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https://www.readbyqxmd.com/read/28342850/structural-basis-for-differential-activities-of-enantiomeric-ppar%C3%AE-agonists-binding-of-s35-to-the-alternate-site
#1
Jun Young Jang, Minseob Koh, Hwan Bae, Doo Ri An, Ha Na Im, Hyoun Sook Kim, Ji Young Yoon, Hye-Jin Yoon, Byung Woo Han, Seung Bum Park, Se Won Suh
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte differentiation, type 2 diabetes mellitus, and inflammation. Many PPARγ agonists bind to the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12) of the ligand-binding domain (LBD). More recently, an alternate ligand-binding site was identified in PPARγ LBD; it is located beside the Ω loop between the helices H2' and H3...
March 22, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28342550/the-effects-of-endothelin-1-on-satellite-glial-cells-in-peripheral-ganglia
#2
Rachel Feldman-Goriachnik, Menachem Hanani
Endothelins (ET) are a family of highly active neuropeptides with manifold influences via ET receptors (ETR) in both the peripheral and central nervous systems. We have shown previously that satellite glial cells (SGCs) in mouse trigeminal ganglia (TG) are extremely sensitive to ET-1 in evoking [Ca(2+)]in increase, apparently via ETBR activation, but there is no functional information on ETR in SGCs of other peripheral ganglia. Here we tested the effects of ET-1 on SGCs in nodose ganglia (NG), which is sensory, and superior cervical ganglia (Sup-CG), which is part of the sympathetic nervous system, and further investigated the influence of ET-1 on SGCs in TG...
March 18, 2017: Neuropeptides
https://www.readbyqxmd.com/read/28337332/bms-933043-a-selective-%C3%AE-7-nachr-partial-agonist-for-the-treatment-of-cognitive-deficits-associated-with-schizophrenia
#3
Dalton King, Christiana Iwuagwu, Jim Cook, Ivar M McDonald, Robert Mate, F Christopher Zusi, Matthew D Hill, Haiquan Fang, Rulin Zhao, Bei Wang, Amy E Easton, Regina Miller, Debra Post-Munson, Ronald J Knox, Lizbeth Gallagher, Ryan Westphal, Thaddeus Molski, Jingsong Fan, Wendy Clarke, Yulia Benitex, Kimberley A Lentz, Rex Denton, Daniel Morgan, Robert Zaczek, Nicholas J Lodge, Linda J Bristow, John E Macor, Richard E Olson
The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent α7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold)...
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28337258/neuroprotective-effect-of-win55-212-2-against-3-nitropropionic-acid-induced-toxicity-in-the-rat-brain-involvement-of-cb1-and-nmda-receptors
#4
Marisol Maya-López, Ana Laura Colín-González, Gabriela Aguilera, María Eduarda de Lima, Ana Colpo-Ceolin, Edgar Rangel-López, Juana Villeda-Hernández, Daniel Rembao-Bojórquez, Isaac Túnez, Armando Luna-López, Roberto Lazzarini-Lechuga, Viridiana Yazmín González-Puertos, Pedro Posadas-Rodríguez, Alejandro Silva-Palacios, Mina Königsberg, Abel Santamaría
The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity. Actually, CBr agonists can be neuroprotective. The synthetic CBr agonist WIN55,212-2 acts mainly on CB1 receptor. In turn, the mitochondrial toxin 3-nitropropionic acid (3-NP) produces striatal alterations in rats similar to those observed in the brain of Huntington's disease patients...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28336105/tolerance-and-efficacy-of-a-polyamine-deficient-diet-for-the-treatment-of-perioperative-pain
#5
Jean-Pierre Estebe, Cécile Degryse, Gilles Rezzadori, Florin Dimache, Georges Daccache, Alain Le Naoures, Anissa Belbachir, Pierre Schoeffler, Anne-Laure Sérandour
BACKGROUND: Polyamines have been identified as pain agonists and interact with N-methyl-D-aspartate receptors. A prospective, randomized, multicenter, and blinded phase II clinical trial was conducted to evaluate a polyamine-deficient diet for the treatment of perioperative pain in patients during spinal surgery. METHODS: All analyses followed the intention-to-treat principle. The trial was designed to evaluate the dose-ranging effect of a low polyamine diet with respect to a total (group 1) or partial (group 2) polyamine diet on perioperative pain (7 d before and 5 d after surgery)...
April 2017: Nutrition
https://www.readbyqxmd.com/read/28334444/the-partial-dopamine-d2-receptor-agonist-aripiprazole-is-associated-with-weight-gain-in-adolescent-anorexia-nervosa
#6
Guido K W Frank, Megan E Shott, Jennifer O Hagman, Marissa A Schiel, Marisa C DeGuzman, Brogan Rossi
OBJECTIVE: Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience-based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine-related reward circuits are hypersensitive and could provide a treatment target. METHODS: Here, we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program...
March 23, 2017: International Journal of Eating Disorders
https://www.readbyqxmd.com/read/28331332/clinical-role-of-brexpiprazole-in-depression-and-schizophrenia
#7
REVIEW
Nishant B Parikh, Diana M Robinson, Anita H Clayton
Brexpiprazole, a serotonin-dopamine activity modulator, is the second D2 partial agonist to come to market and has been approved for the treatment of schizophrenia and as an adjunctive treatment in major depressive disorder. With less intrinsic activity than aripiprazole at the D2 receptor and higher potency at 5-HT2A, 5-HT1A, and α1B receptors, the pharmacological properties of brexpiprazole suggest a more tolerable side effect profile with regard to akathisia, extrapyramidal dysfunction, and sedation. While no head-to-head data are currently available, double-blind placebo-controlled studies show favorable results, with the number needed to treat (NNT) vs placebo of 6-15 for response in acute schizophrenia treatment and 4 for maintenance...
2017: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/28331191/identification-of-a-novel-small-molecule-partial-agonist-for-the-cyclic-amp-sensor-epac1
#8
Euan Parnell, Stuart P McElroy, Jolanta Wiejak, Gemma L Baillie, Alison Porter, David R Adams, Holger Rehmann, Brian O Smith, Stephen J Yarwood
Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory effects within the primary screening assay. Follow-up characterisation by ligand observed nuclear magnetic resonance (NMR) revealed direct interaction of I942 and I178 with EPAC1 and EPAC2-CNBs in vitro. Moreover, in vitro guanine nucleotide exchange factor (GEF) assays revealed that I942 and, to a lesser extent, I178 had partial agonist properties towards EPAC1, leading to activation of EPAC1, in the absence of cAMP, and inhibition of GEF activity in the presence of cAMP...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28328159/improved-disease-activity-with-fosdagrocorat-pf-04171327-a-partial-agonist-of-the-glucocorticoid-receptor-in-patients-with-rheumatoid-arthritis-a-phase-2-randomized-study
#9
Thomas Stock, Dona Fleishaker, Xin Wang, Arnab Mukherjee, Charles Mebus
AIM: To assess efficacy and safety of fosdagrocorat (PF-04171327), a potential dissociated agonist of the glucocorticoid receptor, in rheumatoid arthritis (RA) patients. METHODS: This multicenter, double-blind, parallel-group, active- and placebo-controlled Phase 2 study (NCT00938587) randomized 86 patients (1 : 1 : 1 : 1) to receive fosdagrocorat 10 mg, fosdagrocorat 25 mg, prednisone 5 mg or placebo, all with stable background methotrexate therapy. The primary outcome was change from baseline in Disease Activity Score of 28 joints (DAS28-4[C-reactive protein (CRP)]) after 2 weeks of treatment...
March 22, 2017: International Journal of Rheumatic Diseases
https://www.readbyqxmd.com/read/28323246/the-role-of-spinal-gabab-receptors-in-cancelr-induced-bone-pain-in-rats
#10
Ya-Qun Zhou, Shu-Ping Chen, Dai-Qiang Liu, Anne Manyande, Wen Zhang, Shao-Bing Yang, Bing-Rui Xiong, Qiao-Chu Fu, Zhen-Peng Song, Heike Rittner, Da-Wei Ye, Yu-Ke Tian
Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients due to our lack of understanding of its mechanisms. Previous studies have demonstrated the vital role of GABAB receptors (GABABRs) in regulating nociception and various neuropathic pain models have shown diminished activity of GABABRs. However, the role of spinal GABABRs in CIBP remains largely unknown. In this study, we investigated the specific cellular mechanisms of GABABRs in the development and maintenance of CIBP in rats...
March 18, 2017: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/28323103/cr-vi-induces-cytotoxicity-in-vitro-through-activation-of-ros-mediated-endoplasmic-reticulum-stress-and-mitochondrial-dysfunction-via-the-pi3k-akt-signaling-pathway
#11
Yujing Zhang, Fang Xiao, Xinmin Liu, Kaihua Liu, Xiaoxin Zhou, Caigao Zhong
The occupational and environmental toxicant hexavalent chromium [Cr(VI)] can cause severe damage to the liver; however, the exact mechanisms associated with its toxicity have not been thoroughly demonstrated. In the present study, the underlying mechanisms of Cr(VI)-induced hepatotoxicity were investigated. Our results showed that Cr(VI) inhibited the growth and proliferation of L-02 hepatocytes. Further study revealed that Cr(VI) significantly induced S-phase cell cycle arrest and apoptosis accompanying with the overproduction of reactive oxygen species (ROS)...
March 17, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28322465/opioid-substitution-therapy-or-hidden-opioids-are-a-minefield-for-nalmefene-an-atypical-case-series-of-11-patients-in-lorraine
#12
Melissa Yéléhé-Okouma, Hervé Martini, Jérémie Lemarié, Pierre Labroca, Nadine Petitpain, Valérie Gibaja, François Paille, Pierre Gillet
Opioid antagonists such as naltrexone and nalmefene are used in drug therapy for alcoholism. Nalmefene, approved in Europe in February 2013 for the reduction of alcohol consumption is used in patients with alcohol dependence. We report 11 cases of opioid withdrawal syndrome after a single dose of nalmefene in patients usually treated with methadone, buprenorphine, but also with fentanyl or loperamide. Nalmefene is both a partial agonist and an antagonist of opioid receptors. Regarding to its opioid antagonist activity, nalmefene is contraindicated in patients with an opioid treatment...
March 21, 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28322281/identification-of-a-novel-fast-acting-gabaergic-antidepressant
#13
K M J McMurray, M J Ramaker, A M Barkley-Levenson, P S Sidhu, P K Elkin, M K Reddy, M L Guthrie, J M Cook, V H Rawal, L A Arnold, S C Dulawa, A A Palmer
Current pharmacotherapies for depression exhibit slow onset, side effects and limited efficacy. Therefore, identification of novel fast-onset antidepressants is desirable. GLO1 is a ubiquitous cellular enzyme responsible for the detoxification of the glycolytic byproduct methylglyoxal (MG). We have previously shown that MG is a competitive partial agonist at GABA-A receptors. We examined the effects of genetic and pharmacological inhibition of GLO1 in two antidepressant assay models: the tail suspension test (TST) and the forced swim test (FST)...
March 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28322152/serotonin-receptor-binding-characteristics-of-geissoschizine-methyl-ether-an-indole-alkaloid-in-uncaria-hook
#14
Yasushi Ikarashi, Kyoji Sekiguchi, Kazushige Mizoguchi
Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological symptoms of dementia (BPSD) in patients with several types of dementia. The pharmacological action of GM has been related to various serotonin (5-HT) receptor subtypes. Here we describe previous findings and our own data to review the binding characteristics of GM to the 5-HT receptor subtypes. Competitive receptor-binding assays showed that GM bound the following 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4, 5-HT5A, 5-HT6, and 5-HT7...
March 20, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28314512/modulation-of-opioid-receptor-affinity-and-efficacy-via-n-substitution-of-9%C3%AE-hydroxy-5-3-hydroxyphenyl-morphan-synthesis-and-computer-simulation-study
#15
Phong M Truong, Sergio A Hassan, Yong-Sok Lee, Theresa A Kopajtic, Jonathan L Katz, Aaron M Chadderdon, John R Traynor, Jeffrey R Deschamps, Arthur E Jacobson, Kenner C Rice
The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3 to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ(35)S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(-) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3...
March 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28303901/mutual-reinforcement-between-telomere-capping-and-canonical-wnt-signalling-in-the-intestinal-stem-cell-niche
#16
Ting-Lin B Yang, Qijun Chen, Jennifer T Deng, Geetha Jagannathan, John W Tobias, David C Schultz, Shan Wang, Christopher J Lengner, Anil K Rustgi, John P Lynch, F Brad Johnson
Critical telomere shortening (for example, secondary to partial telomerase deficiency in the rare disease dyskeratosis congenita) causes tissue pathology, but underlying mechanisms are not fully understood. Mice lacking telomerase (for example, mTR(-/-) telomerase RNA template mutants) provide a model for investigating pathogenesis. In such mice, after several generations of telomerase deficiency telomeres shorten to the point of uncapping, causing defects most pronounced in high-turnover tissues including intestinal epithelium...
March 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28300338/chinese-1-strain-of-toxoplasma-gondii-excreted-secreted-antigens-negatively-modulate-foxp3-via-inhibition-of-the-tgf%C3%A3-rii-smad2-smad3-smad4-pathway
#17
Jinling Chen, Caiqun Huang, Dandan Zhu, Pei Shen, Yinong Duan, Jianxin Wang, Chunzhao Yang, Liting Wu
Toxoplasma gondii is an opportunistic intracellular parasite and is considered an important aetiological factor in the process of abortion, especially as occurs in early gestation. Chinese 1 strain of T. gondii is a dominant genotype prevalent in China. Although it is known that early foetal resorption triggered by RH strain of T. gondii is attributable to immune mechanisms rather than its direct effect in uterus, the underlying mechanism of the abortion caused by Chinese 1 strain remains unclear. This study was designed to investigate the effect of excreted-secreted antigens (ESA) of Chinese 1 strain of T...
March 16, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28295449/hepatic-mtdna-tlr9-microrna-223-forms-a-negative-feedback-loop-to-limit-neutrophil-over-activation-and-acetaminophen-hepatotoxicity
#18
Yong He, Dechun Feng, Man Li, Yanhang Gao, Teresa Ramirez, Haixia Cao, Seung-Jin Kim, Yang Yang, Yan Cai, Cynthia Ju, Hua Wang, Jun Li, Bin Gao
Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide, in which mitochondrial DNA (mtDNA) released by damaged hepatocytes activates neutrophils via the binding of TLR9, further aggravating liver injury. Here, we demonstrated that mtDNA/TLR9 also activates a negative feedback pathway via the induction of microRNA-223 (miR-223) to limit neutrophil over-activation and liver injury. After injection of APAP in mice, levels of miR-223, the most abundant miRNAs in neutrophils, were highly elevated in neutrophils...
March 13, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28294132/5-ht2c-agonists-modulate-schizophrenia-like-behaviors-in-mice
#19
Vladimir M Pogorelov, Ramona M Rodriguiz, Jianjun Cheng, Mei Huang, Claire M Schmerberg, Herbert Y Meltzer, Bryan L Roth, Alan P Kozikowski, William C Wetsel
All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2 or serotonin (5-HT2A) receptors, or both; however, these medications are not universally effective, they may produce undesirable side-effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests additional drug-targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT2C receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss promoting capabilities...
March 15, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28292762/gpr40-reduces-food-intake-and-body-weight-through-glp-1
#20
Judith N Gorski, Michele J Pachanski, Joel Mane, Christopher W Plummer, Sarah Souza, Brande S Thomas-Fowlkes, Aimie M Ogawa, Adam B Weinglass, Jerry Di Salvo, Boonlert Cheewatrakoolpong, Andrew D Howard, Steven L Colletti, Maria E Trujillo
GPR40 partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose independent insulin secretagogues. The class of small molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and GLP-1 (17)...
March 14, 2017: American Journal of Physiology. Endocrinology and Metabolism
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