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Positive allosteric modulator

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https://www.readbyqxmd.com/read/28523095/therapeutic-advantage-of-the-positive-allosteric-modulators-of-the-gaba-b-receptor
#1
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28522253/challenges-in-the-development-of-an-m4-pam-preclinical-candidate-the-discovery-sar-and-in-vivo-characterization-of-a-series-of-3-aminoazetidine-derived-amides
#2
James C Tarr, Michael R Wood, Meredith J Noetzel, Jeanette L Bertron, Rebecca L Weiner, Alice L Rodriguez, Atin Lamsal, Frank W Byers, Sichen Chang, Hyekyung P Cho, Carrie K Jones, Colleen M Niswender, Michael W Wood, Nicholas J Brandon, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0...
May 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28521115/anticonvulsant-profile-of-the-neuroactive-steroid-sge-516-in-animal-models
#3
Rebecca S Hammond, Alison L Althaus, Michael A Ackley, Carla Maciag, Gabriel Martinez Botella, Francesco G Salituro, Albert J Robichaud, James J Doherty
Despite the availability of multiple antiepileptic drugs (AED), failure to adequately control seizures is a challenge for approximately one third of epilepsy patients, and new therapies with a differentiated mechanism of action are needed. The neuroactive steroid, SGE-516, is a positive allosteric modulator of both gamma- and delta-containing GABAA receptors. This broad GABAA receptor activity differentiates neuroactive steroids like SGE-516 from benzodiazepines, a class of anticonvulsants which have been shown in vitro to selectively target gamma-subunit containing GABAA receptors...
May 7, 2017: Epilepsy Research
https://www.readbyqxmd.com/read/28520841/chronic-inflammatory-pain-impairs-mglur5-mediated-depolarization-induced-suppression-of-excitation-in-the-anterior-cingulate-cortex
#4
Baolin Guo, Jiaqi Wang, Han Yao, Keke Ren, Jing Chen, Jing Yang, Guohong Cai, Haiying Liu, Yunlong Fan, Wenting Wang, Shengxi Wu
The anterior cingulate cortex (ACC) is a critical hub for nociceptive perception and pain-related anxiety. Long-term synaptic plasticity in ACC was found to be important for chronic inflammatory pain and pain-related anxiety. As short-term synaptic plasticity, depolarization-induced suppression of excitation (DSE) is involved in several conditions, such as chronic stress, epilepsy, and autism. However, it is still unknown whether DSE in the ACC is involved in the central sensitization of pain and anxiety. Using a whole-cell patch clamp, calcium imaging, western blot, and behavioral testing, we found that DSE was induced by a 2 s depolarization in postsynaptic pyramidal cells in ACC...
May 17, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28514449/human-glp-1-receptor-transmembrane-domain-structure-in-complex-with-allosteric-modulators
#5
Gaojie Song, Dehua Yang, Yuxia Wang, Chris de Graaf, Qingtong Zhou, Shanshan Jiang, Kaiwen Liu, Xiaoqing Cai, Antao Dai, Guangyao Lin, Dongsheng Liu, Fan Wu, Yiran Wu, Suwen Zhao, Li Ye, Gye Won Han, Jesper Lau, Beili Wu, Michael A Hanson, Zhi-Jie Liu, Ming-Wei Wang, Raymond C Stevens
The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2...
May 17, 2017: Nature
https://www.readbyqxmd.com/read/28509867/supporting-the-identification-of-novel-fragment-based-positive-allosteric-modulators-using-a-supervised-molecular-dynamics-approach-a-retrospective-analysis-considering-the-human-a2a-adenosine-receptor-as-a-key-example
#6
Giuseppe Deganutti, Stefano Moro
Structure-driven fragment-based (SDFB) approaches have provided efficient methods for the identification of novel drug candidates. This strategy has been largely applied in discovering several pharmacological ligand classes, including enzyme inhibitors, receptor antagonists and, more recently, also allosteric (positive and negative) modulators. Recently, Siegal and collaborators reported an interesting study, performed on a detergent-solubilized StaR adenosine A2A receptor, describing the existence of both fragment-like negative allosteric modulators (NAMs), and fragment-like positive allosteric modulators (PAMs)...
May 16, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28505538/synthesis-and-pharmacological-evaluation-of-neurosteroid-photoaffinity-ligands
#7
Pavel Y Savechenkov, David C Chiara, Rooma Desai, Alexander T Stern, Xiaojuan Zhou, Alexis M Ziemba, Andrea L Szabo, Yinghui Zhang, Jonathan B Cohen, Stuart A Forman, Keith W Miller, Karol S Bruzik
Neuroactive steroids are potent positive allosteric modulators of GABAA receptors (GABAAR), but the locations of their GABAAR binding sites remain poorly defined. To discover these sites, we synthesized two photoreactive analogs of alphaxalone, an anesthetic neurosteroid targeting GABAAR, 11β-(4-azido-2,3,5,6-tetrafluorobenzoyloxy)allopregnanolone, (F4N3Bzoxy-AP) and 11-aziallopregnanolone (11-AziAP). Both photoprobes acted with equal or higher potency than alphaxalone as general anesthetics and potentiators of GABAAR responses, left-shifting the GABA concentration - response curve for human α1β3γ2 GABAARs expressed in Xenopus oocytes, and enhancing [(3)H]muscimol binding to α1β3γ2 GABAARs expressed in HEK293 cells...
April 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28495376/gabaa-receptor-positive-allosteric-modulators-modify-the-abuse-related-behavioral-and-neurochemical-effects-of-methamphetamine-in-rhesus-monkeys
#8
Laís F Berro, Monica L Andersen, Sergio Tufik, Leonard L Howell
GABAA receptor positive allosteric modulators (GABAA receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABAA receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABAA receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5)...
May 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28494140/identification-of-%C3%AE-7-nicotinic-acetylcholine-receptor-silent-agonists-based-on-the-spirocyclic-quinuclidine-%C3%AE-2-isoxazoline-scaffold-synthesis-and-electrophysiological-evaluation
#9
Clelia Mariangiola Luisa Dallanoce, Marta Quadri, Carlo Matera, Almin Silnović, Maria Chiara Pismataro, Nicole Alana Horenstein, Clare Stokes, Roger Lee Papke
Compound 11 (3-(benzyloxy)-1'-methyl-1'-azonia-4H-1'-azaspiro[isoxazole-5,3'-bicyclo[2.2.2]octane] iodide) was selected from a previous set of nicotinic ligands as a suitable model ligand for the design of new silent agonists of α7 nAChRs. Silent agonists evoke little or no channel activation but can induce the α7 desensitized Ds state, sensitive to a type II positive allosteric modulator (PAM) such as PNU-120596. Introduction of meta-substituents into the benzyloxy moiety of 11 led to the two sets of tertiary amines and quaternary ammonium salts based on the spirocyclic quinuclidinyl-Δ2-isoxazoline scaffold...
May 11, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28487067/selective-and-interactive-effects-of-d2-receptor-antagonism-and-positive-allosteric-mglur4-modulation-on-waiting-impulsivity
#10
Sarah N Isherwood, Trevor W Robbins, Janet R Nicholson, Jeffrey W Dalley, Anton Pekcec
BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity...
May 6, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28479061/crystal-structures-of-human-glyr%C3%AE-3-bound-to-ivermectin
#11
Xin Huang, Hao Chen, Paul L Shaffer
Ivermectin acts as a positive allosteric modulator of several Cys-loop receptors including the glutamate-gated chloride channels (GluCls), γ-aminobutyric acid receptors (GABAARs), glycine receptors (GlyRs), and neuronal α7-nicotinic receptors (α7 nAChRs). The crystal structure of Caenorhabditis elegans GluCl complexed with ivermectin revealed the details of its ivermectin binding site. Although the electron microscopy structure of zebrafish GlyRα1 complexed with ivermectin demonstrated a similar binding orientation, detailed structural information on the ivermectin binding and pore opening for Cys-loop receptors in vertebrates has been elusive...
May 4, 2017: Structure
https://www.readbyqxmd.com/read/28477386/persistent-activation-of-%C3%AE-7-nachrs-associated-with-stable-induction-of-different-desensitized-states
#12
Roger L Papke, Clare Stokes, M Imad Damaj, Ganesh A Thakur, Khan Manther, Millet Treinin, Deniz Bagdas, Abhijit R Kulkarni, Nicole A Horenstein
BACKGROUND AND PURPOSE: GAT107 is a positive allosteric modulator and agonist (ago-PAM) of α7 nicotinic acetylcholine receptors that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel-active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non-conducting states, interestingly, both agents have been shown to be effective treatment for inflammation and inflammatory pain models...
May 6, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28464338/new-anti-seizure-arylalkyl-azole-derivatives-synthesis-in-vivo-and-in-silico-studies
#13
Suat Sari, Sevim Dalkara, Filiz Betül Kaynak, Jóhannes Reynisson, Selma Saraç, Arzu Karakurt
(Arylalkyl)azoles are a class of antiepileptic compounds including nafimidone, denzimol, and loreclezole (LRZ). Nafimidone and denzimol are thought to inhibit voltage-gated sodium channels (VGSCs) and enhance γ-aminobutyric acid (GABA)-mediated response. LRZ, a positive allosteric modulator of A-type GABA receptors (GABAA Rs), was reported to be sensitive to Asn265 of the β2/β3 subunit. Here, we report new N-[1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene]hydroxylamine esters showing anticonvulsant activity in animal models, including the 6-Hz psychomotor seizure test, a model for therapy-resistant partial seizure...
May 2, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28463783/synthesis-and-biological-evaluation-of-chemokine-receptor-ligands-with-2-benzazepine-scaffold
#14
Simone Thum, Artur K Kokornaczyk, Tomoaki Seki, Monica De Maria, Natalia V Ortiz Zacarias, Henk de Vries, Christina Weiss, Michael Koch, Dirk Schepmann, Masato Kitamura, Nuska Tschammer, Laura H Heitman, Anna Junker, Bernhard Wünsch
Targeting CCR2 and CCR5 receptors is considered as promising concept for the development of novel antiinflammatory drugs. Herein, we present the development of the first probe-dependent positive allosteric modulator (PAM) of CCR5 receptors with a 2-benzazepine scaffold. Compound 14 (2-isobutyl-N-({[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-1-oxo-2,3-dihydro-1H-2-benzazepine-4-carboxamide) activates the CCR5 receptor in a CCL4-dependent manner, but does not compete with [(3)H]TAK-779 binding at the CCR5...
April 22, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28462839/synthesis-of-both-enantiomers-of-1-2-3-4-tetrahydroisoquinoline-derivative-ippam-1-and-enantio-dependency-of-its-positive-allosteric-modulation-of-prostacyclin-receptor
#15
Kohki Yamamoto, Toshifumi Suzuki, Riyo Imamura, Tetsuo Nagano, Takayoshi Okabe, Hiroyuki Miyachi
We present a practical synthesis of both enantiomers of 1,2,3,4-tetrahydroisoquinoline derivative IPPAM-1 (1), which is a positive allosteric modulator (PAM) of prostacyclin receptor (IP) and a candidate for treatment of pulmonary arterial hypertension without the side effects caused by IP agonists. Assay of cAMP production by CHO-K1 cells stably expressing human IP clearly demonstrated that the IPPAM activity resides exclusively on the R-form of 1.
March 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28457974/a-novel-nmda-receptor-positive-allosteric-modulator-that-acts-via-the-transmembrane-domain
#16
Tzu-Ming Wang, Brandon M Brown, Lunbin Deng, Benjamin D Sellers, Patrick J Lupardus, Heidi J A Wallweber, Amy Gustafson, Evera Wong, Matthew Volgraf, Jacob B Schwarz, David H Hackos, Jesse E Hanson
Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating process within the transmembrane domain (TMD). We have discovered a novel NMDAR positive allosteric modulator (PAM), GNE-9278, with a unique binding site on the extracellular surface of the TMD. Mutation of a single residue near the Lurcher motif on GluN1 M3 can convert GNE-9278 modulation from positive to negative, and replacing three AMPAR pre-M1 residues with corresponding NMDAR residues can confer GNE-9278 sensitivity to AMPARs...
April 27, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28456686/the-dual-modulatory-effects-of-efavirenz-on-gabaa-receptors-are-mediated-via-two-distinct-sites
#17
Renqi Huang, Zhenglan Chen, Sean Dolan, John A Schetz, Glenn H Dillon
Efavirenz is a widely prescribed medicine used to treat type 1 human immunodeficiency virus (HIV-1), the most prevalent pathogenic strain of the virus responsible for the acquired immune deficiency syndrome (AIDS) pandemic. Under prescribed dosing conditions, either alone or in combination therapy, efavirenz-induced CNS disturbances are frequently reported. Efavirenz was recently reported to interact in a similar concentration range with a number of receptors, transporters and ion channels including recombinant rat α1β2γ2 GABAA receptors whose actions were potentiated (Gatch et al...
April 27, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28456011/neurosteroid-biosynthesis-downregulation-and-changes-in-gabaa-receptor-subunit-composition-a-biomarker-axis-in-stress-induced-cognitive-and-emotional-impairment
#18
REVIEW
Andrea Locci, Graziano Pinna
By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABAA receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction...
April 29, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28455697/the-differentiation-of-skin-mesenchymal-stem-cells-towards-a-schwann-cell-phenotype-impact-of-sigma-1-receptor-activation
#19
L Saulite, E Vavers, L Zvejniece, M Dambrova, U Riekstina
Neural crest stem cells (NCSCs) are the source of mature Schwann cells in the peripheral nervous system (PNS). The NCSC population resides in the bulge of hair follicles and in the dermis. Recently, it was shown that 2-3% of the human dermis mesenchymal stem cell (MSC) population expresses the NCSC marker CD271, thus enabling the use of skin MSCs for studying Schwann cell differentiation in vitro. The aims of this study were to establish a protocol for human skin MSC differentiation towards Schwann cell-like cells (SC-lcs) and to analyse the expression of sigma-1 receptor (S1R) in SC-lcs...
April 28, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28446611/unraveling-amino-acid-residues-critical-for-allosteric-potentiation-of-%C3%AE-4-3-%C3%AE-2-2-type-nicotinic-acetylcholine-receptor-responses
#20
Ze-Jun Wang, Farah Deba, Tasnim S Mohamed, David C Chiara, Kara Ramos, Ayman K Hamouda
Neuronal nicotinic acetylcholine receptors (nAChRs) are promising drug targets to manage several neurological disorders and nicotine addiction. Growing evidence indicates that positive allosteric modulators (PAMs) of nAChRs improve pharmacological specificity by binding to unique sites present only in a subpopulation of nAChRs. Furthermore, nAChR PAMs such as NS9283 and CMPI have been shown to potentiate responses of (α4)3(β2)2 but not (α4)2(β2)3 nAChR isoforms. This selective potentiation underlines that the α4:α4 interface, which is present only in the (α4)3(β2)2 nAChR, is an important and promising drug target...
April 26, 2017: Journal of Biological Chemistry
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