MR agonist (R?=?0.51; p?agonist; in depressive patients, without ELS the data show differences between placebo vs. MR agonist (R?=?0.69; p?agonist (R?=?0.53; p?agonist, indicating that patients with ELS are sensitive to MR agonists. In contrast with depressed patients without ELS, we find suppression after both MR and GR agonist. These data suggested that in ELS an imbalance exists between MR and GR with MR dysfunction. PMID:24478730

Baes, Cristiane von Werne; Martins, Camila Maria Severi; Tofoli, Sandra Márcia de Carvalho; Juruena, Mário Francisco



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


Combination corticosteroid/?-agonist inhaler as reliever therapy: a solution for intermittent and mild asthma?  


The recommended treatment of mild asthma is regular maintenance inhaled corticosteroids (ICSs) with a short-acting ?-agonist as a separate inhaler used when needed for symptom relief. However, the benefits of regular ICS use in actual clinical practice are limited by poor adherence and low prescription rates. An alternative strategy would be the symptom-driven (as-required or "prn") use of a combination ICS/short-acting ?-agonist or ICS/long-acting ?-agonist inhaler as a reliever rather than regular maintenance use. The rationale for this approach is to titrate both the ICS and ?-agonist dose according to need and enhance ICS use in otherwise poorly adherent patients who overrely on their reliever ?-agonist inhaler. This strategy will only work if the ?-agonist component has a rapid onset of action for symptom relief. There is evidence to suggest that this regimen has advantages over regular ICS therapy and might represent an effective, safe, and novel therapy for the treatment of intermittent and mild asthma. In this commentary we review this evidence and propose that randomized controlled trials investigating different combination ICS/?-agonist inhaler products prescribed according to this regimen in intermittent and mild asthma are an important priority. PMID:24369798

Beasley, Richard; Weatherall, Mark; Shirtcliffe, Philippa; Hancox, Robert; Reddel, Helen K



La biogenèse des mélanosomes  

PubMed Central

Les mélanocytes situés à la base de l’épiderme produisent des mélanosomes qui sont transférés aux kératinocytes pour assurer la pigmentation de l’épiderme et sa photoprotection contre les rayons ultraviolets. Les mélanosomes, organites apparentés aux lysosomes, sont le lieu de synthèse et de stockage d’un pigment, la mélanine. Leur formation dépend de protéines mélanosomales qui transitent par les voies de biosynthèse et d’endocytose et exploitent les mécanismes moléculaires du trafic intracellulaire. Les acteurs moléculaires impliqués dans le transport des protéines mélanosomales et la biogenèse des mélanosomes sont la cible de mutations dans des maladies génétiques accompagnées d’hypopigmentation comme l’albinisme et les maladies lysosomales. Les études menées sur les mélanocytes issus de souris modèles de ces maladies permettent de comprendre certaines des étapes-clés de la mélanogenèse ainsi que les dysfonctionnements associés à ces pathologies. De plus, décrypter la mélanogenèse facilite également la compréhension d’autres processus physiologiques, comme l’illustrent les similitudes inattendues avec l’amyloïdogenèse dans les maladies neurodégénératives. PMID:21382323

Delevoye, Cédric; Giordano, Francesca; van Niel, Guillaume; Raposo, Graça



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:



Septembre 2012 Paludisme : des moustiques  

E-print Network

pulvérisations intra domiciliaires d'autres insecticides, les carbamates. Ces derniers agissent différemment au aux pyré- thrinoïdes et pulvérisé des carbamates à l'intérieur des habitations, les scientifiques ont



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


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



Behandlung der Pseudarthrosen des Beckens  

Microsoft Academic Search

Pseudarthrosen des Beckenringes sind selten. Leitsymptom ist der chronische belastungsabhängige Schmerz des Beckenrings. Es muss überprüft werden, ob der Symptomenkomplex durch eine Pseudarthrose, durch eine posttraumatische Fehlstellung oder durch die Kombination von beiden verursacht ist. Diagnostisch wichtig sind die körperliche Untersuchung des ausgezogenen Patienten, Provokationstests, Röntgen (Beckenübersichts-, Inlet-, Outlet-, Ala- und Obturatoraufnahme) sowie die für die Analyse von Fehlstellungen, Instabilitäten

I. Marintschev; T. Mückley; F. Mendler; G. O. Hofmann



Échantillonnage des gisements kimberlitiques à partir des microdiamants : Application à l'estimation des ressources récupérables.  

E-print Network

??La prédiction des ressources récupérables d'un gisement kimberlitique passe par l'estimation de la loi en taille des diamants commercialisables qu'il contient. Cette estimation repose traditionnellement… (more)

Ferreira, Johannes



Effects of ?-opioid receptor agonists on long-term cocaine use and dopamine neurotransmission  

Microsoft Academic Search

?-Opioid receptor agonists have been suggested as treatments for cocaine addiction based on studies showing that they block cocaine-related behaviors. To determine the effects of ?-opioid receptor agonists on long-term behavioral effects associated with cocaine and the neurochemical bases underlying these effects, rats were treated with the selective ?-opioid receptor agonist U-69593 ((+)(5?,7?,8?)-N-methyl-N-[7-(1-pyrrolidinyl)-1 oxaspiro[4.5]dec-8-yl]-benzeneacetamide) alone or in combination with cocaine

Stephanie L Collins; Claudio D'Addario; Sari Izenwasser



Inhaled adenosine A(2A) receptor agonists for the treatment of chronic obstructive pulmonary disease.  


COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained. PMID:18243699

Mantell, Simon J; Stephenson, Peter T; Monaghan, Sandra M; Maw, Graham N; Trevethick, Michael A; Yeadon, Michael; Keir, Ruth F; Walker, Don K; Jones, Rhys M; Selby, Matthew D; Batchelor, David V; Rozze, Stuart; Chavaroche, Helene; Hobson, Tim J; Dodd, Peter G; Lemaitre, Arnaud; Wright, Karen N; Stuart, Emilio F



Anaphylactic reaction to different gonadotropin-releasing hormone agonists for the treatment of endometriosis.  


Anaphylactic reactions to gonadotropin-releasing hormone (GnRH) agonists are exceedingly rare, but if they occur, they can be life threatening. This case describes a 33-year-old patient with endometriosis who developed an acute allergic reaction on leuprolide (Lucrin) administration. Although skin tests with the replacement goserelin (Zoladex) were negative, usage of this medication resulted in a similar allergic reaction. This is the first case report that shows that, in case of a proven allergy to one GnRH agonist, a switch to another GnRH agonist should not be made even if allergy tests are negative for this medication. PMID:21233692

Lüchinger, Annemarie B; Mijatovic, Velja; Rustemeyer, Thomas; Hompes, Peter G A



Liver X Receptor (LXR) partial agonists: Biaryl pyrazoles and imidazoles displaying a preference for LXR?.  


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

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



Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation  

PubMed Central

The farnesoid X receptor (FXR) is involved in glucose and lipid metabolism regulation, which makes it an attractive target for the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. In order to find novel FXR agonists, a structure-based pharmacophore model collection was developed and theoretically evaluated against virtual databases including the ChEMBL database. The most suitable models were used to screen the National Cancer Institute (NCI) database. Biological evaluation of virtual hits led to the discovery of a novel FXR agonist with a piperazine scaffold (compound 19) that shows comparable activity as the endogenous FXR agonist chenodeoxycholic acid (CDCA, compound 2). PMID:22018919

Schuster, Daniela; Markt, Patrick; Grienke, Ulrike; Mihaly-Bison, Judit; Binder, Markus; Noha, Stefan M.; Rollinger, Judith M.; Stuppner, Hermann; Bochkov, Valery N.; Wolber, Gerhard



Facult des arts et des sciences cole de bibliothconomie et des sciences de l'information  

E-print Network

Faculté des arts et des sciences �cole de bibliothéconomie et des sciences de l'information COMMUNIQU� POUR DIFFUSION IMM�DIATE Aïda Chebbi, nouvelle docteure en sciences de l'information Montréal, le 26 février 2013 - L'�cole de bibliothéconomie et des sciences de l'information (EBSI) de l

Parrott, Lael


Facult des arts et des sciences cole de bibliothconomie et des sciences de l'information  

E-print Network

Faculté des arts et des sciences �cole de bibliothéconomie et des sciences de l'information POURQ. Montréal, le 17 octobre 2014 -- L'�cole de bibliothéconomie et des sciences de l'information (EBSI) de l aux missions de BAnQ. Madame Majela Guzmán Gómez réalise actuellement son doctorat en sciences de l'information

Parrott, Lael


Facult des arts et des sciences cole de bibliothconomie et des sciences de l'information  

E-print Network

Faculté des arts et des sciences �cole de bibliothéconomie et des sciences de l'information POUR l'information à l'EBSI Montréal, le 18 février 2014 -- L'�cole de bibliothéconomie et des sciences première �cole d'été internationale de la Francophonie en sciences de l'information, du 2 au 11 juillet

Leclercq, Remi


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



Multivalent design of long-acting ?(2)-adrenoceptor agonists incorporating biarylamines.  


A series of potent ?2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical ?2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human ?2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting ?2-agonist discovery programs. PMID:24813741

Jacobsen, John R; Aggen, James B; Church, Timothy J; Klein, Uwe; Pfeiffer, Juergen W; Pulido-Rios, Teresa M; Thomas, G Roger; Yu, Cecile; Moran, Edmund J



Food intake and rumen motility in dwarf goats. Effects of some serotonin receptor agonists and antagonists  

Microsoft Academic Search

The serotonergic regulation of feeding behaviour has not so far been studied in ruminants. Therefore, the effects of some serotonin (5-HT) receptor agonists and antagonists on food intake and forestomach motility were studied in dwarf goats.

F. Kaya; C. T. M. van Duin; G. H. Veenendaal; A. S. J. P. A. M. van Miert



Pleuropulmonary fibrosis after long-term treatment with the dopamine agonist pergolide for Parkinson Disease.  


Dopamine agonists are increasingly used in the treatment of Parkinson disease, but they may cause serious adverse effects. In December 1983, symptoms of Parkinson disease developed in a 55-year-old man with no history of pulmonary disease, smoking, or asbestos exposure. He began treatment with dopamine agonists bromocriptine mesylate (in 1984) and pergolide mesylate (in 1989). In late 2000, pulmonary symptoms developed. Chest radiographs and computed tomographic findings showed a mass in the right upper lobe and effusion. A biopsy specimen showed pleural and parenchymal fibrosis. This syndrome resolved after cessation of pergolide therapy and a switch to pramipexole dihydrochloride. This case draws attention to the association of long-term ergot dopamine agonist therapy with pleuropulmonary fibrosis, which can develop as late as 11 years after the initiation of therapy. We also review evidence that the risk of this complication is substantially lower with the newer nonergot dopamine agonists. PMID:16087771

Tintner, Ron; Manian, Prasad; Gauthier, Polly; Jankovic, Joseph



nAChR agonist-induced cognition enhancement: Integration of cognitive and neuronal mechanisms  

E-print Network

Review nAChR agonist-induced cognition enhancement: Integration of cognitive and neuronal for cognition enhancers . . . . . . . . . . . . . . . . . . . . . 661 5. Circuitry model for signal detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664 1. Introduction Drug-induced improvement of the cognitive capacities of patients suffering from


New Agonists / Antagonists for Toll-like Receptors (TLR7 and TLR9)  

E-print Network

New Agonists / Antagonists for Toll-like Receptors (TLR7 and TLR9) Technologieangebot B 67104 activity is observed. Industrial Sector Pharmaceutigs & Medicine Key Words TLR9, TLR7, Toll-like receptors


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

Technology Transfer Automated Retrieval System (TEKTRAN)

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


Red dominates black: agonistic signalling among head morphs in the colour polymorphic  

E-print Network

in the Gouldian finch (Erythrura gouldiae), a species displaying three completely discrete but naturally co polymorphism; Gouldian finch; male competition; status signalling; melanin; carotenoids 1. INTRODUCTIONRed dominates black: agonistic signalling among head morphs in the colour polymorphic Gouldian


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

PubMed Central

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

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



Structure-dependent Ah receptor agonist activities of chlorinated biphenylenes.  


Polychlorinated biphenylenes (PCBP) have been identified as combustion by-products that bind the aryl hydrocarbon receptor (AhR) and exhibit 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-like activity. This study investigates the Ah-responsiveness of 2,3,6,7-tetrachlorobiphenylene (2,3,6,7-CBP), 2,3,6-CBP, 2,3-CBP and 2-CBP in breast cancer cells. MCF-7 or ZR-75 cells were treated with different concentrations (1-100 nM) of the compounds alone to determine their activity as inducers of CYP1A1 protein expression or luciferase activity in cells transfected with a construct (pDRE(3)) containing three tandem dioxin responsive elements (DREs) linked to a luciferase reporter gene. In both assays, the order of potency was 2,3,6,7-CBP>2,3,6-CBP>2,3-CBP approximately 2-CBP, and 2,3,6,7-CBP and TCDD were equipotent. Similar results were also observed in an antiestrogenic assay in MCF-7 cells, confirming the high AhR agonist activity of 2,3,6,7-CBP in breast cancer cells. PMID:16759834

Khan, Shaheen; Konstantinov, Alex; Chittim, Brock; McAlees, Alan; Yeo, Brian; Safe, Stephen



The Vanilloid Agonist Resiniferatoxin for Interventional-Based Pain Control  

PubMed Central

The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as subcutaneous, intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the molecular and preclinical animal experiments that form the underpinnings of our clinical trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiological actions, and the molecular biology of the capsaicin receptor TRPV1. PMID:21671877

Iadarola, Michael J.; Mannes, Andrew J.



Agonist Derived Molecular Probes for A2A Adenosine Receptors  

PubMed Central

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

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



Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization  

PubMed Central

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



Ontogenesis of agonistic vocalizations in the cichlid fish Metriaclima zebra.  


While acoustic communication has been described in adults of various fish species, our knowledge about the ontogeny of fish sound production is limited. In adults, sound signals are known to be involved during aggressive interactions. However, aggressive behaviour may appear early in the life of fishes due to the possible competition for food and space. If acoustic signals are used to send information to competitors, sounds are likely to play a role during interactions between juvenile fish as well. The apparition and evolution of sound production were monitored in a group of juveniles of the cichlid fish Metriaclima zebra from hatching to 4 months of age. In addition, the link between vocalizations and agonistic behaviour was studied during dyadic interactions at three different ages. Sounds production appeared to be present early in the development of this fish and increased along with the number of aggressive behaviours. Recorded sounds consisted, in juveniles, in isolated pulses showing a decrease in frequency and duration as the fish grew. In adults, sounds became bursts of pulses but the transition from isolated to repetitive pulses was not observed. These results are compared to the existing literature on sound production ontogeny in fishes. PMID:22938919

Bertucci, Frédéric; Scaion, Delphine; Beauchaud, Marilyn; Attia, Joël; Mathevon, Nicolas



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



Competitive molecular docking approach for predicting estrogen receptor subtype ? agonists and antagonists  

PubMed Central

Background Endocrine disrupting chemicals (EDCs) are exogenous compounds that interfere with the endocrine system of vertebrates, often through direct or indirect interactions with nuclear receptor proteins. Estrogen receptors (ERs) are particularly important protein targets and many EDCs are ER binders, capable of altering normal homeostatic transcription and signaling pathways. An estrogenic xenobiotic can bind ER as either an agonist or antagonist to increase or inhibit transcription, respectively. The receptor conformations in the complexes of ER bound with agonists and antagonists are different and dependent on interactions with co-regulator proteins that vary across tissue type. Assessment of chemical endocrine disruption potential depends not only on binding affinity to ERs, but also on changes that may alter the receptor conformation and its ability to subsequently bind DNA response elements and initiate transcription. Using both agonist and antagonist conformations of the ER?, we developed an in silico approach that can be used to differentiate agonist versus antagonist status of potential binders. Methods The approach combined separate molecular docking models for ER agonist and antagonist conformations. The ability of this approach to differentiate agonists and antagonists was first evaluated using true agonists and antagonists extracted from the crystal structures available in the protein data bank (PDB), and then further validated using a larger set of ligands from the literature. The usefulness of the approach was demonstrated with enrichment analysis in data sets with a large number of decoy ligands. Results The performance of individual agonist and antagonist docking models was found comparable to similar models in the literature. When combined in a competitive docking approach, they provided the ability to discriminate agonists from antagonists with good accuracy, as well as the ability to efficiently select true agonists and antagonists from decoys during enrichment analysis. Conclusion This approach enables evaluation of potential ER biological function changes caused by chemicals bound to the receptor which, in turn, allows the assessment of a chemical's endocrine disrupting potential. The approach can be used not only by regulatory authorities to perform risk assessments on potential EDCs but also by the industry in drug discovery projects to screen for potential agonists and antagonists. PMID:25349983



des ateliers artistiques  

E-print Network

trompe-l'oeil... Des peaux brûlées en mal d'amour et de repères dans un monde ordinaire, étouffant'est-ce pas la même chose dans une histoire d'amour ? du 10 au 21 juin exposition de l'Atelier photo paris 6


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



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?



?7 Receptor-selective agonists and modes of ?7 receptor activation  

Microsoft Academic Search

The ?7-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) ?7-type receptor, to

Roger L. Papke; Edwin Meyer; Tom Nutter; Vladimir V. Uteshev



Increased Risk of Pneumonia in Patients Receiving Gonadotropin-Releasing Hormone Agonists for Prostate Cancer  

PubMed Central

Background This study aimed to investigate the relationship between the use of gonadotropin-releasing hormone (GnRH) agonists and subsequent risk of pneumonia in patients with prostate cancer (PC) using a population-based dataset. Methods We obtained the data from Taiwan's Longitudinal Health Insurance Database 2000. We included 2064 PC in this study. Of the sampled PC patients, 1207 received treatment with GnRH agonists. We individually traced each PC patient for a 1-year period to identify those who were hospitalized with pneumonia. We performed a Cox proportional hazard regression to explore the association between the use of GnRH agonists and the risk of pneumonia during the 1-year follow-up period. Results Incidence rates of pneumonia during the 1-year follow-up period were 4.35 (95% confidence interval (CI): 1.89?9.64) per 100 person-years and 2.14 (95% CI: 1.31?3.32) per 100 person-years for PC patients who did and those who did not receive treatment with GnRH agonists, respectively. The log-rank test suggested that there was a significant difference in the 1-year pneumonia-free survival rate between PC patients who did and those who did not receive treatment with GnRH agonists (p<0.002). After adjusting for age, monthly income, and the Charlson Comorbidities Index score, PC patients who received treatment with GnRH agonists were more likely to have been hospitalized for pneumonia during the 1-year follow-up period than PC patients who did not receive treatment with GnRH agonists (hazard ratio: 1.92, 95% CI: 1.10?3.36). Conclusions PC patients who received treatment with GnRH agonists had an increased risk of pneumonia. PMID:24971988

Lin, Herng-Ching; Wang, Li-Hsuan



The risk of new onset heart failure associated with dopamine agonist use in Parkinson's disease.  


The aim of present study was to investigate the risk of heart failure associated with dopamine agonist use in patients with Parkinson's disease. The data sources of this study were four different population-based, healthcare databases in United Kingdom, Italy and Netherlands. A case control study nested within a cohort of Parkinson's disease patients who were new users of either dopamine agonist or levodopa was conducted. Incident cases of heart failure were identified and validated, using Framingham criteria. Controls were matched to cases on age, gender and database. To estimate the risk of newly diagnosed heart failure with ergot and non-ergot derived dopamine agonists, as compared to levodopa, odds ratios and 95% confidence intervals were calculated through conditional logistic regression. In the cohort of 25,459 Parkinson's disease patients (11,151 new users of dopamine agonists, 14,308 new users of levodopa), 518 incident heart failure cases were identified during follow-up. Compared to levodopa, no increased risk of heart failure was found for ergot dopamine agonists (odds ratio: 1.03; 95% confidence interval: 0.69-1.55). Among non-ergot dopamine agonists, only pramipexole was associated with an increased risk of heart failure (odds ratio: 1.61; 95%confidence interval: 1.09-2.38), especially in the first three months of therapy (odds ratio: 3.06; 95% confidence interval: 1.74-5.39) and in patients aged 80 years and older (odds ratio: 3.30; 95% confidence interval: 1.62-7.13). The results of this study indicate that ergot dopamine agonist use in Parkinson's disease patients was not associated with an increased risk of newly diagnosed heart failure. Among non-ergot dopamine agonists, we observed a statistically significant association between pramipexole use and heart failure, especially during the first months of therapy and in very old patients. PMID:22123498

Mokhles, M Mostafa; Trifirò, Gianluca; Dieleman, Jeanne P; Haag, Mendel D; van Soest, Eva M; Verhamme, Katia M C; Mazzaglia, Giampiero; Herings, Ron; Luise, Cynthia de; Ross, Douglas; Brusselle, Guy; Colao, Annamaria; Haverkamp, Willem; Schade, Rene; Camp, Guy van; Zanettini, Renzo; Sturkenboom, Miriam C J M



The Efficacy of a NOP1 Agonist (SCH486757) in Subacute Cough  

Microsoft Academic Search

Currently, opiates are widely used as antitussives but have substantial side effects. Recently, it has been proposed that\\u000a NOP1 receptor agonists may be useful as a novel approach to cough suppression. Therefore, we compared the effect of NOP1 receptor\\u000a agonist SCH486757 with matched placebo and codeine in a multicentre, double-blind, parallel-group study in patients with subacute\\u000a cough. The primary outcome

Ashley Woodcock; Robbie L. McLeod; Jonathan Sadeh; Jaclyn A. Smith



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

Microsoft Academic Search

The agonist actions of seven commercial neonicotinoid insecticides and nicotine were studied on nicotinic acetylcholine receptors (nAChRs) expressed by neurons isolated from the three thoracic ganglia of the American cockroach, Periplaneta americana. Single electrode voltage clamp recording was used to measure agonist-induced inward currents. Acetylcholine, nicotine and all neonicotinoids tested, except thiamethoxam, caused inward currents which were blocked reversibly by

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



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



Inhaled adenosine A 2A receptor agonists for the treatment of chronic obstructive pulmonary disease  

Microsoft Academic Search

COPD is a major cause of mortality in the western world. A2A agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A2A agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR

Simon J. Mantell; Peter T. Stephenson; Sandra M. Monaghan; Graham N. Maw; Michael A. Trevethick; Michael Yeadon; Ruth F. Keir; Don K. Walker; Rhys M. Jones; Matthew D. Selby; David V. Batchelor; Stuart Rozze; Helene Chavaroche; Tim J. Hobson; Peter G. Dodd; Arnaud Lemaitre; Karen N. Wright; Emilio F. Stuart



Agonist-induced Isomerization in a Glutamate Receptor Ligand-binding Domain  

Microsoft Academic Search

Agonist binding to glutamate receptor ion channels occurs within an extracellular domain (S1S2) that re- tains ligand affinity when expressed separately. S1S2 is homologous to periplasmic binding proteins, and it has been proposed that a Venus flytrap-style cleft closure triggers opening of glutamate receptor ion channels. Here we compare the kinetics of S1S2-agonist binding to those of the periplasmic binding

Rupert Abele; Kari Keinanen; Dean R. Madden


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



Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells  

Microsoft Academic Search

BACKGROUND: LXRs (Liver X Receptor ? and ?) are nuclear receptors that act as ligand-activated transcription factors. LXR activation causes upregulation of genes involved in reverse cholesterol transport (RCT), including ABCA1 and ABCG1 transporters, in macrophage and intestine. Anti-atherosclerotic effects of synthetic LXR agonists in murine models suggest clinical utility for such compounds. OBJECTIVE: Blood markers of LXR agonist exposure\\/activity

Elizabeth A DiBlasio-Smith; Maya Arai; Elaine M Quinet; Mark J Evans; Tad Kornaga; Michael D Basso; Liang Chen; Irene Feingold; Anita R Halpern; Qiang-Yuan Liu; Ponnal Nambi; Dawn Savio; Shuguang Wang; William M Mounts; Jennifer A Isler; Anna M Slager; Michael E Burczynski; Andrew J Dorner; Edward R LaVallie



The D 1 dopamine agonist SKF 38393 functions as a discriminative stimulus in rats  

Microsoft Academic Search

Rats (N=11) were trained to discriminate SKF 38393 (8.0 mg\\/kg, IP), a D1 dopamine receptor agonist, from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. The discrimination was acquired by nine rats within an average of 77±6 (SEM) sessions. Subsequently, various doses of SKF 38393 as well as SKF 82526, a potent, selective D1 agonist that does not

Jonathan B. Kamien; William L. Woolverton



Synthesis and structure–activity relationships of a series of pyrrole cannabinoid receptor agonists  

Microsoft Academic Search

We designed and synthesized a series of pyrrole derivatives with the aim of investigating the structure–activity relationship (SAR) for the binding of non-classical agonists to CB1 and CB2 cannabinoid receptors. Superposition of two pyrrole-containing cannabinoid agonists, JWH-007 and JWH-161, allowed us to identify positions 1, 3 and 4 of the pyrrole nucleus as amenable to additional investigation. We prepared the

Giorgio Tarzia; Andrea Duranti; Andrea Tontini; Gilberto Spadoni; Marco Mor; Silvia Rivara; Pier Vincenzo Plazzi; Satish Kathuria; Daniele Piomelli



Azepinone as a conformational constraint in the design of kappa-opioid receptor agonists.  


A new class of kappa-opioid receptor agonists is described. The design of these agents was based upon energy minimization and structural overlay studies of the generic azepin-2-one structure 3 with the crystal structure of arylacetamide kappa agonist 1, ICI 199441. The most active compound identified was ligand 4a (K(i)=0.34 nM), which demonstrated potent antinociceptive activity after oral administration in rodents. PMID:15482950

Tuthill, Paul A; Seida, Pamela R; Barker, William; Cassel, Joel A; Belanger, Serge; DeHaven, Robert N; Koblish, Michael; Gottshall, Susan L; Little, Patrick J; DeHaven-Hudkins, Diane L; Dolle, Roland E



Discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB2 agonists.  


Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB(2) agonists. Selective CB(2) agonist 31 (K(i)=2.7; CB(1)/CB(2)=190) displayed robust activity in a rodent model of postoperative pain. PMID:19646869

Worm, Karin; Weaver, Damian G; Green, Rosalyn C; Saeui, Christopher T; Dulay, Doreen-Marie S; Barker, William M; Cassel, Joel A; Stabley, Gabriel J; DeHaven, Robert N; LaBuda, Christopher J; Koblish, Michael; Brogdon, Bernice L; Smith, Steven A; Dolle, Roland E



Distinguishing a benzodiazepine agonist (triazolam) from a nonagonist anxiolytic (buspirone) by electroencephalography: Kinetic-dynamic studies  

Microsoft Academic Search

Background and objectives: Benzodiazepine agonists and azaperone derivatives are used clinically as anxiolytics but have different neuroreceptor mechanisms of action. This study evaluated clinical pharmacodynamic approaches to distinguishing these two classes of compounds.Methods: Healthy volunteers received single oral doses of placebo, the benzodiazepine agonist triazolam (0.25 mg) or the azaperone anxiolytic buspirone (20 mg), in a double-blind, three-way crossover study.

David J Greenblatt; Jerold S Harmatz; Terry A Gouthro; Jenifer Locke; Richard I Shader



Rapid access towards follow-up NOP receptor agonists using a knowledge based approach.  


A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel. PMID:19818611

Palin, Ronald; Clark, John K; Evans, Louise; Feilden, Helen; Fletcher, Dan; Hamilton, Niall M; Houghton, Andrea K; Jones, Philip S; McArthur, Duncan; Montgomery, Brian; Ratcliffe, Paul D; Smith, Alasdair R C; Sutherland, Aaron; Weston, Mark A; Wishart, Grant



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

PubMed Central

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

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



Quelques propriétés des théories de Jonsson  

Microsoft Academic Search

On étudie les propriétés des théories de Jonsson et des conditions nécessaires afin que des théories soient de Jonsson ; on caractérise les théories de Jonsson cosémantiques c’est-à-dire ayant un modèle homogène universel commun ainsi que certaines théories complètes contenant des théories de Jonsson. On donne des exemples de certaines situations.

Yerulan Mustafin



Flow-injection chemiluminescence method to detect a ?2 adrenergic agonist.  


A new method for the detection of ?2 adrenergic agonists was developed based on the chemiluminescence (CL) reaction of ?2 adrenergic agonist with potassium ferricyanide-luminol CL. The effect of ?2 adrenergic agonists including isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine on the CL intensity of potassium ferricyanide-luminol was discovered. Detection of the ?2 adrenergic agonist was carried out in a flow system. Using uniform design experimentation, the influence factors of CL were optimized. The optimal experimental conditions were 1?mmol/L of potassium ferricyanide, 10?µmol/L of luminol, 1.2?mmol/L of sodium hydroxide, a flow speed of 2.6?mL/min and a distance of 1.2?cm from 'Y2 ' to the flow cell. The linear ranges and limit of detection were 10-100 and 5?ng/mL for isoprenaline hydrochloride, 20-100 and 5?ng/mL for salbutamol sulfate, 8-200 and 1?ng/mL for terbutaline sulfate, 20-100 and 4?ng/mL for ractopamine, respectively. The proposed method allowed 200 injections/h with excellent repeatability and precision. It was successfully applied to the determination of three ?2 adrenergic agonists in commercial pharmaceutical formulations with recoveries in the range of 96.8-98.5%. The possible CL reaction mechanism of potassium ferricyanide-luminol-?2 adrenergic agonist was discussed from the UV/vis spectra. Copyright © 2014 John Wiley & Sons, Ltd. PMID:24830367

Zhang, Guangbin; Tang, Yuhai; Shang, Jian; Wang, Zhongcheng; Yu, Hua; Du, Wei; Fu, Qiang



Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody  

PubMed Central

Background Selective neutralization of the IL21/IL21R signaling pathway is a promising approach for the treatment of a variety of autoimmune diseases. Ab-01 is a human neutralizing anti-IL21R antibody. In order to ensure that the activities of Ab-01 are restricted to neutralization even under in vitro cross-linking and in vivo conditions, a comprehensive assessment of agonistic potential of Ab-01 was undertaken. Methods In vitro antibody cross-linking and cell culture protocols reported for studies with a human agonistic antibody, TGN1412, were followed for Ab-01. rhIL21, the agonist ligand of the targeted receptor, and cross-linked anti-CD28 were used as positive controls for signal transduction. In vivo agonistic potential of Ab-01 was assessed by measuring expression levels of cytokine storm-associated and IL21 pathway genes in blood of cynomolgus monkeys before and after IV administration of Ab-01. Results Using a comprehensive set of assays that detected multiple activation signals in the presence of the positive control agonists, in vitro Ab-01-dependent activation was not detected in either PBMCs or the rhIL21-responsive cell line Daudi. Furthermore, no difference in gene expression levels was detected in blood before and after in vivo Ab-01 dosing of cynomolgus monkeys. Conclusions Despite efforts to intentionally force an agonistic signal from Ab-01, none could be detected. PMID:20504348



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



Low sensitivity of the positron emission tomography ligand [11C]diprenorphine to agonist opiates.  


Previously, we reported minimal opioid receptor occupancy following a clinical dose of the micro-opioid agonist, methadone, measured in vivo using positron emission tomography (PET) with [(11)C]diprenorphine and subsequently used rats to obtain experimental data in support of a high receptor reserve hypothesis (Melichar et al., 2005). Here, we report on further preclinical studies investigating opioid receptor occupancy with oxycodone (micro- and kappa-receptor agonist), morphine (micro-receptor agonist), and buprenorphine (partial agonist at the micro-receptor and antagonist at the delta- and kappa-receptors), each given at antinociceptive doses. In vivo binding of [(11)C]diprenorphine was not significantly reduced after treatment with the full agonists but was reduced by approximately 90% by buprenorphine. In addition, given that [(11)C]diprenorphine is a non-subtype-specific PET tracer, there was no regional variation that might feasibly be interpreted as due to differences in opioid subtype distribution. The data support minimal competition between the high-efficacy agonists and the non-subtype-selective antagonist radioligand and highlight the limitations of [(11)C]diprenorphine PET to monitor in vivo occupancy. Alternative means may be needed to address clinical issues regarding opioid receptor occupancy that are required to optimize treatment strategies. PMID:17488881

Hume, Susan P; Lingford-Hughes, Anne R; Nataf, Valerie; Hirani, Ella; Ahmad, Rabia; Davies, Andrew N; Nutt, David J



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


Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans. PMID:23421672

Lin, Ann P; Ko, Mei-Chuan



?-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



fevrier 2012 Journes Francophones des Langages Applicatifs JFLA12 Separation des couleurs dans un -calcul bichrome  

E-print Network

AlligatorEggs3 cherche `a expliquer le -calcul `a des enfants. Pour cela il utilise la couleur pour relier des alligators affam´es et des oeufs afin de constituer des familles. La couleur sert `a expliciter les liaisons des variables dans les termes, des oeufs naissent de nouveaux alligators ou familles lors

Paris-Sud XI, Université de


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; Müller, Christa E.; Yang, Huaiyu; Jiang, Hualiang; Cherezov, Vadim; Katritch, Vsevolod; Jacobson, Kenneth A.; Stevens, Raymond C.; Wu, Beili; Zhao, Qiang



Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPAR? agonist.  


The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPAR? (peroxisome-proliferator-activated receptor ?), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPAR? systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPAR? in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)-PPAR?. Direct binding of FPP to PPAR? was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPAR? target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPAR?-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPAR?-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPAR? agonist and regulate gene expression in adipocytes. PMID:21605082

Goto, Tsuyoshi; Nagai, Hiroyuki; Egawa, Kahori; Kim, Young-Il; Kato, Sota; Taimatsu, Aki; Sakamoto, Tomoya; Ebisu, Shogo; Hohsaka, Takahiro; Miyagawa, Hiroh; Murakami, Shigeru; Takahashi, Nobuyuki; Kawada, Teruo



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



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; Grötzinger, Joachim; Jacques, Yannick; Goormaghtigh, Erik; Devreese, Bart; Content, Jean



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.



Interleukin 2 production, not the pattern of early T-cell antigen receptor-dependent tyrosine phosphorylation, controls anergy induction by both agonists and partial agonists.  

PubMed Central

Full activation of T cells requires signaling through the T-cell antigen receptor (TCR) and additional surface molecules interacting with ligands on the antigen-presenting cell. TCR recognition of agonist ligands in the absence of accessory signals frequently results in the induction of a state of unresponsiveness termed anergy. However, even in the presence of costimulation, anergy can be induced by TCR partial agonists. The unique pattern of early receptor-induced tyrosine phosphorylation events induced by partial agonists has led to the hypothesis that altered TCR signaling is directly responsible for the development of anergy. Here we show that anergy induction is neither correlated with nor irreversibly determined by the pattern of early TCR-induced phosphorylation. Rather, it appears to result from the absence of downstream events related to interleukin 2 receptor occupancy and/or cell division. This implies that the anergic state can be manipulated independently of the precise pattern of early biochemical changes following TCR occupancy, a finding with implications for understanding the induction of self-tolerance and the use of partial agonist ligands in the treatment of autoimmune diseases. Images Fig. 2 Fig. 4 PMID:8790400

Madrenas, J; Schwartz, R H; Germain, R N



The Efficiency of CD4 Recruitment to Ligand-engaged TCR Controls the Agonist\\/Partial Agonist Properties of Peptide-MHC Molecule Ligands  

Microsoft Academic Search

Summary One hypothesis seeking to explain the signaling and biological properties of T cell receptor for antigen (TCR) partial agonists and antagonists is the coreceptor density\\/kinetic model, which proposes that the pharmacologic behavior of a TCR ligand is largely determined by the relative rates of ( a ) dissociation of ligand from an engaged TCR and ( b ) recruitment

Joaquín Madrenas; Luan A. Chau; Judy Smith; Jeffrey A. Bluestone; Ronald N. Germain



Role of mu opioid receptor reserve and mu agonist efficacy as determinants of mu agonist effects on intracranial self-stimulation in rats  

PubMed Central

The net effect of mu opioid receptor agonists on intracranial self-stimulation (ICSS) in rats reflects an integration of rate-increasing and rate-decreasing effects. Prior opioid exposure is associated with tolerance to rate-decreasing effects and augmented expression of abuse-related rate-increasing effects. This finding was replicated here with morphine. Subsequent studies then tested the hypothesis that opioid agonist-induced rate-decreasing effects require activation of a larger relative fraction of mu receptors, and hence are more vulnerable to tolerance-associated reductions in receptor density, than rate-increasing effects. Two sets of experiments were conducted to test this hypothesis. First, morphine effects on ICSS were examined after pretreatment with the irreversible mu antagonist ?-funaltrexamine (?-FNA) to reduce density of available mu receptors. Second, effects were examined for a range of mu opioids that varied in relative efficacy at mu receptors. The hypothesis predicted that (a) morphine after ?-FNA treatment or (b) low-efficacy mu agonists would mimic effects of morphine tolerance to produce reduced expression of rate-decreasing effects and enhanced expression of rate-increasing effects. Neither of these predictions was supported. These results suggest that mu agonist-induced facilitation and depression of ICSS may be mediated by distinct populations of mu receptors that respond differently to regimens of opioid exposure. PMID:22914074

Altarifi, Ahmad A.; Miller, Laurence L.; Negus, S. Stevens



RXR Partial Agonist Produced by Side Chain Repositioning of Alkoxy RXR Full Agonist Retains Antitype 2 Diabetes Activity without the Adverse Effects.  


We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5. PMID:25486327

Kawata, Kohei; Morishita, Ken-Ichi; Nakayama, Mariko; Yamada, Shoya; Kobayashi, Toshiki; Furusawa, Yuki; Arimoto-Kobayashi, Sakae; Oohashi, Toshitaka; Makishima, Makoto; Naitou, Hirotaka; Ishitsubo, Erika; Tokiwa, Hiroaki; Tai, Akihiro; Kakuta, Hiroki



Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer.  


Androgen deprivation therapy (ADT) resulting in testosterone suppression is central to the management of prostate cancer (PC). As PC incidence increases, ADT is more frequently prescribed, and for longer periods of time as survival improves. Initial approaches to ADT included orchiectomy or oral estrogen (diethylstilbestrol [DES]). DES reduces PC-specific mortality, but causes substantial cardiovascular (CV) toxicity. Currently, luteinizing hormone-releasing hormone agonists (LHRHa) are mainly used; they produce low levels of both testosterone and estrogen (as estrogen in men results from the aromatization of testosterone), and many toxicities including osteoporosis, fractures, hot flashes, erectile dysfunction, muscle weakness, increased risk for diabetes, changes in body composition, and CV toxicity. An alternative approach is parenteral estrogen, it suppresses testosterone, appears to mitigate the CV complications of oral estrogen by avoiding first-pass hepatic metabolism, and avoids complications caused by estrogen deprivation. Recent research on the toxicity of ADT and the rationale for revisiting parenteral estrogen is discussed. PMID:24932461

Phillips, Iain; Shah, Syed I A; Duong, Trinh; Abel, Paul; Langley, Ruth E



Select G-protein coupled receptors modulate agonist-induced signaling via a ROCK, LIMK and ?-arrestin 1 pathway  

PubMed Central

G-protein coupled receptors (GPCRs) are typically present in a basal, inactive state, but when bound to agonist they activate downstream signaling cascades. In studying arrestin regulation of opioid receptors in dorsal root ganglia (DRG) neurons, we find that agonists of delta opioid receptors (?ORs) activate cofilin through Rho-associated coiled-coiled containing protein kinase (ROCK), LIM domain kinase (LIMK) and ?- arrestin 1 (?-arr1), to regulate actin polymerization. This controls receptor function, as assessed by agonist-induced inhibition of voltage-dependent Ca2+ channels in DRGs. Agonists of opioid-receptor like receptors (ORL1) similarly influence the function of this receptor through ROCK, LIMK and ?-arr1. Functional evidence of this cascade was demonstrated in vivo where the behavioral effects of ?OR or ORL1 agonists were enhanced in the absence of ?-arr1 or prevented by inhibiting ROCK. This pathway allows ?OR and ORL1 agonists to rapidly regulate receptor function. PMID:24239352

Mittal, Nitish; Roberts, Kristofer; Pal, Katsuri; Bentolila, Laurent A.; Fultz, Elissa; Minasyan, Ani; Cahill, Catherine; Pradhan, Amynah; Conner, David; DeFea, Kathryn; Evans, Christopher; Walwyn, Wendy



Dopamine agonists, anti-progestins, anti-androgens, long-term-release GnRH agonists and anti-estrogens in canine reproduction: a review.  


Over the last 10 years, new drugs have been applied to canine reproduction, widening the spectrum of therapeutic possibilities for diseases that were previously surgically treated, and facilitating better control of the estrous cycle and fertility. Some are not approved for use in dogs; their use is experimental and further clinical trials are necessary. Dopamine agonists such as cabergoline, bromocriptine or metergoline are ergoderivative alkaloids that exert an anti-prolactinergic effect via stimulation of D2 pituitary receptors or inhibition of central serotoninergic ones. Their main indication is suppression of lactation. Anti-prolactinergic compounds have also been successfully used for pregnancy termination and shortening of interestrous intervals. Anti-progestins, (e.g. mifepristone and aglepristone) are synthetic steroids that bind with high affinity to progesterone (P4) receptors, preventing P4 from exerting its biological effects. Anti-progestins have been indicated in P4-dependent conditions, such as pregnancy termination, induction of parturition and the medical treatment of pyometra. Several groups of drugs have been described to have anti-androgenic properties through different mechanisms of action: progestins, receptor binding anti-androgens (e.g. flutamide), competitive enzyme inhibitors (e.g. finasteride), aromatase inhibitors, and GnRH agonists. Their main application is medical treatment of benign prostatic hyperplasia. Long-term release formulations of GnRH agonists (e.g. leuprolide or deslorelin acetate) postponed puberty and reversibly suppressed reproductive function in male and female dogs for periods exceeding 1 year. Anti-estrogens (e.g. clomiphene and tamoxifen citrate) are synthetic non-steroidal type I anti-estrogenic compounds that competitively block estrogen receptors with a combined antagonist-agonistic effect. In dogs, their action is more agonistic than antagonistic. PMID:16542717

Gobello, C



Evaluation of the D3 Dopamine Receptor Selective Agonist/Partial Agonist PG01042 on L-Dopa Dependent Animal Involuntary Movements in Rats  

PubMed Central

The substituted 4-phenylpiperazine D3 dopamine receptor selective antagonist PG01037 ((E)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-(pyridin-2-yl)benzamide) was reported to attenuate L-dopa associated abnormal involuntary movements (AIMs) in unilaterally lesioned rats, a model of L-dopa-dependent dyskinesia in patients with Parkinson’s Disease (Kumar et al., 2009a). We now report that PG01042 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-3-yl)benzamide), which is a D3 dopamine receptor selective agonist for adenylyl cyclase inhibition and a partial agonist for mitogenesis, is also capable of attenuating AIMs scores. The intrinsic activity of PG01037 and PG01042 were determined using a) a forskolin-dependent adenylyl cyclase inhibition assay and b) an assay for agonist-associated mitogenesis. It was observed that the in vivo efficacy of PG01042 increased when administered by intraperitoneal (i.p.) injection simultaneously with L-dopa/benserazide (8 mg/kg each), as compared to a 60 minute or 30 minute pretreatment. PG01042 was found to attenuate AIM scores in these animals in a dose dependent manner. While PG01042 did not effectively inhibit SKF 81297-dependent AIMs, it inhibited apomorphine-dependent AIM scores. Rotarod studies indicate that PG01042 at a dose of 10 mg/kg did not adversely affect motor coordination of the unilaterally lesioned rats. Evaluation of lesioned rats using a cylinder test behavioral paradigm indicated that PG01042 did not dramatically attenuate the beneficial effects of L-dopa. These studies and previously published studies suggest that both D3 dopamine receptor selective antagonists, partial agonists and agonists, as defined by an adenylyl cyclase inhibition assay and a mitogenic assay, are pharmacotherapeutic candidates for the treatment of L-dopa-associated dyskinesia in patients with Parkinson’s Disease. PMID:20850462

Riddle, Lindsay R.; Kumar, Rakesh; Griffin, Suzy A.; Grundt, Peter; Newman, Amy Hauck; Luedtke, Robert R.



The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats  

PubMed Central

Background Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats. Methods Fifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed. Results Whole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate. Conclusions The PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats. PMID:21615901



Agonists and antagonists bind to different domains of the cloned kappa opioid receptor.  

PubMed Central

Opium and its derivatives are potent analgesics that can also induce severe side effects, including respiratory depression and addiction. Opioids exert their diverse physiological effects through specific membrane-bound receptors. Three major types of opioid receptors have been described, termed delta, kappa, and mu. The recent molecular cloning of these receptor types opens up the possibility to identify the ligand-binding domains of these receptors. To identify the ligand-binding domains of the kappa and delta receptors, we have expressed in COS-7 cells the cloned mouse delta and kappa receptors and chimeric delta/kappa and kappa/delta receptors in which the NH2 termini have been exchanged. The opioid antagonist naloxone binds potently to wild-type kappa receptor but not to wild-type delta receptor. The kappa/delta chimera bound [3H]naloxone with high affinity. In contrast, the kappa-specific agonist [3H]U-69,593 did not bind to the kappa/delta chimera. These findings indicate that selective agonists and antagonists interact with different recognition sites in the kappa receptor and localize the antagonist-binding domain to the NH2 terminus. Consistent with the results of radioligand-binding studies, the kappa/delta chimera did not mediate kappa-agonist inhibition of cAMP formation. In contrast, the delta/kappa chimera did mediate kappa-agonist inhibition of cAMP formation, but this effect was not blocked by naloxone. Furthermore, a truncated kappa receptor lacking its NH2 terminus was able to mediate agonist inhibition of cAMP accumulation in a naloxone-insensitive manner. This result further indicates that the NH2 terminus of the kappa receptor contains the selective antagonist-binding domain. The ability to dissociate agonist- and antagonist-binding sites will facilitate the development of more specific kappa agonists, which could have analgesic properties devoid of side effects. PMID:8058754

Kong, H; Raynor, K; Yano, H; Takeda, J; Bell, G I; Reisine, T



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



Glucagon-like peptide-1 receptor agonist administration suppresses both water and saline intake in rats  

PubMed Central

Glucagon-like peptide-1 (GLP-1) plays an important role in energy homeostasis. Injections of GLP-1 receptor (GLP-1R) agonists suppress food intake, and endogenous GLP-1 is released when nutrients enter the gut. There is also growing evidence that the GLP-1 system is involved in the regulation of body fluid homeostasis. GLP-1R agonists suppress water intake independent of their effects on food intake. It is unknown, however, whether this suppressive effect of GLP-1R agonists extends to saline intake. Accordingly, we tested the effect of the GLP-1R agonists liraglutide (0.05 µg) and exendin-4 (0.05 µg) on water and saline intakes stimulated either by angiotensin II (AngII) or by water deprivation with partial rehydration (WD-PR). Each agonist suppressed AngII-induced water intake; however, only exendin-4 suppressed saline intake. WD-PR-induced water and saline intakes were both attenuated by each agonist. Analysis of drinking microstructure after WD-PR found a reliable effect of the agonists on burst number. Furthermore, exendin-4 conditioned a robust taste avoidance to saccharine; however, there was no similar effect of liraglutide. To evaluate the relevance of the conditioned taste avoidance, we tested whether inducing visceral malaise by injection of lithium chloride (LiCl) suppressed fluid intake. Injection of LiCl did not suppress water or saline intakes. Overall, these results indicate that the fluid intake suppression by GLP-1R activation is not selective to water intake, is a function of post-ingestive feedback, and is not secondary to visceral malaise. PMID:23957745

McKay, Naomi J.; Daniels, Derek



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



Selective ?4?2 Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons  

PubMed Central

Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD67) expression. Here we explored the impact of synthetic ?4?2 and ?7 nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at ?4?2 and a lower affinity full agonist at ?7 neuronal nAChR, injected in doses of 1–5?mg/kg/s.c. twice daily for 5 days, elicited a 30–40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD67 mRNA and protein. This upregulation of GAD67 was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP2 binding to GAD67 promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD67 expression were obtained after administration of A–85380, an agonist that binds to ?4?2 but has negligible affinity for ?3?4 or ?7 subtypes containing nAChR. In contrast, PNU–282987, an agonist of the homomeric ?7 nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD67 expression. The present study suggests that the ?4?2 nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the ?7 nAChR agonists. PMID:21368748

Maloku, Ekrem; Kadriu, Bashkim; Zhubi, Adrian; Dong, Erbo; Pibiri, Fabio; Satta, Rosalba; Guidotti, Alessandro



Geschichte des Widerstandes in Film und Fernsehen.  

E-print Network

??In der Diplomarbeit „Geschichte des Widerstandes in Film und Fernsehen“ wird die unterschiedliche Darstellungsweise des Stauffenberg-Attentats auf den „Führer“ Adolf Hitler vom 20. Juli 1944… (more)

Bauer, Marlies



Structural Determinants of Agonist Efficacy at the Glutamate Binding Site of N-Methyl-d-Aspartate Receptors  

PubMed Central

N-methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We used a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. Using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single-channel recordings, we show that propyl- and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (<1–72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits. PMID:23625947

Hansen, Kasper B.; Tajima, Nami; Risgaard, Rune; Perszyk, Riley E.; Jørgensen, Lars; Vance, Katie M.; Ogden, Kevin K.; Clausen, Rasmus P.



TIC et commerce lectronique : laboratoires de la libralisation des changes et des volutions des rgles  

E-print Network

1 TIC et commerce électronique : laboratoires de la libéralisation des échanges et des évolutions/Département Sciences Economiques et Sociales Les échanges internationaux de produits TIC et le commerce électroniques à terme à l'abolition des droits de douane pour les produits de la filière TIC et les échanges

Paris-Sud XI, Université de


Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation  

PubMed Central

Background Although there are successful examples of the discovery of new PPAR? agonists, it has recently been of great interest to identify new PPAR? partial agonists that do not present the adverse side effects caused by PPAR? full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPAR? partial agonists among natural products. Methodology/Principal Findings We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPAR? partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPAR? partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPAR? partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPAR? partial agonists: they bind to PPAR?, do not or only moderately stimulate the transactivation activity of PPAR?, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. Conclusions/Significance We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPAR? partial agonists. PMID:23226391

Guasch, Laura; Sala, Esther; Castell-Auví, Anna; Cedó, Lidia; Liedl, Klaus R.; Wolber, Gerhard; Muehlbacher, Markus; Mulero, Miquel; Pinent, Montserrat; Ardévol, Anna; Valls, Cristina; Pujadas, Gerard; Garcia-Vallvé, Santiago



Discovery of N-sulfonyl-7-azaindoline derivatives as potent, orally available and selective M(4) muscarinic acetylcholine receptor agonists.  


We designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1-10 mg/kg, po). PMID:24852118

Suwa, Atsushi; Konishi, Yasuko; Uruno, Yoshiharu; Takai, Kentaro; Nakako, Tomokazu; Sakai, Mutsuko; Enomoto, Takeshi; Ochi, Yoshiaki; Matsuda, Harumi; Kitamura, Atsushi; Uematsu, Yasuaki; Kiyoshi, Akihiko; Sumiyoshi, Takaaki



Localisation des salles UFR SLHS : Facult des Lettres  

E-print Network

Promotion Formation Recherche des Sports 31 rue de l'épitaphe, 25000 Besançon IUT: Institut Universitaire de'Observatoire 25000 Besançon UFR ST : Faculté des Sciences 16 route de Gray, 25000 Besançon UPFR Sports : Unité de

Jeanjean, Louis



E-print Network

épineux des DSSC. J'associe aussi à ces remerciements Yann Pellegrin et Errol Blart, qui ont été des personnes très sympathiques à rencontrer et qui ont rendus les réunions "DSSC" plus agréables, entre autre

Paris-Sud XI, Université de


Selective imidazoline agonist moxonidine in obese hypertensive patients.  


Obesity is the major risk factor for the development of hypertension. This association accentuates the risk of cardiovascular disease, as it is frequently accompanied by the components of the metabolic syndrome. This randomised open parallel study evaluated the chronic effects of moxonidine--a selective imidazoline receptor agonist--on blood pressure, plasma catecholamines, leptin, insulin and components of the metabolic syndrome in obese hypertensives. Amlodipine was used as the control drug. Our results showed that moxonidine and amlodipine significantly reduced blood pressure when measured using the oscillometric method and 24-hour blood pressure monitoring. Moxonidine therapy decreased systolic blood pressure from 160.4 +/- 2.4 to 142.1 +/- 3.3 mmHg (p < 0.005) and diastolic blood pressure from 102.4 +/- 1.3 to 89.7 +/- 1.6 mmHg (p < 0.005) after 24 weeks of treatment. Moxonidine administration reduced the supine arterial plasma levels of adrenaline from 63.2 +/- 6.6 to 49.0 +/- 6.7 pg/ml (p < 0.005), the supine arterial plasma levels of noradrenaline from 187.9 +/- 10.7 to 149.7 +/- 13.2 pg/ml (p < 0.01) and the orthostatic venous plasma levels of noradrenaline from 258.6 +/- 25.0 to 190.3 +/- 16.4 pg/ml (p = 0.03). Those variables were not changed by amlodipine. The plasma levels of leptin and insulin 120 min after a glucose load decreased after moxonidine administration from 27.2 +/- 3.5 to 22.6 +/- 2.9 pg/ml (p < 0.05) and from 139.7 +/- 31.2 to 76.0 +/- 15.2 U/ml (p < 0.05), respectively. Amlodipine, however, did not modify those variables. This study showed a comparable reduction in blood pressure with both antihypertensive drugs. Moxonidine decreased sympathetic nervous activity, improved insulin resistance and reduced the plasma levels of leptin. PMID:16700870

Sanjuliani, A F; de Abreu, V G; Francischetti, E A



Facult des arts et des sciences cole de bibliothconomie et des sciences de l'information  

E-print Network

Faculté des arts et des sciences �cole de bibliothéconomie et des sciences de l'information -- L'�cole de bibliothéconomie et des sciences de l'information (EBSI) de l'Université de Montréal est destinée aux étudiants de doctorat ou de maîtrise en sciences de l'information qui démontrent un intérêt

Parrott, Lael


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

PubMed Central

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

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



?2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model.  


?(2)-Adrenoceptor (?2AR) agonists are the most effective class of bronchodilators and a mainstay of asthma management. The first potent ?2AR agonist discovered and widely used in reversing the airway constriction associated with asthma exacerbation was the endogenous activator of the ?2AR, epinephrine. In this study, we demonstrate that activation of the ?2AR by epinephrine is paradoxically required for development of the asthma phenotype. In an antigen-driven model, mice sensitized and challenged with ovalbumin showed marked elevations in three cardinal features of the asthma phenotype: inflammatory cells in their bronchoalveolar lavage fluid, mucin over production, and airway hyperresponsiveness. However, genetic depletion of epinephrine using mice lacking the enzyme to synthesize epinephrine, phenylethanolamine N-methyltransferase, or mice that had undergone pharmacological sympathectomy with reserpine to deplete epinephrine, had complete attenuation of these three cardinal features of the asthma phenotype. Furthermore, administration of the long-acting ?2AR agonist, formoterol, a drug currently used in asthma treatment, to phenylethanolamine N-methyltransferase-null mice restored the asthma phenotype. We conclude that ?2AR agonist-induced activation is needed for pathogenesis of the asthma phenotype. These findings also rule out constitutive signaling by the ?2AR as sufficient to drive the asthma phenotype, and may help explain why chronic administration of ?2AR agonists, such as formoterol, have been associated with adverse outcomes in asthma. These data further support the hypothesis that chronic asthma management may be better served by treatment with certain "?-blockers." PMID:23204390

Thanawala, Vaidehi J; Forkuo, Gloria S; Al-Sawalha, Nour; Azzegagh, Zoulikha; Nguyen, Long P; Eriksen, Jason L; Tuvim, Michael J; Lowder, Thomas W; Dickey, Burton F; Knoll, Brian J; Walker, Julia K L; Bond, Richard A



Reconstitution of high-affinity opioid agonist binding in brain membranes  

SciTech Connect

In synaptosomal membranes from rat brain cortex, the {mu} selective agonist ({sup 3}H)dihydromorphine in the absence of sodium, and the nonselective antagonist ({sup 3}H)naltrexone in the presence of sodium, bound to two populations of opioid receptor sites with K{sub d} values of 0.69 and 8.7 nM for dihydromorphine, and 0.34 and 5.5 nM for naltrexone. The addition of 5 {mu}M guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)) strongly reduced high-affinity agonist but not antagonist binding. Exposure of the membranes to high pH reduced the number of GTP({gamma}-{sup 35}S) binding sites by 90% and low K{sub m}, opioid-sensitive GTPase activity by 95%. In these membranes, high-affinity agonist binding was abolished and modulation of residual binding by GTP({gamma}S) was diminished. Alkali treatment of the glioma cell membranes prior to fusion inhibited most of the low K{sub m} GTPase activity and prevented the reconstitution of agonist binding. The results show that high-affinity opioid agonist binding reflects the ligand-occupied receptor - guanine nucleotide binding protein complex.

Remmers, A.E.; Medzihradsky, F. (Univ. of Michigan Medical School, Ann Arbor (United States))



Evaluation of a Novel Calcium Channel Agonist for Therapeutic Potential in Lambert–Eaton Myasthenic Syndrome  

PubMed Central

We developed a novel calcium (Ca2+) channel agonist that is selective for N- and P/Q-type Ca2+ channels, which are the Ca2+ channels that regulate transmitter release at most synapses. We have shown that this new molecule (GV-58) slows the deactivation of channels, resulting in a large increase in presynaptic Ca2+ entry during activity. GV-58 was developed as a modification of (R)-roscovitine, which was previously shown to be a Ca2+ channel agonist, in addition to its known cyclin-dependent kinase activity. In comparison with the parent molecule, (R)-roscovitine, GV-58 has a ?20-fold less potent cyclin-dependent kinase antagonist effect, a ?3- to 4-fold more potent Ca2+ channel agonist effect, and ?4-fold higher efficacy as a Ca2+ channel agonist. We have further evaluated GV-58 in a passive transfer mouse model of Lambert–Eaton myasthenic syndrome and have shown that weakened Lambert–Eaton myasthenic syndrome-model neuromuscular synapses are significantly strengthened following exposure to GV-58. This new Ca2+ channel agonist has potential as a lead compound in the development of new therapeutic approaches to a variety of disorders that result in neuromuscular weakness. PMID:23785168

Tarr, Tyler B.; Malick, Waqas; Liang, Mary; Valdomir, Guillermo; Frasso, Michael; Lacomis, David; Reddel, Stephen W.; Garcia-Ocano, Adolfo



Systemic kappa opioid receptor agonists in the treatment of chronic pruritus: a literature review.  


Chronic pruritus is frequently refractory to currently available treatments. Studies suggest that pruritus may arise from an imbalance of the mu- and kappa-opioid receptor system activity in either the skin or the central nervous system. Stimulation of kappa-opioid receptors by their agonists inhibits pruritus in both animals and humans. The antipruritic effect of kappa-opioid receptors agonists can currently be assumed to be related to their binding to kappa-opioid receptors on keratinocytes and cutaneous and/or central itch neurones. To date, several case reports and 2 controlled trials have demonstrated a beneficial effect of systemic kappa-opioid receptor agonists in the treatment of uraemic pruritus, prurigo nodularis, paraneoplastic and cholestatic pruritus. Nalfurafine hydrochloride (Remitch(®)), a selective kappa-opioid receptor agonist, is approved for the treatment of chronic pruritus in Japan. The aim of this review is to provide an overview of the promising role of kappa- opioid receptors and their agonist in the pathophysiology and treatment of pruritus. PMID:22504709

Phan, Ngoc Quan; Lotts, Tobias; Antal, Attila; Bernhard, Jeffrey D; Ständer, Sonja



Inhibitory Effects of Sigma-2 Receptor Agonists on T Lymphocyte Activation  

PubMed Central

Sigma (?) receptor ligands are essentially known for their effects on the nervous system although recent studies have shown their potential effects modulating some other pathophysiological processes as cell proliferation, cancer, and the immune response. Here, we have analyzed the actions of ?-1 and ?-2 receptors ligands on T cell activation. Our results show that treatment of Jurkat T cells with ?-2 agonists decreased the induction of the expression of Interleukin (IL)-2, Tumor necrosis factor (TNF)-?, and Cyclooxygenase (COX)-2 by activated T cells in a dose-dependent manner. These effects take place at the transcriptional level since ?-2 agonists BD-737 and CB-184 diminished the activity of the promoters of those genes. Those immunosuppressive effects could be attributable to interference with transcription factor activation. Induced transcription mediated by Nuclear factor (NF)-?B or Nuclear Factor of Activated T cells (NFAT) was inhibited by ?-2 agonists. These effects seem to be specific for ?-2 agonists as no significant effects on T cell activation by ?-1 ligands PRE-084 and BD-1063 were found. Our results provide new insights into the immunomodulatory actions of ? ligands and describe a new property of ?-2 agonists, through inhibition of activation of transcription factors as NFAT by which these compounds are regulating gene expression. This may have important consequences on the possible therapeutic use of those compounds. PMID:23494519

Iñiguez, Miguel A.; Punzón, Carmen; Nieto, Raquel; Burgueño, Javier; Vela, José M.; Fresno, Manuel



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



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



Duration of L-dopa and dopamine agonist monotherapy in Parkinson's disease.  


The expected duration of initial antiparkinson monotherapy before the need for supplementation is not clearly defined for routine practice. The aim of this study was to define the length of L-dopa (L-3, 4-dihydrophenylalanine) and dopamine agonist monotherapy. The duration of monotherapy and discontinuation rates were investigated in a natural observational setting by plotting Kaplan-Meier survival curves. Out of 345 patients, 180 (52.2%) received L-dopa and 165 (47.8%) received a dopamine agonist as initial monotherapy. Half of the patients starting L-dopa received supplementary therapy with- in 3.6 years (95% confidence interval, 3.2-4.6), significantly longer than for dopamine agonist monotherapy (half required a second agent at 2.3 years [2.0-2.9]; P = 0.00017). Discontinuation of L-dopa therapy was 1%. Dopamine agonists were stopped (due to side-effects like impulse control disorders [6%], somnolence [4%] and light-headedness [3%]) in 20% over four years. The duration and tolerability of L-dopa and dopamine agonists as initial Parkinson's disease monotherapy are defined in this study; this may form part of the information exchange with patients. PMID:23002158

Nissen, T; Newman, E J; Grosset, K A; Daghem, M; Pal, G; Stewart, M; Odin, P; Macphee, G J; Grosset, D G



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



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



Ageismus – Sprachliche Diskriminierung des Alters  

Microsoft Academic Search

Daniel Sanders, einer der bedeutendsten Lexikografen des 19. Jahrhunderts, wertete für sein Wörterbuch Quellen seit der Lutherzeit aus und\\u000a vermerkt im Wörterbuchartikel zu alt eine „bald lobende, bald tadelnde“ Bedeutung des Adjektivs. Sein Zeit- und Berufsgenosse Jacob Grimm benennt in seiner Rede über das Alter die zeitgenössischen Synonyme zu alt und Alter: „aus einheimischen schriftstellern liesze sich eine lange reihe

Undine Kramer


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.



Clinical use of deslorelin (GnRH agonist) in companion animals: a review.  


Over the years, many contraceptive medications have been developed for companion animals, but many secondary adverse effects have limited their use. A major advancement was achieved with the use of gonadotropin-releasing hormone (GnRH) analogues, mainly GnRH agonists, which mimic the effects of native GnRH. The development of effective low-dose, slow-release implants with potent agonists such as deslorelin (Suprelorin®, Virbac) have allowed their use to become widespread in recent years, with many potential benefits in companion animals. While the major application of deslorelin was initially male contraception, due to its two differing actions, either the stimulation of oestrus or the sterilization of fertility, its use has been increasing in the bitch as well. The aim of this study is to review the applications of deslorelin GnRH agonist implants in companion animal, such as dogs, cats and some exotic pets. PMID:25277434

Lucas, X



Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via Melanocortin-4 Receptor Signaling Pathways  

PubMed Central

Summary The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT2CR) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT2CR agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT2CRs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes. PMID:17983585

Zhou, Ligang; Sutton, Gregory M.; Rochford, Justin J.; Semple, Robert K.; Lam, Daniel D.; Oksanen, Laura J.; Thornton-Jones, Zoe D.; Clifton, Peter G.; Yueh, Chen-Yu; Evans, Mark L.; McCrimmon, Rory J.; Elmquist, Joel K.; Butler, Andrew A.; Heisler, Lora K.



5-HT2C receptor agonists as an innovative approach for psychiatric disorders.  


Modulating activity at the 5-HT(2C) receptor holds a tremendous amount of therapeutic promise in multiple psychiatric indications. However, the signaling and regulation of the 5-HT(2C) receptor is highly complex due to multiple signaling pathways and agonist-directed trafficking of this receptor. Moreover, the 5-HT(2C) receptor is differentially regulated via RNA editing in multiple psychiatric disorders and following either pharmacological or environmental manipulation. Direct and indirect data suggest that both agonists and antagonists may provide benefits in several disorders. The current review highlights the underlying complexities of this area and provides the rationale for using 5-HT(2C) agonists in the treatment of both schizophrenia and depressive disorders. PMID:18176661

Rosenzweig-Lipson, Sharon; Dunlop, John; Marquis, Karen L



Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons.  


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. PMID:1358255

Zheng, F; Gallagher, J P



An aryloxypropanolamine h?3-adrenoceptor agonist as bladder smooth muscle relaxant.  


The relaxant effect of an aryloxypropanolamine ?3-adrenoceptor agonist on carbachol pre-contracted human detrusor muscle strips was evaluated and compared with literature results from reference compounds of similar mode of action, including mirabegron. A significant relaxation was observed for rac-4-{2-hydroxy-3-[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino]propoxy}-2-(hydroxymethyl)phenol which was similar to that exerted by mirabegron. In order to allow for a thorough discussion of results in comparison to reference compounds, their affinity, selectivity and efficacy as h?3-AR agonists have been evaluated and discussed thoroughly. A ranking of h?3-AR agonists by relative efficacy resulted in the closest analogy to the order of relaxation potential, with only the relaxant effect of mirabegron not reflecting its excellent relative efficacy as such. PMID:22430195

Tasler, Stefan; Baumgartner, Roland; Behr-Roussel, Delphine; Oger-Roussel, Stephanie; Gorny, Diane; Giuliano, Francois; Ney, Peter



Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks  

NASA Astrophysics Data System (ADS)

Insulin is thought to elicit its effects by crosslinking the two extracellular -subunits of its receptor, thereby inducing a conformational change in the receptor, which activates the intracellular tyrosine kinase signaling cascade. Previously we identified a series of peptides binding to two discrete hotspots on the insulin receptor. Here we show that covalent linkage of such peptides into homodimers or heterodimers results in insulin agonists or antagonists, depending on how the peptides are linked. An optimized agonist has been shown, both in vitro and in vivo, to have a potency close to that of insulin itself. The ability to construct such peptide derivatives may offer a path for developing agonists or antagonists for treatment of a wide variety of diseases.

Schäffer, Lauge; Brissette, Renee E.; Spetzler, Jane C.; Pillutla, Renuka C.; Østergaard, Søren; Lennick, Michael; Brandt, Jakob; Fletcher, Paul W.; Danielsen, Gillian M.; Hsiao, Ku-Chuan; Andersen, Asser S.; Dedova, Olga; Ribel, Ulla; Hoeg-Jensen, Thomas; Hertz Hansen, Per; Blume, Arthur J.; Markussen, Jan; Goldstein, Neil I.



Total synthesis and dual PPAR?/? agonist effects of amorphastilbol and its synthetic derivatives.  


Amorphastilbol (APH-1), isolated from a Robinia pseudoacacia var. umbraculifer [corrected] seed extract, is a biologically interesting natural trans-stilbene compound with dual peroxisome proliferator-activated receptor (PPAR) ?/? agonist activity. After total synthesis of APH-1 and its derivatives by Pd-catalyzed Suzuki-Miyaura cross-coupling of a common (E)-styryl bromide intermediate and various aromatic trifluoroborate compounds, we biologically evaluated APH-2-APH-12 for PPAR agonist activity. APH-4 and APH-11 were effective PPAR?/? transcriptional activators, compared with APH-1. Therefore, we suggest that APH-4 and APH-11 are novel dual PPAR?/? agonists and are potentially useful for treating type 2 diabetes by enhancing glucose and lipid metabolism. PMID:22579420

Kim, Taejung; Lee, Woojung; Jeong, Kyu Hyuk; Song, Jung Ho; Park, Soon-Hye; Choi, Pilju; Kim, Su-Nam; Lee, Seokjoon; Ham, Jungyeob



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



Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands  

PubMed Central

Newly designed bivalent ligands—opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials—carboxy-derivatives of Fentanyl (1a–1c) was developed. These products have been transformed to ‘isoimidium perchlorates’ (2a–c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds—amides (3a–c). Perchlorates (2a–c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited ?-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds. PMID:21925887

Vardanyan, Ruben; Kumirov, Vlad K.; Nichol, Gary S.; Davis, Peg; Liktor-Busa, Erika; Rankin, David; Varga, Eva; Vanderah, Todd; Porreca, Frank; Lai, Josephine; Hruby, Victor J.



Suppression of castor oil-induced diarrhoea by alpha 2-adrenoceptor agonists.  


The effects of systemic administration of alpha 2-adrenoceptor agonists on migrating myoelectric complexes and castor oil-induced diarrhoea of the small intestine were studied in conscious rats. Castor oil (1 mg/kg, intraduodenally) disrupted the migrating myoelectric complexes and induced irregular spiking activity with sporadic bursts of myoelectric activity. This change of motility pattern was present concomitant with diarrhoea 1-2 h after instillation of castor oil and during the whole period of diarrhoea. Pre-treatment with clonidine (5-10 micrograms/kg i.v.) or oxymetazoline (5.6-11.2 micrograms/kg i.v.), a peripherally active alpha 2-agonist, inhibited the irregular spiking induced by castor oil and no diarrhoea occurred during the experimental period of 6 h. Thus, the antidiarrhoeal action of peripherally acting alpha 2-adrenoceptor agonists such as oxymetazoline, may be of clinical value in the treatment of diarrhoea. PMID:1679667

Thollander, M; Hellström, P M; Svensson, T H



[Possibilities using prolonged release dopamine receptor agonists in elderly and old age.  


Treatment efficacy of Parkinson's disease has been essentially improved due to the introduction of dopamine receptors agonists to clinical practice. However, these drugs are not recommended to patients over 70 years because of the high probability of side-effects that significantly reduce therapeutic opportunities in elderly patients. It is known, that many dopaminergic side-effects are due to unstable and high peak concentrations of drugs. Application of prolonged forms of dopamine receptors agonists, and careful selection of elderly patients, allows to use these drugs as safely, as in patients of middle age. This fact has been proved by several clinical trials. Criteria for selection of elderly patients for treatment with dopamine receptors agonists are: the absence of severe cognitive disturbances, REM-sleep behavioral disorders, orthostatic hypotension, frequent falling and decompensated somatic diseases. PMID:25042506

Artem'ev, D V



Thrombin receptor agonist Peptide immobilized in microspheres stimulates reparative processes in rats with gastric ulcer.  


The effect of synthetic thrombin receptor (PAR1) agonist peptide encapsulated in microspheres made of lactic and glycolic acid copolymer on tissue reparation was studied in rats with acetate-induced ulcer. PAR1 agonist peptide was immobilized in biodegraded lactic and glycolic acid microspheres by double emulgation, the kinetics of peptide release was analyzed, and the dynamics of ulcer healing was studied in experimental (administration of microspheres with the peptide into the stomach) and two control groups (administration of saline or spheres without peptide). Thrombin receptor agonist peptide gradually released from lactic and glycolic acid microspheres into the stomach shortened the inflammation phase and shifted the proliferation phase to the earlier period, thus accelerating healing of experimental ulcers in rats. PMID:17369897

Rusanova, A V; Makarova, A M; Strukova, S M; Markvicheva, E A; Gorbachyova, L R; Stashevskaya, K S; Vasil'eva, T V; Sidorova, E I; Bespalova, Zh D; Grandfils, Ch



Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists.  


Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified. PMID:25599839

Sasmal, Pradip K; Krishna, C Vamsee; Adabala, S Sudheerkumar; Roshaiah, M; Rawoof, Khaji Abdul; Thadi, Emima; Sukumar, K Pavan; Cheera, Srisailam; Abbineni, Chandrasekhar; Rao, K V L Narasimha; Prasanthi, A; Nijhawan, Kamal; Jaleel, Mahaboobi; Iyer, Lakshmi Ramachandran; Chaitanya, T Krishna; Tiwari, Nirbhay Kumar; Krishna, N Lavanya; Potluri, Vijay; Khanna, Ish; Frimurer, Thomas M; Lückmann, Michael; Rist, Øystein; Elster, Lisbeth; Högberg, Thomas



Protective effects of glycyrrhizin against ??-adrenergic receptor agonist-induced receptor internalization and cell apoptosis.  


It has been reported that treatment with ?? adrenergic receptor (??AR) agonist bronchodilators may result in airway ??ARs internalization and cardiac muscle cells apoptosis. This could lead to the loss of pharmacological effect of ??AR agonists and increase adverse cardiovascular events in asthma patients receiving ??AR agonist therapy. Glycyrrhizin, the major bioactive component of licorice root extract, has been reported to exhibit protective effect on respiratory system. Here, we investigate the effects of glycyrrhizin against ??AR agonist salbutamol-induced receptor internalization and cell apoptosis. In our study, the live cell confocal imaging and fixed-cell enzyme-linked immunosorbent assay (ELISA) assay revealed that glycyrrhizin significantly inhibited salbutamol-induced surface ??AR internalization. The underlying mechanisms were then identified to be that glycyrrhizin could reduce the association of ??ARs with ?-arrestins and clathrin heavy chain as well as the level of G protein-coupled receptor kinase (GRK) mediated phosphorylation of ??ARs. The inhibition of receptor internalization by glycyrrhizin further lead to stabilization of the ??AR mRNA and protein expression, thus amplified the transmembrane signaling via the ??ARs. We also proved that glycyrrhizin could profoundly attenuate salbutamol-induced early cellular apoptosis by regulating the expressions of B-cell lymphoma 2 (Bcl-2) family genes. Taken together, our results suggest that glycyrrhizin exhibits protective effects against ??AR agonist-induced receptor internalization and cell apoptosis. These findings might have practical implications for future strategies of combined application of glycyrrhizin with ??AR receptor agonists to improve the efficacy of bronchodilators in patients with asthma and chronic obstructive pulmonary disease (COPD). PMID:21532146

Shi, Qian; Hou, Yuanyuan; Yang, Yang; Bai, Gang



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



STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus.  


Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted. PMID:25512416

Guo, Fang; Han, Yanxing; Zhao, Xuesen; Wang, Jianghua; Liu, Fei; Xu, Chunxiao; Wei, Lai; Jiang, Jian-Dong; Block, Timothy M; Guo, Ju-Tao; Chang, Jinhong



PPAR? Agonists Promote Oligodendrocyte Differentiation of Neural Stem Cells by Modulating Stemness and Differentiation Genes  

PubMed Central

Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPAR?) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPAR? agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPAR? agonist ciglitazone or 15-Deoxy-?12,14-Prostaglandin J2 (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPAR? agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3–7 days. In vitro treatment with PPAR? agonists and ATRA also induced modest increase in the expression of neuronal ?-III tubulin and astrocyte-specific GFAP in NSCs in 3–7 days. Further analyses showed that PPAR? agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPAR? agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases. PMID:23185633

Kanakasabai, Saravanan; Pestereva, Ecaterina; Chearwae, Wanida; Gupta, Sushil K.; Ansari, Saif; Bright, John J.



Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists  

PubMed Central

Infiltrating monocytes and macrophages play a crucial role in the progression of HIV-1 infection in the CNS. Previous studies showed that activation of the CB2 can attenuate inflammatory responses and affect HIV-1 infectivity in T cells and microglia. Here, we report that CB2 agonists can also act as immunomodulators on HIV-1-infected macrophages. First, our findings indicated the presence of elevated levels of CB2 expression on monocytes/macrophages in perivascular cuffs of postmortem HIV-1 encephalitic cases. In vitro analysis by FACS of primary human monocytes revealed a step-wise increase in CB2 surface expression in monocytes, MDMs, and HIV-1-infected MDMs. We next tested the notion that up-regulation of CB2 may allow for the use of synthetic CB2 agonist to limit HIV-1 infection. Two commercially available CB2 agonists, JWH133 and GP1a, and a resorcinol-based CB2 agonist, O-1966, were evaluated. Results from measurements of HIV-1 RT activity in the culture media of 7 day-infected cells showed a significant decrease in RT activity when the CB2 agonist was present. Furthermore, CB2 activation also partially inhibited the expression of HIV-1 pol. CB2 agonists did not modulate surface expression of CXCR4 or CCR5 detected by FACS. We speculate that these findings indicate that prevention of viral entry is not a central mechanism for CB2-mediated suppression in viral replication. However, CB2 may affect the HIV-1 replication machinery. Results from a single-round infection with the pseudotyped virus revealed a marked decrease in HIV-1 LTR activation by the CB2 ligands. Together, these results indicate that CB2 may offer a means to limit HIV-1 infection in macrophages. PMID:23463725

Ramirez, Servio H.; Reichenbach, Nancy L.; Fan, Shongshan; Rom, Slava; Merkel, Steven F.; Wang, Xu; Ho, Wen-zhe; Persidsky, Yuri



Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists.  


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



Des Moines Water Works  

NSDL National Science Digital Library

Users can access information about educational programs and materials for teachers and students, including tours, traveling exhibits and presentations by the staff of the Des Moines Water Works. "Water Trunks", which contain water-related literature, books, science experiments, videos, games, CD-ROMs, hands-on activities, picture cards, career information, and a teacher resource book, are available to order. There are also links to other water websites, a teachers' newsletter and pollution prevention tips for classroom use and for the general public.



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



The role of inhaled long-acting beta-2 agonists in the management of asthma.  

PubMed Central

The role of inhaled beta-2 agonists in the management of asthma has changed significantly over the last several years. This review outlines the most recent understanding of the pathophysiology of asthma and the studies that define the roles that both short- and long-acting beta-2 agonists play in therapy for this disease. A concentration on the clinical pharmacology and genetic implications for clinical use of this class of drugs in accordance with the national and international guidelines are described. PMID:16532973

Kelly, H. William; Harkins, Michelle S.; Boushey, Homer



Discovery of Benzodiazepine Sulfonamide-Based Bombesin Receptor Subtype 3 Agonists and Their Unusual Chirality  

PubMed Central

We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring. PMID:24900283



Evaluation of cannabinoid agonists using punished responding and midazolam discrimination procedures in squirrel monkeys  

Microsoft Academic Search

Rationale  Clinical studies have suggested that marijuana and nabilone have anxiolytic effects in humans, yet studies of anxiolytic-like\\u000a effects of cannabinoid agonists in mice and rats have yielded mixed results.\\u000a \\u000a \\u000a \\u000a Objective  The purpose of the present study was to compare the effects of cannabinoid agonists and clinically used anxiolytic drugs in\\u000a monkeys using punished responding and midazolam discrimination procedures.\\u000a \\u000a \\u000a \\u000a Methods  Monkeys were trained

Marcus S. Delatte; Carol A. Paronis



? opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes.  


Opioids are irreplaceable for the treatment of severe pain. However, opioid-induced immunomodulation affects therapies. Here we report that treatment of human T lymphocytes with the opioids fentanyl, methadone, loperamide and beta-endorphin resulted in a strong induction of the cytokine interleukin-4. In contrast, morphine and buprenorphine induced markedly and significantly lower levels of interleukin-4 mRNA and protein. These findings suggest agonist-biased ? opioid receptor signaling in T cells. In the future, better knowledge about agonist-specific immunomodulatory effects of opioids offers the possibility to select drugs for a therapy with more favorable and/or less detrimental side effects in immune cells. PMID:23965172

Börner, Christine; Lanciotti, Sara; Koch, Thomas; Höllt, Volker; Kraus, Jürgen



EGF Receptor Transactivation Mediated by the Proteolytic Production of EGF-like Agonists  

NSDL National Science Digital Library

The epidermal growth factor (EGF) receptor is activated not only by EGF-like ligands, but also by stimuli that do not directly act on the receptor, including agonists of G protein–coupled receptors and certain environmental stresses such as ionizing radiation. Carpenter discusses two reports that indicate EGF receptor activation by such heterologous stimuli may occur through the action of proteases that release cell surface EGF-like growth factor precursors. This mechanism of EGF receptor transactivation appears to involve the generation of soluble agonists.

Graham Carpenter (Vanderbilt University School of Medicine; Department of Biochemistry REV)



The Beta Agonist Lung Injury TrIal (BALTI) - prevention trial protocol  

Microsoft Academic Search

Background  Acute lung injury complicates approximately 25-30% of subjects undergoing oesophagectomy. Experimental studies suggest that\\u000a treatment with beta agonists may prevent the development of acute lung injury by decreasing inflammatory cell infiltration,\\u000a activation and inflammatory cytokine release, enhancing basal alveolar fluid clearance and improving alveolar capillary barrier\\u000a function.\\u000a \\u000a \\u000a \\u000a \\u000a Methods\\/Design  The Beta Agonist Lung Injury TrIal (prevention) is a multi-centre, randomised, double blind,

Gavin D Perkins; Daniel Park; Derek Alderson; Matthew W Cooke; Fang Gao; Simon Gates; Sarah E Lamb; Dipesh Mistry; David R Thickett



Effects of Atypical ?-Opioid Receptor Agonists on Intrathecal Morphine-Induced Itch and Analgesia in Primates  

PubMed Central

Itch/pruritus is the most common side effect associated with spinal administration of morphine given to humans for analgesia. The aim of this study was to investigate the effectiveness of ?-opioid receptor (KOR) agonists with diverse chemical structures as antipruritics and to elucidate the receptor mechanism underlying the antipruritic effect in monkeys. In particular, previously proposed non-KOR-1 agonists, including nalfurafine [TRK-820, 17-cyclopropylmethyl-3,14?-dihydroxy-4,5?-epoxy-6?-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan], bremazocine [(±)-6-ethyl-1,2,3,4,5,6-hexahydro-3-[(1-hydroxycyclopropy)-methyl]-11,11-dimethyl-2,6-methano-3-benzazocin-8-ol], and GR 89696 [4-[(3,4-dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazinecarboxylic acid methyl ester] were studied in various behavioral assays for measuring itch/scratching, analgesia, and respiratory depression. Systemic administration of nalfurafine (0.1–1 ?g/kg), bremazocine (0.1–1 ?g/kg), or GR 89696 (0.01–0.1 ?g/kg) dose-dependently attenuated intrathecal morphine (0.03 mg)-induced scratching responses without affecting morphine antinociception. The combination of intrathecal morphine with these KOR agonists did not cause sedation. In addition, pretreatment with effective antiscratching doses of nalfurafine, bremazocine, or GR 89696 did not antagonize systemic morphine-induced antinociception and respiratory depression. The dose-addition analysis revealed that there is no subadditivity for nalfurafine in combination with morphine in the antinociceptive effect. Furthermore, the KOR antagonist study revealed that antiscratching effects of both nalfurafine and a prototypical KOR-1 agonist, U-50488H [trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide], could be blocked completely by a selective KOR antagonist, nor-binaltorphimine (3 mg/kg). These findings suggest that the agonist action on KOR mainly contributes to the effectiveness of these atypical KOR agonists as antipruritics, and there is no evidence for KOR subtypes or ?-opioid antagonist action underlying the effects of these KOR agonists. This mechanism-based study further supports the clinical potential of KOR agonists as antipruritics under the context of spinal opioid analgesia. PMID:18842704

Ko, Mei-Chuan; Husbands, Stephen M.



Arylacetamide kappa opioid receptor agonists with reduced cytochrome P450 2D6 inhibitory activity.  


Some kappa opioid receptor agonists of the arylacetamide class, for example, ICI 199441 (1), were found to strongly inhibit the activity of cytochrome P450 2D6 (CYP2D6) (1: CYP2D6 IC50=26 nM). Certain analogs bearing a substituted sulfonylamino group, for example, 13, were discovered to have significantly reduced CYP2D6 inhibitory activity (13: CYP2D6 IC50>10 microM) while displaying high affinity toward the cloned human kappa opioid receptor, good kappa/delta and kappa/mu selectivity, and potent in vitro and in vivo agonist activity. PMID:15863335

Le Bourdonnec, Bertrand; Ajello, Christopher W; Seida, Pamela R; Susnow, Roberta G; Cassel, Joel A; Belanger, Serge; Stabley, Gabriel J; DeHaven, Robert N; DeHaven-Hudkins, Diane L; Dolle, Roland E



Novel sulfamoyl benzamides as selective CB(2) agonists with improved in vitro metabolic stability.  


A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain. PMID:19919895

Sellitto, Ian; Le Bourdonnec, Bertrand; Worm, Karin; Goodman, Allan; Savolainen, Markku A; Chu, Guo-Hua; Ajello, Christopher W; Saeui, Christopher T; Leister, Lara K; Cassel, Joel A; Dehaven, Robert N; Labuda, Christopher J; Koblish, Michael; Little, Patrick J; Brogdon, Bernice L; Smith, Steven A; Dolle, Roland E



Design of potent and selective GPR119 agonists for type II diabetes.  


Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC(50)=3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58). PMID:21273063

Szewczyk, Jason W; Acton, John; Adams, Alan D; Chicchi, Gary; Freeman, Stanley; Howard, Andrew D; Huang, Yong; Li, Cai; Meinke, Peter T; Mosely, Ralph; Murphy, Elizabeth; Samuel, Rachel; Santini, Conrad; Yang, Meng; Zhang, Yong; Zhao, Kake; Wood, Harold B



Trisubstituted Sulfonamides: A New Chemotype for Development of Potent and Selective CB2 Receptor Inverse Agonists  

PubMed Central

An extensive exploration of the structure–activity relationship of a trisubstituted sulfonamide series led to the identification of 39, which is a potent and selective CB2 receptor inverse agonist [Ki(CB2) = 5.4 nM, and Ki(CB1) = 500 nM]. The functional properties measured by cAMP assays indicated that the selected compounds were CB2 inverse agonists with high potency values (for 34, EC50 = 8.2 nM, and for 39, EC50 = 2.5 nM). Furthermore, an osteoclastogenesis bioassay indicated that trisubstituted sulfonamide compounds showed great inhibition of osteoclast formation. PMID:24729834



Gntique formelle des pigmentations humaines variations continues  

E-print Network

Génétique formelle des pigmentations humaines à variations continues : beaucoup d'hypothèses, peu et de mesures sont actuellement disponibles concer- nant la biochimie des pigments humains, leur génétique physiologique, les répartitions mondiales des pigmentations de la peau et des cheveux. La

Boyer, Edmond


Les revenus primaires des ménages en 1975  

Microsoft Academic Search

[fre] Tous les 5 ans environ, l'INSEE procède à une enquête sur les revenus des ménages en utilisant les déclarations fiscales de la Direction générale des impôts. Les premiers résultats de 1975 sont à présent disponibles. Malgré la diversité des critères d'inégalité (revenu par ménage, par tête ou par unité de consommation), une réduction progressive des écarts se fait jour,

André Villeneuve



Patrimoine des ménages : déterminants et disparités  

Microsoft Academic Search

[fre] Patrimoine des ménages : déterminants et disparités . En 1992, le patrimoine brut des ménages est, en moyenne, de 900 000 francs. Mais la dispersion et la concentration sont fortes : le pécule des 10 % de ménages les moins fortunés ne dépasse pas 24 600 francs, alors que l'avoir des 10 % les plus riches excède 1 830

Daniel Verger; Stéfan Lollivier




E-print Network

119 CARTOGRAPHIE DES ACCIDENTS G�OLOGIQUES PAR IMAGERIE SATELLITAIRE LANDSAT-7 ETM+ ET ANALYSE DES cartographier les réseaux de fractures dans les roches cristallines et métamorphiques à l'aide des images les images brutes, permettant une meilleure cartographie des accidents géologiques. La carte

Paris-Sud XI, Université de



E-print Network

GERMANIUM PAR DIFFUSION D'ATOMES MARQU�S Par MAREK BRAFMAN, OLGA KRUSZEWSKA, WALDEMAR WRONSKI et KAROL'exemple des monocristaux de germanium et comparaison des résultats obtenus avec les mêmes déterminations measurement of the density of the autoradio- grams. The method is illustrated by example of germanium

Boyer, Edmond


ER-? agonist induces conversion of fibroblasts into myofibroblasts, while ER-? agonist increases ECM production and wound tensile strength of healing skin wounds in ovariectomised rats.  


Oestrogen deprivation is one of the major factors responsible for many age-related processes, including poor wound healing in women. Previously, it has been shown that oestrogens have a modulatory effect in different wound-healing models. Therefore, in this study, the effect of selective oestrogen receptor (ER) agonists (PPT - ER-? agonist, DPN - ER-? agonist) on excisional and incisional wound-healing models was compared in ovariectomised rats in vivo as well as on human dermal fibroblasts (HDF) and human umbilical endothelial cells (HUVEC) in vitro. In the in vivo study, 4 months after either ovariectomy or sham ovariectomy, Sprague-Dawley rats were randomly divided into four groups and subjected to two incisional and excisional wounds: (i) control - sham operated, vehicle-treated; (ii) ovariectomised, vehicle-treated; (iii) ovariectomised, PPT treated; (iv) ovariectomised, DPN treated. In the in vitro study, HDFs and HUVECs were used. After treatment with ER agonists, cells were processed for immunocytochemistry and gelatin zymography. Our study shows that stimulation of ER-? leads to the differentiation of fibroblasts into myofibroblasts both in vivo and in vitro. On the other hand, the formation of extracellular matrix was more prominent, and wound tensile strength (TS) was increased when ER-? was stimulated. In contrast, stimulation of ER-? led to a more prominent increase in the expression of MMP-2 and decrease in wound TS. New information is presented in this investigation concerning oestrogen replacement therapy (ERT) in different wound-healing models. This study demonstrates that the ERT should be both wound and receptor-type specific. PMID:21507066

Novotný, Martin; Vasilenko, Tomáš; Varinská, Lenka; Smetana, Karel; Szabo, Pavol; Sarišský, Marek; Dvo?ánková, Barbora; Mojžiš, Ján; Bobrov, Nikita; Toporcerová, Silvia; Sabol, Franitšek; Matthews, Bryan J O; Gál, Peter



Thiamethoxam, a poor agonist of nicotinic acetylcholine receptors expressed on isolated cell bodies, acts as a full agonist at cockroach cercal afferent/giant interneuron synapses.  


Thiamethoxam (TMX) is a second-generation neonicotinoid which is known to induce toxic effects on insects and mammalians. Recently, it has been proposed that TMX is a poor agonist of insect nicotinic acetylcholine receptors (nAChRs) on isolated cell bodies. Here, we have studied its effect on synaptic transmission. Our results demonstrate that TMX acts as an agonist of nAChRs expressed on cockroach cercal afferent giant/interneuron synapses as bath applications of TMX induce a strong reversible depolarization of the sixth abdominal ganglion. This response was reduced by the nicotinic antagonists mecamylamine and methyllicaconitine, but was insensitive to d-tubocurarine. Interestingly, TMX-induced depolarization was partially reduced by the muscarinic antagonist atropine, suggesting that TMX could bind to a 'mixed nicotinic/muscarinic' receptor. Compared to previous studies, we proposed that TMX is able to act as agonist of insect nAChRs expressed at cercal afferent/giant interneuron synapses. Moreover, our results suggest that nAChRs expressed on synaptic ganglion are distinct to nAChRs expressed on isolated cell bodies and that synaptic receptors have higher affinity to TMX resulting to a depolarization of postsynaptic nicotinic receptors. PMID:21172360

Thany, Steeve H



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 Use of Anchored Agonists of Phagocytic Receptors for Cancer Immunotherapy: B16-F10 Murine Melanoma Model  

PubMed Central

The application of the phagocytic receptor agonists in cancer immunotherapy was studied. Agonists (laminarin, molecules with terminal mannose, N-Formyl-methioninyl-leucyl-phenylalanine) were firmly anchored to the tumor cell surface. When particular agonists of phagocytic receptors were used together with LPS (Toll-like receptor agonist), high synergy causing tumour shrinkage and a temporary or permanent disappearance was observed. Methods of anchoring phagocytic receptor agonists (charge interactions, anchoring based on hydrophobic chains, covalent bonds) and various regimes of phagocytic agonist/LPS mixture applications were tested to achieve maximum therapeutic effect. Combinations of mannan/LPS and f-MLF/LPS (hydrophobic anchors) in appropriate (pulse) regimes resulted in an 80% and 60% recovery for mice, respectively. We propose that substantial synergy between agonists of phagocytic and Toll-like receptors (TLR) is based on two events. The TLR ligand induces early and massive inflammatory infiltration of tumors. The effect of this cell infiltrate is directed towards tumor cells, bearing agonists of phagocytic receptors on their surface. The result of these processes was effective killing of tumor cells. This novel approach represents exploitation of innate immunity mechanisms for treating cancer. PMID:24454822

Janotová, Tereza; Jalovecká, Marie; Auerová, Marie; Švecová, Ivana; Bruzlová, Pavlína; Maierová, Veronika; Kumžáková, Zuzana; ?unátová, Št?pánka; Vl?ková, Zuzana; Caisová, Veronika; Rozsypalová, Petra; Luká?ová, Katarína; Vácová, Nikol; Wachtlová, Markéta; Salát, Ji?í; Lieskovská, Jaroslava; Kopecký, Jan; Ženka, Jan



The interaction of cannabinoid receptor agonists, CP55940 and WIN55212-2 with membranes using solid state 2  

E-print Network

The interaction of cannabinoid receptor agonists, CP55940 and WIN55212-2 with membranes using solid Available online 1 December 2010 Keywords: Cannabinoid receptor agonist Win55212-2 CP55940 THC Lipid of the bilayer. Our studies show that the cannabinoid ligands induce lateral phase separation in the lipid

Yang, De-Ping


Promotion of Agonist Activity of Antiandrogens by the Androgen Receptor Coactivator, ARA70, in Human Prostate Cancer DU145 Cells  

Microsoft Academic Search

Although hormone therapy with antiandrogens has been widely used for the treatment of prostate cancer, some antiandrogens may act as androgen receptor (AR) agonists that may result in antiandrogen withdrawal syndrome. The molecular mechanism of this agonist response, however, remains unclear. Using mammalian two-hybrid assay, we report that antiandrogens, hydroxyflutamide, bicalutamide (casodex), cyproterone acetate, and RU58841, and other compounds such

Hiroshi Miyamoto; Shuyuan Yeh; George Wilding; Chawnshang Chang



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



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



Sécurité au-delà des mythes et des croyances  


Présentation orale en français, support visuel en français et en anglais. La pire des failles de sécurité est l'impression de sécurité. Le décalage entre la compréhension que l?on a des technologies utilisées, et leurs potentiels réels, ainsi que l'impact potentiellement négatif qu'elles peuvent avoir sur nos vies, n'est pas toujours compris, ou pris en compte par la plupart d'entre-nous. On se contente de nos perceptions pour ne pas avoir à se confronter à la réalité... Alors qu'en est-il vraiment ? En matière de sécurité qui de l'humain ou des technologies a le contrôle ?




A propos des divergences en théorie des champs quantifiés [83  

NASA Astrophysics Data System (ADS)

Comme nous le montrons ailleurs1), la causalité impose à la matrice S qui décrit l'évolution d'un système une structure bien déterminée : lorsqu'on développe celle-ci suivant les opérateurs de translation dans l'espace des quanta, les coefficients S^{(i)} left[ {tau ''; u''../tau '; u' \\cdot \\cdot } right] sont des intégrales multiples où n'apparaissent, à cOté des champs liés à un seul point de l'espace temps, que les functions*): D^c (x/y) = D^s (x/y) + _2^i D^1 (x/y) x ne y


Pacs des villes et pas des champs ? Emmanuel Jaurand  

E-print Network

). Après le pic de 2000, le total annuel de signatures de pacs entre personnes du même sexe a oscillé entre désormais être affinée en fonction du sexe des pacsés. La répartition des pacs entre personnes du même sexe'organiser juridiquement une vie de couple quel que soit le sexe des partenaires, le pacs a d'abord été une innovation

Paris-Sud XI, Université de


Die Rolle des Publikums fokussiert auf die Optionen der Mitgestaltung im öffentlich-rechtlichen Fernsehangebot des ORF in Österreich.  

E-print Network

??Untersuchungsgegenstand: Im Zentrum steht die Option und Ausführung des „Mitspracherechts“ des Publikums an fernsehpublizistischen Inhalten des öffentlich-rechtlichen Rundfunks ORF in Österreich, sowie das Angebot der… (more)

Scherzinger, Ronja-Svenja



Effects of Peripherally Restricted ? Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats  

PubMed Central

? Opioid receptor agonists that do not readily cross the blood-brain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted ? agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral ? receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central ? receptors. The present study used assays of pain-related stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted ? agonists [the tetrapeptide d-Phe-d-Phe-d-Ile-d-Arg-NH2 (ffir) and the nonpeptidic compound ((R,S)-N-[2-(N-methyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride (ICI204448)], 2) a centrally penetrating ? agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal anti-inflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted ? agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted ? agonists had little effect, and salvinorin A exacerbated acid-induced depression of ICSS. These results suggest that peripherally restricted ? agonists may be safer than centrally penetrating ? agonists but less efficacious than NSAIDS or ? opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with ? agonists capable of greater peripheral selectivity are warranted. PMID:22128346

O'Connell, Robert; Morrissey, Ember; Cheng, Kejun; Rice, Kenner C.



Synthesis and pharmacological characterization of 1-benzyl-4-aminoindole-based thyroid hormone receptor ? agonists.  


A series of 1-benzylindole-based TR? agonists were prepared and evaluated. Compounds 11b' and 11c' were found to have cholesterol-lowering in a rat model with marginal effects on cardiac function and HPT axis. The present work illustrates the potential use of indoles as inner ring isosteres. PMID:24290064

Takahashi, Naoki; Maeda, Koji; Asano, Yukiyasu; Watanabe, Nobuhide



Do We Really Need to Keep Redesigning ?2-Agonists for the Management of Asthma?  


There is an enormous drive to refine therapeutic designs and delivery systems, but in this review we ask if this is always the right direction? We choose to play devil's advocate, and argue that refining drug design is not always needed, and what is actually needed is a greater understanding of the biology of the disease. Here we focus on asthma and the ?2-agonist group of bronchodilators as an example of how a class of therapeutic has been developed and continues to be developmentally refined. In this review we define viral-induced exacerbations as the greatest cause of lung attacks and the most crucial time ?2-agonist therapy is needed. We explore the reasons why ?2-agonist therapy fails in patients with rhinovirus-induced exacerbations, and explain why further "engineered" ?2-agonist therapies is likely to continue to fail in this subset of asthmatic population. We justify our perspective by returning to the biology that underlies the cause of disease and highlight the need for "more research" into alternative therapies for this population of asthmatic patients. PMID:24909291

Van Ly, David; Oliver, Brian G G



An Assessment of the Potential Uses of Agonistic Behaviors in Termite Control1  

E-print Network

An Assessment of the Potential Uses of Agonistic Behaviors in Termite Control1 Barbara L. Thorne Michael I. Haverty2 Abstract: The potential use of termite-termite agonism in pest control is explored and evaluated. Intra- and interspecific en- counters among termites from different colonies are known to result

Standiford, Richard B.


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



Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene  

SciTech Connect

To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

Bass, Jonathan Y.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Mills, Wendy Y.; Navas, III, Frank; Parks, Derek J.; Smalley, Jr., Terrence L.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce (GSKNC)




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...


PPAR-? receptor agonists—a review of their role in diabetic management in Trinidad and Tobago  

Microsoft Academic Search

The PPAR-? receptor agonists, as a relatively new and perhaps still not very widely used class of antidiabetic agent in the Caribbean and particularly the Trinidadian context, possess pharmacologic properties that certainly have been shown to have impact on many of the inflammatory, metabolic, biochemical and structural macrovascular aberrations that occur in the type 2 diabetic. Activation of PPAR(gamma) nuclear

Steve Ian Smith



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



Long-Term Consequences of Agonistic Interactions Between Socially Naive Juvenile American Lobsters  

E-print Network

Long-Term Consequences of Agonistic Interactions Between Socially Nai¨ve Juvenile American Lobsters¨ve juvenile American lobsters (Homarus americanus) by examining the time frame over which be- havior changes- cially nai¨ve juvenile lobsters is influenced by fight experi- ence for at least 4 days. Though

Cromarty, Stuart I.


Do cuttlefish (Cephalopoda) signal their intentions to conspecifics during agonistic encounters?  

Microsoft Academic Search

Abstract. Male cuttlefish adopt a specific body pattern during agonistic behaviour called the Intense Zebra Display. Some components of the Display were variable, especially the chromatic component termed ‘dark face’, which could vary in the degree of darkness. Facial darkness was measured using a video analysis system. Males that eventually withdrew from conspecifics without fighting maintained a lighter face during




Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class  

E-print Network

(secretin-like), class B2 (adhesion- like), class C (glutamate-like), and Frizzled/Taste2 (12). Class B1Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor Andrea Kirkpatrick, Jiyoung Heo1 , Ravinder Abrol2 , and William A. Goddard III2 Materials

Goddard III, William A.


LETTER TO THE EDITOR Cannabinoid agonist WIN-55,212-2 partially restores  

E-print Network

LETTER TO THE EDITOR Cannabinoid agonist WIN-55,212-2 partially restores neurogenesis in the aged,212-2 administra- tion for 3 weeks can partially restore neurogenesis in the hippocampus of aged rats. Cannabinoid-inflammatory cytokines and modulation of microglial activation.1­4 The endo- cannabinoid system is composed of two G

Wenk, Gary


2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor  

E-print Network

2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor Lumi´r Hanus 18, 2001 (received for review November 23, 2000) Two types of endogenous cannabinoid and was confirmed by comparison with a synthetic sample. It binds to the CB1 cannabinoid receptor (Ki 21.2 0.5 n

Vogel, Zvi


Neurohypophyseal and Pituitary-Adrenocortical Responses to the Alpha1 Agonist Methoxamine in Humans  

Microsoft Academic Search

To test the hypothesis that the release of neurohypophyseal peptides into plasma in humans is stimulated by a central nervous system (CNS) alpha1 adrenergic mechanism, we measured the responses of arginine vasopressin (AVP) and oxytocin (OT) to intravenous methoxamine, an alphai agonist which enters the CNS following peripheral administration. The potential confound of baroreceptor inhibition of AVP release by the

Allen Radant; Elaine R. Peskind; Charles W. Wilkinson; Richard C. Veith; Daniel M. Dorsa; Rosemary D. Leake; E. Gore Ervin; Murray A. Raskind



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



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.



Gender differences in the intravenous self-administration of mu opiate agonists  

E-print Network

Gender differences in the intravenous self-administration of mu opiate agonists Theodore J. Cicero Gender differences have been observed in a number of aspects of the pharmacology of opiates, including gender differences exist in the intravenous (IV) self-administration of opiates in an operant

Steinbach, Joe Henry


The Three Catecholics Benserazide, Catechol and Pyrogallol are GPR35 Agonists  

PubMed Central

Nearly 1% of all clinically used drugs are catecholics, a family of catechol-containing compounds. Using label-free dynamic mass redistribution and Tango ?-arrestin translocation assays, we show that several catecholics, including benserazide, catechol, 3-methoxycatechol, pyrogallol, (+)-taxifolin and fenoldopam, display agonistic activity against GPR35. PMID:24276120

Deng, Huayun; Fang, Ye



The imidazoline I 1 receptor agonist, moxonidine, inhibits insulin secretion from isolated rat islets of Langerhans  

Microsoft Academic Search

In order to study the pharmacology of the putative imidazoline receptor involved in stimulation of insulin secretion, the potent and selective imidazoline I1 receptor agonist, moxonidine, was employed. Surprisingly, this agent caused a rapid and complete inhibition of glucose-induced insulin secretion in isolated rat islets of Langerhans. This response was reversible upon removal of the compound but was only partially

Efthymia Tsoli; Susan L. F. Chan; Noel G. Morgan



Pathological gambling associated with dopamine agonist use in restless legs syndrome  

Microsoft Academic Search

Dopamine agonists (DA) have been associated with pathological gambling (PG) and other compulsive behaviors in Parkinson's disease (PD). Although these medications are used in other conditions, we are not aware of other reports of PG exclusive to treatment for idiopathic PD. We present a case of PG arising in the context of DA use for restless legs syndrome.

Jeremy Quickfall; Oksana Suchowersky



Design and synthesis of piperazinylpyrimidinones as novel selective 5-HT(2C) agonists.  


This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence. PMID:19692241

Andrews, Mark D; Green, Martin P; Allerton, Charlotte M N; Batchelor, David V; Blagg, Julian; Brown, Alan D; Gordon, David W; McMurray, Gordon; Millns, Daniel J; Nichols, Carly L; Watson, Lesa



Cannabinoid receptor 2 and its agonists mediate hematopoiesis and hematopoietic stem and progenitor cell mobilization  

PubMed Central

Endocannabinoids are arachidonic acid derivatives and part of a novel bioactive lipid signaling system, along with their G-coupled cannabinoid receptors (CB1 and CB2) and the enzymes involved in their biosynthesis and degradation. However, their roles in hematopoiesis and hematopoietic stem and progenitor cell (HSPC) functions are not well characterized. Here, we show that bone marrow stromal cells express endocannabinoids (anandamide and 2-arachidonylglycerol), whereas CB2 receptors are expressed in human and murine HSPCs. On ligand stimulation with CB2 agonists, CB2 receptors induced chemotaxis, migration, and enhanced colony formation of bone marrow cells, which were mediated via ERK, PI3-kinase, and G?i-Rac1 pathways. In vivo, the CB2 agonist AM1241 induced mobilization of murine HSPCs with short- and long-term repopulating abilities. In addition, granulocyte colony-stimulating factor -induced mobilization of HSPCs was significantly decreased by specific CB2 antagonists and was impaired in Cnr2?/? cannabinoid type 2 receptor knockout mice. Taken together, these results demonstrate that the endocannabinoid system is involved in hematopoiesis and that CB2/CB2 agonist axis mediates repopulation of hematopoiesis and mobilization of HSPCs. Thus, CB2 agonists may be therapeutically applied in clinical conditions, such as bone marrow transplantation. PMID:21063029

Jiang, Shuxian; Alberich-Jorda, Meritxell; Zagozdzon, Radoslaw; Parmar, Kalindi; Fu, Yigong; Mauch, Peter; Banu, Naheed; Makriyannis, Alexandros; Tenen, Daniel G.; Avraham, Shalom; Groopman, Jerome E.



Recurrent laryngeal nerve activation by alpha 2 adrenergic agonists in goats.  


The purpose of this study was to test the hypothesis that respiratory and apneas induced by alpha 2 agonists in anesthetized goats are associated with an increase of upper airway expiratory-related activity, rather than a general depression of breathing. Activities of phrenic (Phr) and recurrent laryngeal nerves (RLN) were recorded in response to the alpha 2 agonists clonidine (0.5-3.0 i.v.) or guanabenz (7.0-20.0 i.v.) in ten chloralose-anesthetized goats. Injection of either alpha 2 agonist resulted in respiratory arrhythmias with a greater than seven-fold increase in TE and a 30% reduction in TI. During apneas RLN expiratory-related activity remained tonic until the next Phr burst, consistent with our hypothesis. Cessation of Phr activity during hypocapnia also resulted in a tonic increase of RLN expiratory activity; and injection of NaCN (50 i.v.) increased Phr and RLN inspiratory activities, while attenuating RLN expiratory-related activity. Inspiratory and expiratory-related activity of RLN motoneurons appear to be reciprocally modulated by alpha 2 agonists or changes in central or peripheral chemoreceptor drive. The results indicate that central apneas and respiratory arrhythmias may be associated with alpha 2-adrenoceptor modulation of laryngeal expiratory-related activity. PMID:8570915

Hedrick, M S; Ryan, M L; Bisgard, G E



Rational design of a humanized glucagon-like Peptide-1 receptor agonist antibody.  


Bovine antibody BLV1H12 possesses a unique "stalk-knob" architecture in its ultralong heavy chain CDR3, allowing substitutions of the "knob" domain with protein agonists to generate functional antibody chimeras. We have generated a humanized glucagon-like peptide-1 (GLP-1) receptor agonist antibody by first introducing a coiled-coil "stalk" into CDR3H of the antibody herceptin. Exendin-4 (Ex-4), a GLP-1 receptor agonist, was then fused to the engineered stalk with flexible linkers, and a Factor Xa cleavage site was inserted immediately in front of Ex-4 to allow release of the N-terminus of the fused peptide. The resulting clipped herceptin-Ex-4 fusion protein is more potent in?vitro in activating GLP-1 receptors than the Ex-4 peptide. The clipped herceptin-Ex-4 has an extended plasma half-life of approximately four days and sustained control of blood glucose levels for more than a week in mice. This work provides a novel approach to the development of human or humanized agonist antibodies as therapeutics. PMID:25556336

Zhang, Yong; Zou, Huafei; Wang, Ying; Caballero, Dawna; Gonzalez, Jose; Chao, Elizabeth; Welzel, Gus; Shen, Weijun; Wang, Danling; Schultz, Peter G; Wang, Feng



Discovery of Natural Phenols as G Protein-Coupled Receptor-35 (GPR35) Agonists  

PubMed Central

We report the discovery and characterization of natural phenols as G protein-coupled receptor-35 (GPR35) agonists. Pharmacological characterization using label-free dynamic mass redistribution and Tango ?-arrestin translocation assays revealed that GPR35-active natural phenols are divergent in their biased agonism. PMID:24900447




E-print Network

that drugs have very limited ability to diffuse out of the ventricles into brain tissue after i delivery is widely utilized to differentiate central versus peripheral drug effects. Briefly, iLIMITED BRAIN DIFFUSION OF THE GLUCOCORTICOID RECEPTOR AGONIST RU28362 FOLLOWING I

Spencer, Robert L.


Discovery of a new series of potent prostacyclin receptor agonists with in vivo activity in rat.  


The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat. PMID:25666818

Tran, Thuy-Anh; Shin, Young-Jun; Kramer, Bryan; Choi, Juyi; Zou, Ning; Vallar, Pureza; Martens, Peter; Douglas Boatman, P; Adams, John W; Ramirez, Juan; Shi, Yunqing; Morgan, Michael; Unett, David J; Chang, Steve; Shu, Hsin-Hui; Tung, Shiu-Feng; Semple, Graeme



Use of toll-like receptor agonists to reduce Salmonella colonization in neonatal swine  

Technology Transfer Automated Retrieval System (TEKTRAN)

Toll-like receptors (TLR) are members of a highly conserved group of receptors which recognize conserved molecular aspects of microbes. The purpose of these experiments were to ascertain the effects of the administration of the TLR 9 agonist, CpG, on the colonization of neonatal swine with Salmonel...


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.


Enantiomers of bronchodilating beta2-adrenoceptor agonists: is there a cause for concern?  


All bronchodilating beta2-adrenoceptor agonists in current clinical use are derivatives of adrenaline and are available as racemates. Whereas the vast majority of the pharmacologic and clinical documentation has been made with the racemates, there are a few studies with the individual enantiomers. It thus appears that all established pharmacologic effects of racemic beta2-agonists reside in the (R)-enantiomer, with the (S)-enantiomer being virtually inactive. In recent years the suspicion has been raised that the (S)-enantiomer of the beta2-agonists is responsible for induction of airway hyperreactivity. This suspicion is based primarily on results obtained in guinea pigs exposed to (S)-enantiomers of beta2-agonists. A number of experiments in vitro have been undertaken to find a mechanism of action for these observations in vivo. Most of the results obtained are equivocal. However, the observation that (S)-salbutamol may cause mobilization of intracellular Ca2+, apparently by means of a cholinergic mechanism, deserves further investigation. The clinical studies are focused on the enantiomers of salbutamol. They confirm the preclinical findings that the pulmonary, as well as the extrapulmonary, effects of salbutamol reside in the (R)-enantiomer. The studies available so far do not convincingly show clinically significant airway hyperreactivity after exposure to the (S)-enantiomer. Further studies are needed to settle this issue. PMID:10329804

Waldeck, B



Design and application of locally delivered agonists of the adenosine A(2A) receptor.  


The broad spectrum anti-inflammatory actions of adenosine A(2A) receptor agonists are well described. The wide distribution of this receptor, however, suggests that the therapeutic potential of these agents is likely to reside in topical treatments to avoid systemic side effects associated with oral administration. Adenosine A(2A) receptor agonists have been assessed as topical agents: GW328267X (GSK; allergic rhinitis and asthma), UK-432097 (Pfizer; chronic obstructive pulmonary disease [COPD]) and Sonedenoson (MRE0094, King Pharmaceuticals; wound healing). All trials failed to achieve effects against the desired clinical end points. This broad-based review will discuss general principles of chemical design of topically applied agents and potential therapeutic topical applications of current adenosine A(2A) receptor agonists. Potential factors contributing to the lack of efficacy in the above clinical trials will be discussed together with design principles, which may influence efficacy in disease states. Our analysis suggests that adenosine A(2A) receptor agonists have a wide therapeutic potential as topical agents in a wide variety of diseases, such as neutrophil-dependent lung diseases (acute lung injury, exacerbations in asthma and COPD), allergic rhinitis, glaucoma and wound repair. Factors that will influence topical activity include formulation, tissue retention, compound potency, receptor kinetics and pharmacokinetics. PMID:22111533

Mantell, Simon; Jones, Rhys; Trevethick, Mike



Highly potent and selective zwitterionic agonists of the ?-opioid receptor. Part 1  

Microsoft Academic Search

A series of zwitterionic ?-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and ?-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog

Donald S. Middleton; Graham N. Maw; Clare Challenger; Alan Jessiman; Patrick S. Johnson; William A. Million; Carly L. Nichols; Jenny A. Price; Michael Trevethick



Inhalation by design: dual pharmacology ?-2 agonists/M3 antagonists for the treatment of COPD.  


This paper describes the successful design and development of dual pharmacology ?-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum. PMID:21075627

Jones, Lyn H; Baldock, Helen; Bunnage, Mark E; Burrows, Jane; Clarke, Nick; Coghlan, Michele; Entwistle, David; Fairman, David; Feeder, Neil; Fulton, Craig; Hilton, Laura; James, Kim; Jones, Rhys M; Kenyon, Amy S; Marshall, Stuart; Newman, Sandra D; Osborne, Rachel; Patel, Sheena; Selby, Matthew D; Stuart, Emilio F; Trevethick, Michael A; Wright, Karen N; Price, David A



The discovery of adamantyl-derived, inhaled, long acting ? 2-adrenoreceptor agonists  

Microsoft Academic Search

The design and profile of a series of adamantyl-containing long acting ?2-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.

Alan D. Brown; Mark E. Bunnage; Paul A. Glossop; Kim James; Rhys Jones; Russell A. Lewthwaite; Simon Mantell; Christelle Perros-Huguet; David A. Price; Mike Trevethick; Rob Webster



Inhalation by design: Dual pharmacology ?-2 agonists\\/M3 antagonists for the treatment of COPD  

Microsoft Academic Search

This paper describes the successful design and development of dual pharmacology ?-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of ‘inhalation by design’. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.

Lyn H. Jones; Helen Baldock; Mark E. Bunnage; Jane Burrows; Nick Clarke; Michele Coghlan; David Entwistle; David Fairman; Neil Feeder; Craig Fulton; Laura Hilton; Kim James; Rhys M. Jones; Amy S. Kenyon; Stuart Marshall; Sandra D. Newman; Rachel Osborne; Sheena Patel; Matthew D. Selby; Emilio F. Stuart; Michael A. Trevethick; Karen N. Wright; David A. Price



Platelet-activating factor receptor agonists mediate xeroderma pigmentosum A photosensitivity.  


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



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.



Mass-spectrometric analysis of agonist-induced retinoic acid receptor gamma conformational change.  

PubMed Central

Apo and holo forms of retinoic acid receptors, and other nuclear receptors, display differential sensitivity to proteolytic digestion that likely reflects the distinct conformational states of the free and liganded forms of the receptor. We have developed a method for rapid peptide mapping of holo-retinoic acid receptor gamma that utilizes matrix-assisted laser-desorption-ionization time-of-flight MS to identify peptide fragments that are derived from the partially proteolysed holo-receptor. The peptide maps of retinoic acid receptor gamma bound by four different agonists were identical, suggesting that all four ligands induced a similar conformational change within the ligand-binding domain of the receptor. In all cases, this agonist-induced conformational change promoted the direct association of retinoic acid receptor gamma with the transcriptional co-activator p300 and inhibited interaction of the receptor with the nuclear receptor co-repressor. SR11253, a compound previously reported to exert mixed retinoic acid receptor gamma agonist/antagonist activities in cultured cells, was found to bind directly to, but only weakly altered the protease-sensitivity of, the receptor and failed to promote interaction of the receptor with p300 or induce dissociation of receptor-nuclear receptor co-repressor complexes. This technique should be generally applicable to other members of the nuclear receptor superfamily that undergo an induced structural alteration upon agonist or antagonist binding, DNA binding and/or protein-protein interaction. PMID:11829754

Peterson, Valerie J; Barofsky, Elisabeth; Deinzer, Max L; Dawson, Marcia I; Feng, Kai-Chia; Zhang, Xiao-kun; Madduru, Machender R; Leid, Mark



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