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Positive allosteric modulator

Shehla Akbar, Fazal Subhan, Nasiara Karim, Muhammad Shahid, Nisar Ahmad, Gowhar Ali, Wajahat Mahmood, Khwaja Fawad
BACKGROUND: Diabetic neuropathy is the most prevalent, persistent and debilitating complication of diabetes mellitus often coupled with vulvodynia that may present as an isolated symptom or as a part of constellation of other neuropathic abnormalities. OBJECTIVE: Flavonoids have selective affinity for GABA receptors and 6-methoxyflavanone (6-MeOF) is a positive allosteric modulator of GABA responses at human recombinant GABAA receptors. GABAergic and opioidergic system inhibition have been shown to facilitate neuropathic pain...
October 17, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Graeme Milligan, Daniele Bolognini, Eugenia Sergeev
A large number of reviews and commentaries have highlighted the potential role of the short-chain fatty acid receptors GPR41 (FFA3) and, particularly, GPR43 (FFA2) as an interface between the intestinal microbiota and metabolic and inflammatory disorders. However, short-chain fatty acids have very modest potency and display limited selectivity between these two receptors, and studies on receptor knockout mice have resulted in non-uniform conclusions; therefore, selective and high-potency/high-affinity synthetic ligands are required to further explore the contribution of these receptors to health and disease...
October 19, 2016: Handbook of Experimental Pharmacology
Anahita Nourmahnad, Alex T Stern, Mayo Hotta, Deirdre S Stewart, Alexis M Ziemba, Andrea Szabo, Stuart A Forman
BACKGROUND: γ-Aminobutyric acid type A (GABAA) receptors mediate important effects of intravenous general anesthetics. Photolabel derivatives of etomidate, propofol, barbiturates, and a neurosteroid get incorporated in GABAA receptor transmembrane helices M1 and M3 adjacent to intersubunit pockets. However, photolabels have not been consistently targeted at heteromeric αβγ receptors and do not form adducts with all contact residues. Complementary approaches may further define anesthetic sites in typical GABAA receptors...
October 7, 2016: Anesthesiology
Luisa F Castiblanco, George W Sundin
Bacterial biofilms are multicellular aggregates encased in an extracellular matrix mainly composed of exopolysaccharides (EPSs), protein, and nucleic acids, which determines the architecture of the biofilm. Erwinia amylovora Ea1189 forms a biofilm inside the xylem of its host, that results in vessel plugging and water transport impairment. Production of the EPSs amylovoran and levan are critical for the formation of a mature biofilm. Additionally, cyclic dimeric GMP (c-di-GMP) was reported to positively regulate amylovoran biosynthesis and biofilm formation in E...
October 18, 2016: Molecular Plant Pathology
Marat R Talipov, Jaladhi Nayak, Michael Lepley, Robert D Bongard, Daniel S Sem, Ramani Ramchandran, Rajendra Rathore
DUSP5 is an inducible nuclear dual-specificity phosphatase that specifically interacts with and deactivates extracellular signal-regulated kinases ERK1 and ERK2, which are responsible for cell proliferation, differentiation, and survival. The phosphatase domain (PD) of DUSP5 has unique structural features absent in other nuclear DUSPs, such as presence of a secondary anion-binding site in the proximity to the reaction center and a glutamic acid E264 positioned next to the catalytic cysteine C263, as well as a remote intra-molecular disulfide linkage...
October 14, 2016: Biochemistry
Guy Griebel, Philippe Pichat, Denis Boulay, Vanessa Naimoli, Lisa Potestio, Robert Featherstone, Sukhveen Sahni, Henry Defex, Christophe Desvignes, Franck Slowinski, Xavier Vigé, Olivier E Bergis, Rosy Sher, Raymond Kosley, Sathapana Kongsamut, Mark D Black, Geoffrey B Varty
Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ(35)S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca(2+) mobilization assay...
October 13, 2016: Scientific Reports
Harry Z E Greenberg, Kazi S Jahan, Jian Shi, W-S Vanessa Ho, Anthony P Albert
The present study investigates the effect of commonly used negative and positive allosteric modulators of the calcium-sensing receptor (CaSR) on vascular reactivity. In wire myography studies, increasing [Ca(2+)]o from 1mM to 6mM induced concentration-dependent relaxations of methoxamine-induced pre-contracted rabbit mesenteric arteries, with 6mM [Ca(2+)]o producing almost complete relaxation. [Ca(2+)]o-induced relaxations were attenuated in the presence of the calcilytics Calhex-231 and NPS 2143, and abolished by the removal of the endothelium...
October 8, 2016: European Journal of Pharmacology
J T Gass, J T McGonigal, L J Chandler
Alcoholism is a chronic relapsing disorder characterized by periods of heavy alcohol consumption and unsuccessful attempts at abstinence. Relapse is one of the most problematic aspects in the treatment of alcoholism and is triggered by ethanol-associated cues. Extinction-based cue exposure therapies have proven ineffective in the treatment of alcoholism. However, positive allosteric modulation of mGlu5 with CDPPB enhances the extinction learning of alcohol-seeking behavior. The current study investigated the impact of chronic alcohol exposure on the extinction of ethanol-seeking behavior...
October 7, 2016: Neuropharmacology
Daniel P Radin, Sheng Zhong, Richard Purcell, Arnold Lippa
Memory loss observed as a consequence of aging is paralleled by a down-regulation of AMPA-type glutamate receptors (AMPARs) that mediate fast excitatory synaptic transmission. Activation of these receptors enhances long-term potentiation (LTP), a neuronal process demonstrated to be crucial for memory storage and thought to be a cellular substrate of learning and memory. In the present studies, we determined that LTP was reduced in aged rats when compared to young rats and that acute treatment with CX1846, a novel AMPAR positive allosteric modulator, fifteen minutes prior to tetanic stimulation completely reversed the significant deficit in LTP observed in aged rats...
October 6, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Agnieszka Potasiewicz, Małgorzata Hołuj, Tomasz Kos, Piotr Popik, Hugo R Arias, Agnieszka Nikiforuk
The cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. Alpha7 nicotinic acetylcholine receptors (α7 nAChRs) have gain considerable attention in this regard. It has been recently proposed that positive allosteric modulators (PAMs) of α7 nAChRs may represent an alternative strategy to that based on orthosteric agonists. The aim of the present study is to evaluate the efficacy of PAM-2 (3-furan-2-yl-N-p-tolyl-acrylamide) against cognitive deficits and negative-like symptoms in a rat model of schizophrenia based on administration of ketamine, a NMDAR antagonist...
October 4, 2016: Neuropharmacology
Ayse Bengisu Seferoglu, Seref Gul, Ugur Meric Dikbas, Ibrahim Baris, Kaan Koper, Mahmut Caliskan, Gul Cevahir, Ibrahim Halil Kavakli
ADP-glucose pyrophosphorylase (AGPase) is a key allosteric enzyme in plant starch biosynthesis. Plant AGPase is a heterotetrameric enzyme that consists of large (LS) and small subunits (SS), which are encoded by two different genes. In this study, we showed that the conversion of Glu to Gly at position 370 in the LS of AGPase alters the heterotetrameric stability along with the binding properties of substrate and effectors of the enzyme. Kinetic analyses revealed that the affinity of the LS(E370G)SS(WT) AGPase for glucose-1-phosphate is 3-fold less than for wild type (WT) AGPase...
November 2016: Plant Science: An International Journal of Experimental Plant Biology
Guanglin Kuang, Xu Wang, Christer Halldin, Agneta Nordberg, Bengt Långström, Hans Ågren, Yaoquan Tu
Potentiation of the function of the α7 nicotinic acetylcholine receptor (α7-nAChR) is believed to provide a possible way for the treatment of cholinergic system dysfunctions such as Alzheimer's disease and schizophrenia. Positive allosteric modulators (PAMs) are able to augment the peak current response of the endogenous agonist of α7-nAChR by binding to some allosteric sites. In this study, the binding profile of a potent type I PAM, NS-1738, with a chimera structure (termed α7-AChBP) constructed from the extracellular domain of α7-nAChR and an acetylcholine binding protein was investigated with molecular docking, molecular dynamics simulation, and free energy calculation methods...
October 12, 2016: Physical Chemistry Chemical Physics: PCCP
Jun Ren, Xiuqing Ding, John J Greer
Inhalation of capsaicin based sprays can cause central respiratory depression and lethal apneas. There are contradictory reports regarding the sites of capsaicin action. Further, an understanding of the neurochemical mechanisms underlying capsaicin-induced apneas and the development of pharmacological interventions are lacking. The main objectives were to perform a systematic study of the mechanisms of action of capsaicin-induced apneas and to provide insights relevant to pharmacological intervention. In vitro and in vivo rat and TRPV1-null mouse models were used to measure respiratory parameters and seizure-like activity in the presence of capsaicin and compounds that modulate glutamatergic neurotransmission...
October 6, 2016: American Journal of Respiratory Cell and Molecular Biology
Anh Tn Nguyen, Elizabeth A Vecchio, Trayder Thomas, Toan D Nguyen, Luigi Aurelio, Peter J Scammells, Paul J White, Patrick M Sexton, Karen J Gregory, Lauren T May, Arthur Christopoulos
Allosteric modulation of adenosine A1 receptors (A1ARs) offers a novel therapeutic approach for the treatment of numerous central and peripheral disorders. However, despite decades of research, there is a relative paucity of structural information regarding the A1AR allosteric site and mechanisms governing cooperativity with orthosteric ligands. We combined alanine-scanning mutagenesis of the A1AR second extracellular loop (ECL2) with radioligand binding and functional interaction assays to quantify effects on allosteric ligand affinity, cooperativity and efficacy...
September 28, 2016: Molecular Pharmacology
Andrew D Powell, Gillian Grafton, Alexander Roberts, Shannon Larkin, Nathanael O'Neill, Josephine Palandri, Reka Otvos, Alison J Cooper, Chris Ulens, Nicholas M Barnes
BACKGROUND AND PURPOSE: The 5-HT3 receptor is a prototypical member of the Cys-loop ligand-gated ion channel (LGIC) superfamily and an established therapeutic target. In addition to activation via the orthosteric site, receptor function can be modulated by allosteric ligands. We have investigated the pharmacological action of Cl-indole upon the 5-HT3 A receptor and identified that this positive allosteric modulator possesses a novel mechanism of action for LGICs. EXPERIMENTAL APPROACH: The impact of Cl-indole upon the 5-HT3 receptor was assessed using single cell electrophysiological recordings and [(3) H]granisetron binding with HEK293 cells stably expressing the 5-HT3 receptor...
September 28, 2016: British Journal of Pharmacology
James B Fields, Karin L Németh-Cahalan, J Alfredo Freites, Irene Vorontsova, James E Hall, Douglas J Tobias
Aquaporin 0 (AQP0), the major intrinsic protein of the eye lens, plays a vital role in maintaining lens clarity by facilitating the transport of water across lens fiber cell membranes. AQP0 reduces its osmotic water permeability constant (Pf) in response to increases in the external calcium concentration, an effect that is mediated by an interaction with the calcium-binding messenger protein, calmodulin (CaM), and phosphorylation of the CaM binding site abolishes calcium sensitivity. Despite recent structural characterization of the AQP0-CaM complex, the mechanism by which CaM modulates AQP0 remains poorly understood...
September 22, 2016: Journal of Biological Chemistry
Fadil M Hannan, Valerie N Babinsky, Rajesh V Thakker
The extracellular calcium (Ca(2+) o)-sensing receptor (CaSR) is a family C G protein-coupled receptor, which detects alterations in Ca(2+) o concentrations and modulates parathyroid hormone secretion and urinary calcium excretion. The central role of the CaSR in Ca(2+) o homeostasis has been highlighted by the identification of mutations affecting the CASR gene on chromosome 3q21.1. Loss-of-function CASR mutations cause familial hypocalciuric hypercalcaemia (FHH), whereas gain-of-function mutations lead to autosomal dominant hypocalcaemia (ADH)...
October 2016: Journal of Molecular Endocrinology
Fabrizio Vincenzi, Annalisa Ravani, Silvia Pasquini, Stefania Merighi, Stefania Gessi, Romeo Romagnoli, Pier Giovanni Baraldi, Pier Andrea Borea, Katia Varani
Activation of A1 adenosine receptors (ARs) has been associated with anxiolytic-like effects in different behavioral tests, but development of A1AR agonists for therapeutic use has been hampered, most likely due to the presence of side effects. With the aim to identify a safer approach for the treatment of anxiety, we investigated, in mice, the anxiolytic-like properties of a novel A1AR positive allosteric modulator, TRR469. Acute administration of TRR469 (0.3-3 mg/kg) resulted in robust anxiolytic-like effects in the elevated plus maze, the dark/light box, the open field and the marble burying tests...
December 2016: Neuropharmacology
Tamara Timić Stamenić, Michael M Poe, Sabah Rehman, Anja Santrač, Branka Divović, Petra Scholze, Margot Ernst, James M Cook, Miroslav M Savić
We have synthesized and characterized MP-III-022 ((R)-8-ethynyl-6-(2-fluorophenyl)-N,4-dimethyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy-selective positive allosteric modulator of GABAA receptors containing the α5 subunit (α5GABAARs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 1-10mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of α5βγ2 GABAA receptors...
September 14, 2016: European Journal of Pharmacology
Andrew Alt
Allosteric ligands modulate the activity of receptor targets by binding to sites that are distinct from the orthosteric (native agonist) binding site. Allosteric modulators have potential therapeutic advantages over orthosteric agonists and antagonists, including improved selectivity, and maintenance of the spatial and temporal fidelity of native signaling patterns. The identification of allosteric ligands presents unique challenges because of the requirement for screening in the presence of an orthosteric agonist, the small signal window that is produced by many allosteric modulators, the proclivity of allosteric modulators to exhibit activity switching within a chemotype (e...
2016: Current Protocols in Pharmacology
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