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https://www.readbyqxmd.com/read/28105289/development-of-4-heteroarylamino-1-azaspiro-oxazole-5-3-bicyclo-2-2-2-octanes-as-%C3%AE-7-nicotinic-receptor-agonists
#1
Matthew D Hill, Haiquan Fang, H Dalton King, Christiana I Iwuagwu, Ivar M McDonald, James Cook, F Christopher Zusi, Robert A Mate, Ronald J Knox, Debra Post-Munson, Amy Easton, Regina Miller, Kimberley Lentz, Wendy Clarke, Yulia Benitex, Nicholas Lodge, Robert Zaczek, Rex Denton, Daniel Morgan, Linda Bristow, John E Macor, Richard Olson
We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1'S,3'R,4'S)-N-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (20) and (1'S,3'R,4'S)-N-(7-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28101322/brexpiprazole-and-cariprazine-distinguishing-two-new-atypical-antipsychotics-from-the-original-dopamine-stabilizer-aripiprazole
#2
REVIEW
Joshua S Frankel, Thomas L Schwartz
BACKGROUND: Brexpiprazole and cariprazine are the latest US Food and Drug Administration approved atypical antipsychotics available in the United States. Both function as partial agonists of the dopamine-2 receptor (D2R), a mechanism of action shared with aripiprazole. However, all three differ in their affinities for the D2R as well as for serotonin receptors (5-HTRs). This paper seeks to delineate these pharmacodynamic and clinical differences amongst the three dopamine partial agonist atypical antipsychotic drugs...
January 2017: Therapeutic Advances in Psychopharmacology
https://www.readbyqxmd.com/read/28098409/trpv4-contributes-to-resting-membrane-potential-in-retinal-m%C3%A3-ller-cells-implications-in-cell-volume-regulation
#3
Vanina Netti, Juan Fernández, Maia Kalstein, Alejandro Pizzoni, Gisela Di Giusto, Valeria Rivarola, Paula Ford, Claudia Capurro
Neural activity alters osmotic gradients favoring cell swelling in retinal Müller cells. This swelling is followed by a regulatory volume decrease (RVD), partially mediated by an efflux of KCl and water. The transient receptor potential channel 4 (TRPV4), a nonselective calcium channel, has been proposed as a candidate for mediating intracellular Ca(2+) elevation induced by swelling. We previously demonstrated in a human Müller cell line (MIO-M1) that RVD strongly depends on ion channel activation and, consequently, on membrane potential (Vm )...
January 18, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28093646/mechanisms-of-inhibitory-action-of-trk-130-naltalimide-a-%C3%AE-opioid-receptor-partial-agonist-on-the-micturition-reflex
#4
Morihiro Fujimura, Naoki Izumimoto, Sayoko Kanie, Ryosuke Kobayashi, Satoru Yoshikawa, Shinobu Momen, Mikito Hirakata, Toshikazu Komagata, Satoshi Okanishi, Masashi Iwata, Tadatoshi Hashimoto, Takayuki Doi, Naoki Yoshimura, Koji Kawai
PURPOSE: To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique µ-opioid receptor partial agonist, on the micturition reflex. METHODS: The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats...
January 16, 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28090714/transplantation-of-cd51-stem-leydig-cells-a-new-strategy-for-the-treatment-of-testosterone-deficiency
#5
Zhi Jun Zang, Jiancheng Wang, Zhihong Chen, Yan Zhang, Yong Gao, Zhijian Su, Ying Tuo, Yan Liao, Min Zhang, Qunfang Yuan, Chunhua Deng, Mei Hua Jiang, Andy Peng Xiang
Stem Leydig cell (SLC) transplantation could provide a new strategy for treating the testosterone deficiency. Our previous study demonstrated that CD51 (also called integrin αv) might be a putative cell surface marker for SLCs, but the physiological function and efficacy of CD51(+) SLCs treatment remain unclear. Here, we explore the potential therapeutic benefits of CD51(+) SLCs transplantation and whether these transplanted cells can be regulated by the hypothalamic-pituitary-gonadal (HPG) axis. CD51(+) cells were isolated from the testes of 12-weeks-old C57BL/6 mice, and we showed that such cells expressed SLC markers and that they were capable of self-renewal, extensive proliferation, and differentiation into multiple mesenchymal cell lineages and LCs in vitro...
January 16, 2017: Stem Cells
https://www.readbyqxmd.com/read/28090636/my-dad-can-beat-your-dad-agonists-antagonists-partial-agonists-and-inverse-agonists
#6
REVIEW
Peter C Kowalski, Jonathan S Dowben, Norman L Keltner
No abstract text is available yet for this article.
January 16, 2017: Perspectives in Psychiatric Care
https://www.readbyqxmd.com/read/28089846/modulation-of-neuroinflammation-and-pathology-in-the-5xfad-mouse-model-of-alzheimer-s-disease-using-a-biased-and-selective-beta-1-adrenergic-receptor-partial-agonist
#7
Pooneh Memar Ardestani, Andrew K Evans, Bitna Yi, Tiffany Nguyen, Laurence Coutellier, Mehrdad Shamloo
Degeneration of noradrenergic neurons occurs at an early stage of Alzheimer's Disease (AD). The noradrenergic system regulates arousal and learning and memory, and has been implicated in regulating neuroinflammation. Loss of noradrenergic tone may underlie AD progression at many levels. We have previously shown that acute administration of a partial agonist of the beta-1 adrenergic receptor (ADRB1), xamoterol, restores behavioral deficits in a mouse model of AD. The current studies examined the effects of chronic low dose xamoterol on neuroinflammation, pathology, and behavior in the pathologically aggressive 5XFAD transgenic mouse model of AD...
January 12, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28089597/magnesium-and-calcium-ions-differentially-affect-human-serine-racemase-activity-and-modulate-its-quaternary-equilibrium-toward-a-tetrameric-form
#8
Stefano Bruno, Marilena Margiotta, Francesco Marchesani, Gianluca Paredi, Valentina Orlandi, Serena Faggiano, Luca Ronda, Barbara Campanini, Andrea Mozzarelli
Serine racemase is the pyridoxal 5'-phosphate dependent enzyme that catalyzes both production and catabolism of d-serine, a co-agonist of the NMDA glutamate receptors. Mg(2+), or, alternatively, Ca(2+), activate human serine racemase by binding both at a specific site and - as ATP-metal complexes - at a distinct ATP binding site. We show that Mg(2+) and Ca(2+) bind at the metal binding site with a 4.5-fold difference in affinity, producing a similar thermal stabilization and partially shifting the dimer-tetramer equilibrium in favour of the latter...
January 9, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28088486/pharmacological-targeting-of-adenosine-receptor-signaling
#9
REVIEW
Maria Peleli, Bertil Fredholm, Luis Sobrevia, Mattias Carlström
Adenosine receptor signaling plays important roles in normal physiology, but is also known to modulate the development or progression of several different diseases. The design of new, efficient, and safe pharmacological approaches to target the adenosine system may have considerable therapeutic potential, but is also associated with many challenges. This review summarizes the main challenges of adenosine receptor targeted treatment including tolerance, disease stage, cell type-specific effects, caffeine intake, adenosine level assessment and receptor distribution in vivo...
January 11, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28088386/trypsin-induces-biphasic-muscle-contraction-and-relaxation-via-transient-receptor-potential-vanilloid-1-and-neurokinin-receptors-1-2-in-porcine-esophageal-body
#10
Bai Xiaopeng, Yoshimasa Tanaka, Eikichi Ihara, Katsuya Hirano, Kayoko Nakano, Mayumi Hirano, Yoshinao Oda, Kazuhiko Nakamura
Duodenal reflux of fluids containing trypsin relates to refractory gastroesophageal reflux disease (GERD). Esophageal peristalsis and clearance are important factors in GERD pathogenesis. However, the function of trypsin in esophageal body contractility is not fully understood. In this study, effects of trypsin on circular smooth muscle (CSM) and longitudinal smooth muscle (LSM) of the porcine esophageal body were examined. Trypsin elicited a concentration dependent biphasic response, a major contraction and a subsequent relaxation only in CSM...
January 11, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28087808/identification-of-a-novel-liver-x-receptor-agonist-that-regulates-the-expression-of-key-cholesterol-homeostasis-genes-with-distinct-pharmacological-characteristics
#11
Ni Li, Xiao Wang, Yanni Xu, Yuan Lin, Ningyu Zhu, Peng Liu, Duo Lu, Shuyi Si
Activation of Liver X receptor (LXR) is associated with cholesterol metabolism and anti-inflammatory processes, which makes beneficial to anti-atherosclerosis. Nevertheless, existing agonists which target LXR, for example TO901317, are related to unwanted side-effects. In the present study, using a screening method we identified IMB-808, which displayed potent dual LXRα/β agonistic activity. In vitro, IMB-808 effectively increased the expressing quantity of genes related to reverse cholesterol transport process as well as those associated with cholesterol metabolism pathway in multiple cell lines...
January 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28087752/deficient-retinoid-driven-angiogenesis-may-contribute-to-failure-of-adult-human-lung-regeneration-in-emphysema
#12
John-Poul Ng-Blichfeldt, Joana Alçada, M Angeles Montero, Charlotte H Dean, Uta Griesenbach, Mark J Griffiths, Matthew Hind
BACKGROUND: Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease. OBJECTIVES: To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema...
January 13, 2017: Thorax
https://www.readbyqxmd.com/read/28087250/pharmacology-of-cannabinoids-in-the-treatment-of-epilepsy
#13
REVIEW
Tyler E Gaston, Daniel Friedman
The use of cannabis products in the treatment of epilepsy has long been of interest to researchers and clinicians alike; however, until recently very little published data were available to support its use. This article summarizes the available scientific data of pharmacology from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including ∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), ∆9-tetrahydrocannabivarin (∆9-THCV), cannabidivarin (CBDV), and ∆9-tetrahydrocannabinolic acid (Δ9-THCA)...
January 10, 2017: Epilepsy & Behavior: E&B
https://www.readbyqxmd.com/read/28087221/varenicline-provokes-impulsive-action-by-stimulating-%C3%AE-4%C3%AE-2-nicotinic-acetylcholine-receptors-in-the-infralimbic-cortex-in-a-nicotine-exposure-status-dependent-manner
#14
Yu Ohmura, Hitomi Sasamori, Iku Tsutsui-Kimura, Takeshi Izumi, Takayuki Yoshida, Mitsuhiro Yoshioka
Higher impulsivity is a risk factor for criminal involvement and drug addiction. Because nicotine administration enhances impulsivity, the effects of stop-smoking aids stimulating nicotinic acetylcholine receptors (nAChRs) on impulsivity must be determined in different conditions. Our goals were 1) to confirm the relationship between varenicline, a stop-smoking aid and α4β2 nAChR partial agonist, and impulsivity, 2) to elucidate the mechanisms underlying the effects of varenicline, 3) to examine whether a low dose of varenicline that does not evoke impulsive action could block the stimulating effects of nicotine on impulsive action, 4) to determine whether the route of administration could modulate the effects of varenicline on impulsive action, and 5) to determine whether the effects of varenicline on impulsivity could be altered by smoking status...
January 10, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28086830/sigma-2-receptor-agonist-derivatives-of-1-cyclohexyl-4-3-5-methoxy-1-2-3-4-tetrahydronaphthalen-1-yl-propyl-piperazine-pb28-induce-cell-death-via-mitochondrial-superoxide-production-and-caspase-activation-in-pancreatic-cancer
#15
Maria Laura Pati, John R Hornick, Mauro Niso, Francesco Berardi, Dirk Spitzer, Carmen Abate, William Hawkins
BACKGROUND: Despite considerable efforts by scientific research, pancreatic cancer is the fourth leading cause of cancer related mortalities. Sigma-2 receptors, which are overexpressed in several tumors, represent promising targets for triggering selective pancreatic cancer cells death. METHODS: We selected five differently structured high-affinity sigma-2 ligands (PB28, PB183, PB221, F281 and PB282) to study how they affect the viability of diverse pancreatic cancer cells (human cell lines BxPC3, AsPC1, Mia PaCa-2, and Panc1 and mouse Panc-02, KCKO and KP-02) and how this is reflected in vivo in a tumor model...
January 13, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28086800/relevance-of-fxr-p62-sqstm1-pathway-for-survival-and-protection-of-mouse-hepatocytes-and-liver-especially-with-steatosis
#16
Sanae Haga, Yimin, Michitaka Ozaki
BACKGROUND: Liver injury and regeneration involve complicated processes and are affected by various physio-pathological conditions. Surgically, severe liver injury after surgical resection often leads to fatal liver failure, especially with some underlying pathological conditions such as steatosis. Therefore, protection from the injury of hepatocytes and liver is a serious concern in various clinical settings. METHODS: We studied the effects of the farnesoid X receptor (FXR) on cell survival and steatosis in mouse hepatocytes (AML12 mouse liver cells) and investigated their molecular mechanisms...
January 13, 2017: BMC Gastroenterology
https://www.readbyqxmd.com/read/28076827/new-diphenylmethane-derivatives-as-peroxisome-proliferator-activated-receptor-alpha-gamma-dual-agonists-endowed-with-anti-proliferative-effects-and-mitochondrial-activity
#17
Luca Piemontese, Carmen Cerchia, Antonio Laghezza, Pamela Ziccardi, Sabina Sblano, Paolo Tortorella, Vito Iacobazzi, Vittoria Infantino, Paolo Convertini, Fabrizio Dal Piaz, Angelo Lupo, Vittorio Colantuoni, Antonio Lavecchia, Fulvio Loiodice
We screened a short series of new chiral diphenylmethane derivatives and identified potent dual PPARα/γ partial agonists. As both enantiomers of the most active compound 1 displayed an unexpected similar transactivation activity, we performed docking experiments to provide a molecular understanding of their similar partial agonism. We also evaluated the ability of both enantiomers of 1 and racemic 2 to inhibit colorectal cancer cells proliferation: (S)-1 displayed a more robust activity due, at least in part, to a partial inhibition of the Wnt/β-catenin signalling pathway that is upregulated in the majority of colorectal cancers...
December 24, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28074670/metabolism-of-psilocybin-and-psilocin-clinical-and-forensic-toxicological-relevance
#18
Ricardo Jorge Dinis-Oliveira
Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the "magic mushrooms" and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites...
January 11, 2017: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/28070618/blunted-5-ht1a-receptor-mediated-responses-and-antidepressant-like-behavior-in-mice-lacking-the-gabab1a-but-not-gabab1b-subunit-isoforms
#19
Laura H Jacobson, Daniel Hoyer, Dominique Fehlmann, Bernhard Bettler, Klemens Kaupmann, John F Cryan
RATIONALE: There is accumulating evidence for a role of GABAB receptors in depression. GABAB receptors are heterodimers of GABAB1 and GABAB2 receptor subunits. The predominant GABAB1 subunit isoforms are GABAB1a and GABAB1b. GABAB1 isoforms in mice differentially influence cognition, conditioned fear, and susceptibility to stress, yet their influence in tests of antidepressant-like activity has not been fully investigated. OBJECTIVES: Given the interactions between GABAB receptors and the serotonergic system and the involvement of 5-HT1A receptors (5-HT1AR) in antidepressant action, we sought to evaluate 5-HT1AR function in GABAB1a(-/-) and GABAB1b(-/-) mice...
January 9, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28065843/alpha-7-nicotinic-agonists-for-cognitive-deficits-in-neuropsychiatric-disorders-a-translational-meta-analysis-of-rodent-and-human-studies
#20
Alan S Lewis, Gerrit I van Schalkwyk, Michael H Bloch
Cognitive dysfunction in schizophrenia (SCZ) and Alzheimer's disease (AD) is a major driver of functional disability but is largely unresponsive to current therapeutics. Animal models of cognitive dysfunction relevant to both disorders suggest the α7 nicotinic acetylcholine receptor (nAChR) may be a promising drug development target, with multiple clinical trials subsequently testing this hypothesis in individuals with SCZ and AD. However, the translational value of rodent cognitive tasks for predicting the overall efficacy of this therapeutic target in clinical trials is unknown...
January 5, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
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