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https://www.readbyqxmd.com/read/28228713/metabolic-and-cardiovascular-benefits-and-risks-of-emd386088-a-5-ht6-receptor-partial-agonist-and-dopamine-transporter-inhibitor
#1
Magdalena Kotańska, Joanna Śniecikowska, Magdalena Jastrzębska-Więsek, Marcin Kołaczkowski, Karolina Pytka
Since 5-HT6 receptors play role in controlling feeding and satiety and dopamine is essential for normal feeding behavior, we evaluated the ability of EMD 386088-5-HT6 receptor partial agonist and dopamine transporter inhibitor-to reduce body weight in obese rats, as well as its anorectic properties (calorie intake reduction) in rat model of excessive eating and the influence on metabolism (plasma glucose and glycerol levels). We also determined the effect of the studied compound on pica behavior in rats and its influence on blood pressure after single administration...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28228552/core-engagement-with-%C3%AE-arrestin-is-dispensable-for-agonist-induced-vasopressin-receptor-endocytosis-and-erk-activation
#2
Punita Kumari, Ashish Srivastava, Eshan Ghosh, Ravi Ranjan, Shalini Dogra, Prem N Yadav, Arun K Shukla
G Protein-Coupled Receptors (GPCRs) exhibit highly conserved activation and signaling mechanisms where agonist stimulation leads to coupling of heterotrimeric G proteins and generation of second messenger response. This is followed by receptor phosphorylation, primarily in the carboxyl-terminus but also in the cytoplasmic loops, and subsequent binding of arrestins. GPCRs typically recruit arrestins through two different set of interactions, one involving phosphorylated receptor tail and the other mediated by the receptor core...
February 22, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28228071/a-rat-model-of-ischemic-enteritis-pathogenic-importance-of-enterobacteria-inos-no-and-cox-2-pge2
#3
Koji Takeuchi, Yoshino Komatsu, Yuka Nakamori, Tohru Kotani
BACKGROUND: We introduced a rat model of ischemic enteritis and investigated the roles of enterobacteria, nitric oxide (NO), and prostaglandins (PGs) in its pathogenesis. METHODS: Male rats were used after 18 h of fasting. Ischemic enteritis was induced by partial ligation of the superior mesenteric artery (SMA). Under ether anesthesia, SMA was isolated, and a stenosis was made by placing a needle (23 guage) on the vessel and ligating both the vessel and needle, and then a needle was removed from the ligature...
February 20, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28221788/substituted-2-aminopyrimidines-selective-for-%C3%AE-7-nicotinic-acetylcholine-receptor-activation-and-association-with-acetylcholine-binding-proteins
#4
Katarzyna Kaczanowska, Gisela Andrea Camacho Hernandez, Larissa Bendiks, Larissa Kohs, Jose Manuel Cornejo Bravo, Michal Harel, M G Finn, Palmer Taylor
Through studies with ligand binding to the acetylcholine binding protein (AChBP), we previously identified a series of 4,6 substituted 2-aminopyrimidines that associate with this soluble surrogate of the nicotinic acetylcholine receptor (nAChR) in a cooperative fashion, not seen for classical nicotinic agonists and antagonists. To examine receptor interactions of this structural family on ligand-gated ion channels, we employed HEK cells transfected with cDNA's encoding three requisite receptor subtypes: α7-nAChR, α4β2-nAChR and a serotonin receptor (5-HT3AR), along with a fluorescent reporter...
February 21, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28219717/effects-of-tetrahydrocannabinol-on-glucose-uptake-in-the-rat-brain
#5
I Miederer, K Uebbing, J Röhrich, S Maus, N Bausbacher, K Krauter, V Weyer-Elberich, B Lutz, M Schreckenberger, R Urban
Δ(9)-Tetrahydrocannabinol (THC) is the psychoactive component of the plant Cannabis sativa and acts as a partial agonist at cannabinoid type 1 and type 2 receptors in the brain. The goal of this study was to assess the effect of THC on the cerebral glucose uptake in the rat brain. 21 male Sprague Dawley rats (12-13 w) were examined and received five different doses of THC ranging from 0.01 to 1 mg/kg. For data acquisition a Focus 120 small animal PET scanner was used and 24.1-28.0 MBq of [(18)F]-fluoro-2-deoxy-d-glucose were injected...
February 17, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28216062/nalmefene-reduces-reward-anticipation-in-alcohol-dependence-an-experimental-functional-magnetic-resonance-imaging-study
#6
Darren R Quelch, Inge Mick, John McGonigle, Anna C Ramos, Remy S A Flechais, Mark Bolstridge, Eugenii Rabiner, Matthew B Wall, Rexford D Newbould, Björn Steiniger-Brach, Franz van den Berg, Malcolm Boyce, Dorrit Østergaard Nilausen, Lasse Breuning Sluth, Didier Meulien, Christoph von der Goltz, David Nutt, Anne Lingford-Hughes
BACKGROUND: Nalmefene is a µ- and δ-opioid receptor antagonist, κ-opioid receptor partial agonist that has recently been approved in Europe for treating alcohol dependence. It offers a treatment approach for alcohol-dependent individuals with "high-risk drinking levels" to reduce their alcohol consumption. However, the neurobiological mechanism underpinning its effects on alcohol consumption remains to be determined. Using a randomized, double-blind, placebo-controlled, within-subject crossover design we aimed to determine the effect of a single dose of nalmefene on striatal blood oxygen level-dependent (BOLD) signal change during anticipation of monetary reward using the monetary incentive delay task following alcohol challenge...
January 10, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28215489/the-role-of-estrogen-receptor-subtypes-for-induction-of-delayed-effects-on-the-estrous-cycle-and-female-reproductive-organs-in-rats
#7
Miwa Takahashi, Ryohei Ichimura, Kaoru Inoue, Tomomi Morikawa, Kazunori Kuwata, Gen Watanabe, Midori Yoshida
It has been reported that neonatal exposure to estrogens at relatively low doses can induce early onset anovulation as a delayed effect in female rats. Dysfunction of kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) was proposed to be a trigger for this effect. To determine the roles of estrogen receptor (ER) subtypes in the induction of delayed effects, we conducted a series of experiments using Donryu rats to examine whether neonatal injection of an ERα agonist (PPT), an ERβ agonist (DPN) or an ERα antagonist (ICI) could induce delayed effects...
February 16, 2017: Reproductive Biology
https://www.readbyqxmd.com/read/28211453/mechanism-of-partial-agonism-in-ampa-type-glutamate-receptors
#8
Hector Salazar, Clarissa Eibl, Miriam Chebli, Andrew Plested
Neurotransmitters trigger synaptic currents by activating ligand-gated ion channel receptors. Whereas most neurotransmitters are efficacious agonists, molecules that activate receptors more weakly-partial agonists-also exist. Whether these partial agonists have weak activity because they stabilize less active forms, sustain active states for a lesser fraction of the time or both, remains an open question. Here we describe the crystal structure of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) ligand binding domain (LBD) tetramer in complex with the partial agonist 5-fluorowillardiine (FW)...
February 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28202578/p38%C3%AE-mapk-signaling-mediates-exenatide-stimulated-microglial-%C3%AE-endorphin-expression
#9
Hai-Yun Wu, Xiao-Fang Mao, Hui Fan, Yong-Xiang Wang
Upon recent discovery, it has been established that activation of glucagon-like peptide-1 receptors (GLP-1Rs) exhibits neuroprotection and antinociception through microglial β-endorphin expression. This study aims to explore its underlying signaling mechanisms. GLP-1Rs and β-endorphin were co-expressed in primary cultures of microglia. Treatment with the GLP-1R agonist exenatide concentration-dependently stimulated microglial expression of the β-endorphin precursor gene POMC and peptide, with EC50 values of 4...
February 15, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28202387/varenicline-enhances-oxidized-ldl-uptake-by-increasing-expression-of-lox-1-and-cd36-scavenger-receptors-through-%C3%AE-7-nachr-in-macrophages
#10
Yuki Kanaoka, Mitsuhisa Koga, Keita Sugiyama, Kaoru Ohishi, Yasufumi Kataoka, Atsushi Yamauchi
Varenicline is a widely used and effective drug for smoking cessation. It is a partial agonist of the α4β2 nicotinic acetylcholine receptor (nAChR) and full agonist of α7 nAChR. We have reported that varenicline aggravates formation of atherosclerotic plaques through α7 nAChR in apolipoprotein E knockout mice. However, little is known about its effects on macrophages in atherosclerotic plaques. Here, we ascertained whether varenicline promotes oxidized low-density lipoprotein (oxLDL) uptake in mouse peritoneal macrophages in vitro and clarified its mechanism...
February 12, 2017: Toxicology
https://www.readbyqxmd.com/read/28197544/plasticity-in-brainstem-mechanisms-of-pain-modulation-by-nicotinic-acetylcholine-receptors-in-the-rat
#11
Francis J Jareczek, Stephanie R White, Donna L Hammond
Individuals with chronic pain may be driven to smoke more because the analgesic efficacy of nicotine diminishes. To determine whether persistent pain diminishes the actions of a nicotinic acetylcholine receptor (nAChR) agonist in pain modulatory pathways, we examined the effects of epibatidine in the rostral ventromedial medulla (RVM) of rats with and without inflammatory injury induced by intraplantar injection of complete Freund's adjuvant (CFA). In uninjured rats, epibatidine produced a dose-dependent antinociception that was completely blocked by dihydro-β-erythroidine (DHβE; α4β2 antagonist) and partially blocked by methyllycaconitine (MLA; α7 antagonist)...
January 2017: ENeuro
https://www.readbyqxmd.com/read/28197316/design-and-synthesis-of-novel-selective-gpr40-agopams
#12
Christopher W Plummer, Matthew J Clements, Helen Chen, Murali Rajagopalan, Hubert Josien, William K Hagmann, Michael Miller, Maria E Trujillo, Melissa Kirkland, Daniel Kosinski, Joel Mane, Michele Pachanski, Boonlert Cheewatrakoolpong, Andrew F Nolting, Robert Orr, Melodie Christensen, Louis-Charles Campeau, Michael J Wright, Randal Bugianesi, Sarah Souza, Xiaoping Zhang, Jerry Di Salvo, Adam B Weinglass, Richard Tschirret-Guth, Ravi Nargund, Andrew D Howard, Steven L Colletti
GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28191815/bladder-cancer-cell-growth-and-motility-implicate-cannabinoid-2-receptor-mediated-modifications-of-sphingolipids-metabolism
#13
Arianna Bettiga, Massimo Aureli, Giorgia Colciago, Valentina Murdica, Marco Moschini, Roberta Lucianò, Daniel Canals, Yusuf Hannun, Petter Hedlund, Giovanni Lavorgna, Renzo Colombo, Rosaria Bassi, Maura Samarani, Francesco Montorsi, Andrea Salonia, Fabio Benigni
The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC). CB expression on human normal and BC specimens was tested by immunohistochemistry. Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling. CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28190698/therapeutic-effects-of-cannabinoids-in-animal-models-of-seizures-epilepsy-epileptogenesis-and-epilepsy-related-neuroprotection
#14
REVIEW
Evan C Rosenberg, Pabitra H Patra, Benjamin J Whalley
The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the >100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection...
February 9, 2017: Epilepsy & Behavior: E&B
https://www.readbyqxmd.com/read/28190661/the-novel-antipsychotic-drug-brexpiprazole-alone-and-in-combination-with-escitalopram-facilitates-prefrontal-glutamatergic-transmission-via-a-dopamine-d1-receptor-dependent-mechanism
#15
Carl Björkholm, Monica M Marcus, Åsa Konradsson-Geuken, Kent Jardemark, Torgny H Svensson
Brexpiprazole (Rexulti(®)), a novel D2/3 receptor (R) partial agonist, was recently approved as monotherapy for schizophrenia, demonstrating effectiveness against both positive and negative symptoms, and also approved as add-on treatment to antidepressant drugs, inducing a potent antidepressant effect with a faster onset compared to an antidepressant given alone. Moreover, brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. To explore whether the observed effects may be mediated via modulation of prefrontal glutamatergic transmission, we investigated the effect of brexpiprazole, alone and in combination with the SSRI escitalopram, on prefrontal glutamatergic transmission using in vitro electrophysiological intracellular recordings of deep layer pyramidal cells of the rat medial prefrontal cortex (mPFC)...
February 9, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28188737/genetic-variation-in-the-behavioral-effects-of-buprenorphine-in-female-mice-derived-from-a-murine-model-of-the-oprm1-a118g-polymorphism
#16
Caroline A Browne, Rebecca L Erickson, Julie A Blendy, Irwin Lucki
Pharmacogenetic studies have identified the non-synonymous single nucleotide polymorphism (A118G) in the human mu opioid receptor (MOR) gene (OPRM1) as a critical genetic variant capable of altering the efficacy of opioid therapeutics. To date few studies have explored the potential impact of the OPRM1 A118G polymorphism on the pharmacological effects of buprenorphine (BPN), a potent MOR partial agonist and kappa opioid receptor antagonist, which is approved by the FDA for the treatment of opioid addiction and chronic pain...
February 7, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28188284/glucagon-and-insulin-cooperatively-stimulate-fibroblast-growth-factor-21-gene-transcription-by-increasing-the-expression-of-activating-transcription-factor-4
#17
Kimberly M Alonge, Gordon P Meares, F Bradley Hillgartner
Previous studies have shown that glucagon cooperatively interacts with insulin to stimulate hepatic fibroblast growth factor 21 (FGF21) gene expression. Here, we investigated the mechanism by which glucagon and insulin increased FGF21 gene transcription in primary hepatocyte cultures. Transfection analyses demonstrated that glucagon plus insulin induction of FGF21 transcription was conferred by two activating transcription factor 4 (ATF4) binding sites in the FGF21 gene. Glucagon plus insulin stimulated a 5-fold increase in ATF4 protein abundance, and knockdown of ATF4 expression suppressed the ability of glucagon plus insulin to increase FGF21 expression...
February 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28186717/gating-motions-and-stationary-gating-properties-of-ionotropic-glutamate-receptors-computation-meets-electrophysiology
#18
Huan-Xiang Zhou
Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels essential to all aspects of brain function, including higher order processes such as learning and memory. For decades, electrophysiology was the primary means for characterizing the function of iGluRs and gaining mechanistic insight. Since the turn of the century, structures of isolated water-soluble domains and transmembrane-domain-containing constructs have provided the basis for formulating mechanistic hypotheses. Because these structures only represent sparse, often incomplete snapshots during iGluR activation, significant gaps in knowledge remain regarding structures, energetics, and dynamics of key substates along the functional processes...
February 10, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28185342/untargeted-metabolomics-analysis-of-adipogenic-transformation-in-op9-dl1-cells-using-liquid-chromatography-mass-spectrometry-implications-for-thymic-adipogenesis
#19
Jianxin Tan, Yajun Wang, Siliang Wang, Nannan Zhang, Simeng Wu, Zhe Yuan, Xike Zhu
Adipocyte deposition is a key feature of age-related thymic involution, but the underlying mechanisms responsible for thymic adiposity remain to be elucidated. In the present study, we utilized rosiglitazone, a potent peroxisome proliferator-activated receptor γ agonist, to induce adipogenic differentiation of OP9-DL1 cells, and detected the metabolomics alterations during adipogenic differentiation by using liquid chromatography-mass spectrometry. The obtained metabolites were further processed by multivariate statistical analysis, including principal component analysis, partial least squares discriminant analysis, and orthogonal projection on latent-structures discriminant analysis...
February 9, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28183259/targeting-melatonin-mt2-receptors-a-novel-pharmacological-avenue-for-inflammatory-and-neuropathic-pain
#20
Luca Posa, Danilo De Gregorio, Gabriella Gobbi, Stefano Comai
Melatonin (MLT) has been implicated in several pathophysiological states, including pain. MLT mostly activates two G-protein coupled receptors, MT1 and MT2. In this review, we present the analgesic properties of MLT in preclinical and clinical studies, giving particular emphasis to the effects mediated by MT2 receptors and to recent investigations demonstrating the analgesic effects of MT2 receptor partial agonists in chronic and acute/inflammatory pain conditions. MT2 receptors are localized in specific brain areas, including the reticular and the ventromedial nuclei of the thalamus (part of the ascending nociceptive pathway) and the ventrolateral periaqueductal grey matter (vlPAG) (part of the descending antinociceptive pathway)...
February 8, 2017: Current Medicinal Chemistry
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