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Positive allosteric modulator

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https://www.readbyqxmd.com/read/29220747/effects-of-group-ii-metabotropic-glutamate-receptor-modulation-on-ethanol-and-sucrose-seeking-and-consumption-in-the-rat
#1
Kyle A Windisch, Cristine L Czachowski
Previous studies suggest that group II metabotropic glutamate receptors (mGluR2/3) are involved in regulating ethanol-seeking and consumption. The mGluR2/3 agonist LY379268 (LY37) and selective mGluR2 positive allosteric modulator biphenyl‑indanone A (BINA) were used to investigate the relative contribution of mGlu2 and mGlu3 receptors on ethanol- and sucrose-seeking and consumption. A microinjection study was then performed to examine the role of nucleus accumbens (NAc) core mGluR2/3 on ethanol-seeking. For the systemic experiments, separate groups of male Wistar rats [LY37 (0-2...
September 23, 2017: Alcohol
https://www.readbyqxmd.com/read/29214652/pharmacology-in-translation-the-preclinical-and-early-clinical-profile-of-the-novel-%C3%AE-2-3-functionally-selective-gabaa-receptor-positive-allosteric-modulator-pf-06372865
#2
Sarah A Nickolls, Rachel Gurrell, Guido van Amerongen, Juha Kammonen, Lishuang Cao, Adam R Brown, Clara Stead, Andy Mead, Christine Watson, Cathleen Hsu, Robert M Owen, Andy Pike, Rebecca L Fish, Laigao Chen, Ruolun Qiu, Evan D Morris, Gang Feng, Mark Whitlock, Donal Gorman, Joop van Gerven, David S Reynolds, Pinky Dua, Richard P Butt
BACKGROUND AND PURPOSE: Benzodiazepines (BZDs), non-selective positive allosteric modulators (PAMs) of GABAA receptors, have significant side-effects that limit their clinical utility. As many of these side-effects are mediated by the α1 subunit there has been a concerted effort to develop α2/3 subtype-selective PAMs. EXPERIMENTAL APPROACH: In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits...
December 7, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29213077/allosteric-nanobodies-uncover-a-role-of-hippocampal-mglu2-receptor-homodimers-in-contextual-fear-consolidation
#3
Pauline Scholler, Damien Nevoltris, Dimitri de Bundel, Simon Bossi, David Moreno-Delgado, Xavier Rovira, Thor C Møller, Driss El Moustaine, Michaël Mathieu, Emilie Blanc, Heather McLean, Elodie Dupuis, Gérard Mathis, Eric Trinquet, Hervé Daniel, Emmanuel Valjent, Daniel Baty, Patrick Chames, Philippe Rondard, Jean-Philippe Pin
Antibodies have enormous therapeutic and biotechnology potential. G protein-coupled receptors (GPCRs), the main targets in drug development, are of major interest in antibody development programs. Metabotropic glutamate receptors are dimeric GPCRs that can control synaptic activity in a multitude of ways. Here we identify llama nanobodies that specifically recognize mGlu2 receptors, among the eight subtypes of mGluR subunits. Among these nanobodies, DN10 and 13 are positive allosteric modulators (PAM) on homodimeric mGlu2, while DN10 displays also a significant partial agonist activity...
December 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29206810/mglur5-modulation-of-behavioral-and-epileptic-phenotypes-in-a-mouse-model-of-tuberous-sclerosis-complex
#4
Elyza Kelly, Samantha M Schaeffer, Sameer C Dhamne, Jonathan O Lipton, Lothar Lindemann, Michael Honer, Georg Jaeschke, Chloe E Super, Stephen Ht Lammers, Meera E Modi, Jill L Silverman, John R Dreier, David J Kwiatkowski, Alexander Rotenberg, Mustafa Sahin
Drugs targeting metabotropic glutamate receptor 5 (mGluR5) have therapeutic potential in autism spectrum disorders (ASD), including Tuberous Sclerosis Complex (TSC). The question whether inhibition or potentiation of mGluR5 could be beneficial depends, among other factors, on the specific indication. To facilitate the development of mGluR5 treatment strategies, we tested the therapeutic utility of mGluR5 negative and positive allosteric modulators (an mGluR5 NAM and PAM) for TSC, using a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes including behavioral symptoms of ASD and epilepsy...
December 5, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29204799/dorsomedial-prefrontal-cortex-5-ht6-receptors-regulate-anxiety-like-behavior
#5
Fei Geng, Jia Tian, Jian-Lin Wu, Yun Luo, Wen-Jun Zou, Chao Peng, Gui-Feng Lu
The dorsomedial prefrontal cortex (dmPFC) plays a very important role in decision-related and anxiety-related information processing. It has enriched 5-HT6 receptors; however, the precise role of dmPFC 5-HT6 receptors in anxiety remains to be fully investigated. In this study, we injected dmPFC with the 5-HT6 receptor agonist EMD 386088 and antagonist SB 271046 using stereotactic technology. 5-HT6 receptor activation in mice increased time spent in the center area on the open-field test, increased exploration of the open arms on the elevated plus maze test, and increased ratio on the social interaction test...
December 4, 2017: Cognitive, Affective & Behavioral Neuroscience
https://www.readbyqxmd.com/read/29202454/fentanyl-related-designer-drugs-w-18-and-w-15-lack-appreciable-opioid-activity-in-vitro-and-in-vivo
#6
Xi-Ping Huang, Tao Che, Thomas J Mangano, Valerie Le Rouzic, Ying-Xian Pan, Michael D Cameron, Michael H Baumann, Gavril W Pasternak, Bryan L Roth
W-18 (4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide) and W-15 (4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide) represent two emerging drugs of abuse chemically related to the potent opioid agonist fentanyl (N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide). Here, we describe the comprehensive pharmacological profiles of W-18 and W-15, as examination of their structural features predicted that they might lack opioid activity. We found W-18 and W-15 to be without detectible activity at μ, δ, κ, and nociception opioid receptors in a variety of assays...
November 16, 2017: JCI Insight
https://www.readbyqxmd.com/read/29196491/diversity-of-nicotinic-acetylcholine-receptor-positive-allosteric-modulators-revealed-by-mutagenesis-and-a-revised-structural-model
#7
Joseph Newcombe, Anna Chatzidaki, Tom D Sheppard, Maya Topf, Neil S Millar
By combining electrophysiological and computational approaches we have examined a series of positive allosteric modulators (PAMs) acting on the human α7 nicotinic acetylcholine receptor (nAChR). Electrophysiological studies have focussed on three α7-selective PAMs (A-867744, TBS-516 and TQS) that display similar effects on wild-type α7 nAChRs. In addition to potentiating agonist-evoked responses, all three compounds reduce receptor desensitisation and, consequently, are classed as type II PAMs. Despite having similar effects on wild-type receptors, A-867744 was found to have profoundly differing effects to TBS-516 and TQS on mutated receptors, a finding that is consistent with previous studies indicating that A-867744 may have a different mechanism of action to other α7-selective type II PAMs...
December 1, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29192662/cannabinoid-receptor-1-positive-allosteric-modulators-for-posttraumatic-stress-disorder
#8
Anantha Shekhar, Ganesh A Thakur
No abstract text is available yet for this article.
January 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29191791/electrophysiological-investigation-of-the-effect-of-structurally-different-bispyridinium-non-oxime-compounds-on-human-%C3%AE-7-nicotinic-acetylcholine-receptor-activity-an-in-vitro-structure-activity-analysis
#9
Corinna Scheffel, Karin V Niessen, Sebastian Rappenglück, Klaus T Wanner, Horst Thiermann, Franz Worek, Thomas Seeger
Organophosphorus compounds, including nerve agents and pesticides, exert their toxicity through irreversible inhibition of acetylcholinesterase (AChE) resulting in an accumulation of acetylcholine and functional impairment of muscarinic and nicotinic acetylcholine receptors. Current therapy comprises oximes to reactivate AChE and atropine to antagonize effects induced by muscarinic acetylcholine receptors. Nicotinic malfunction leading to depression of the central and peripheral respiratory system is not directly treated calling for alternative therapeutic interventions...
November 27, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29188558/breakthrough-in-gpcr-crystallography-and-its-impact-on-computer-aided-drug-design
#10
Antonella Ciancetta, Kenneth A Jacobson
Recent crystallographic structures of G protein-coupled receptors (GPCRs) have greatly advanced our understanding of the recognition of their diverse agonist and antagonist ligands. We illustrate here how this applies to A2A adenosine receptors (ARs) and to P2Y1 and P2Y12 receptors (P2YRs) for ADP. These X-ray structures have impacted the medicinal chemistry aimed at discovering new ligands for these two receptor families, including receptors that have not yet been crystallized but are closely related to the known structures...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29186675/inactivation-of-mechanically-activated-piezo1-ion-channels-is-determined-by-the-c-terminal-extracellular-domain-and-the-inner-pore-helix
#11
Jason Wu, Michael Young, Amanda H Lewis, Ashley N Martfeld, Breanna Kalmeta, Jörg Grandl
Piezo proteins form mechanically activated ion channels that are responsible for our sense of light touch, proprioception, and vascular blood flow. Upon activation by mechanical stimuli, Piezo channels rapidly inactivate in a voltage-dependent manner through an unknown mechanism. Inactivation of Piezo channels is physiologically important, as it modulates overall mechanical sensitivity, gives rise to frequency filtering of repetitive mechanical stimuli, and is itself the target of numerous human disease-related channelopathies that are not well understood mechanistically...
November 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/29185480/initial-cross-over-test-of-a-positive-allosteric-modulator-of-alpha-7-nicotinic-receptors-to-aid-cessation-in-smokers-with-or-without-schizophrenia
#12
Kenneth A Perkins, Kn Roy Chengappa, Joshua L Karelitz, Margaret C Boldry, Valerie Michael, Taylor Herb, Jessica Gannon, Jaspreet Brar, Lisa Ford, Stephanie Rassnick, Darlene Brunzell
Preclinical research shows that compounds acting at α7 nicotinic receptors (nAChRs) can reduce nicotine self-administration, suggesting that a positive allosteric modulator (PAM) of α7 receptors, JNJ-39393406, may aid smoking cessation. Moreover, individuals with schizophrenia, who have very high rates of smoking, have reduced expression of α7 nAChRs and may particularly benefit from this compound. In two parallel studies using a within-subject crossover design, 36 healthy smokers (Study 1) and 62 smokers with schizophrenia (Study 2), both groups high in quit interest, attempted to initiate quitting temporarily during each of two 3-week phases...
November 29, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29184203/arid1b-haploinsufficiency-disrupts-cortical-interneuron-development-and-mouse-behavior
#13
Eui-Man Jung, Jeffrey Jay Moffat, Jinxu Liu, Shashank Manohar Dravid, Channabasavaiah Basavaraju Gurumurthy, Woo-Yang Kim
Haploinsufficiency of the AT-rich interactive domain 1B (ARID1B) gene causes autism spectrum disorder and intellectual disability; however, the neurobiological basis for this is unknown. Here we generated Arid1b-knockout mice and examined heterozygotes to model human patients. Arid1b-heterozygous mice showed a decreased number of cortical GABAergic interneurons and reduced proliferation of interneuron progenitors in the ganglionic eminence. Arid1b haploinsufficiency also led to an imbalance between excitatory and inhibitory synapses in the cerebral cortex...
December 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/29176430/the-role-of-n-methyl-d-aspartate-receptors-and-metabotropic-glutamate-receptor-5-in-the-prepulse-inhibition-paradigms-for-studying-schizophrenia-pharmacology-neurodevelopment-and-genetics
#14
Zhemeng Wu, Zhigang Yang, Mengjiao Zhang, Xiaohan Bao, Fang Han, Liang Li
Treatments for the positive and negative symptoms of schizophrenia have been explored for decades, but no completely successful therapy has been found as yet. Metabotropic glutamate receptor 5 (mGluR5), which potentiates N-methyl-D-aspartate receptors in brain regions implicated in schizophrenia, has become a novel drug target in the treatment of schizophrenia, especially for the mGluR5-positive allosteric modulators. Individuals with schizophrenia show deficits in prepulse inhibition (PPI), which is an operational measurement of sensorimotor gating...
November 24, 2017: Behavioural Pharmacology
https://www.readbyqxmd.com/read/29174812/amino-acid-and-peptide-prodrugs-of-diphenylpropanones-positive-allosteric-modulators-of-%C3%AE-7-nicotinic-receptors-with-analgesic-activity
#15
Beatriz Balsera, José Mulet, Salvador Sala, Francisco Sala, Roberto de la Torre-Martínez, Sara González-Rodríguez, Adrián Plata, Lieve Naesens, Asia Fernández-Carvajal, Antonio Ferrer-Montiel, Manuel Criado, María Jesús Pérez de Vega, Rosario González-Muñiz
α7 Nicotinic acetylcholine receptors (nAChRs) are ion channels implicated in a number of CNS pathological processes, including pain and psychiatric, cognitive and inflammatory diseases. Comparing with orthosteric agonism, positive allosteric modulation of these channels constitutes an interesting approach to achieve selectivity versus other nicotinic receptors. We have recently described new chalcones and 1,3-diphenylpropanones as positive allosteric modulators (PAMs) of α7 nAChRs, which proved to have good analgesic activities but poor pharmacokinetic properties...
November 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29167913/synergistic-enhancing-memory-effect-of-donepezil-and-s-47445-an-ampa-positive-allosteric-modulator-in-middle-aged-and-aged-mice
#16
S Bretin, A Krazem, N Henkous, C Froger-Colleaux, E Mocaer, C Louis, N Perdaems, A Marighetto, D Beracochea
Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging...
November 22, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/29166726/-interaction-between-trpc1-and-stim1-in-calcium-sensing-receptor-mediated-calcium-influx-and-nitric-oxide-production-in-human-umbilical-vein-endothelial-cells
#17
L M Wang, H Zhong, N Tang, L J Pang, C J Zhang, F He
Objective: To investigate the interaction of Ca(2+) protein TRPC1 and STIM1 in extracellular Ca(2+) -sensing receptor (CaR)-induced extracellular Ca(2+) influx and the production of nitric oxide (NO). Methods: Human umbilical vein endothelial cells (HUVECs) were cultured and incubated with CaR agonist spermine (activating store-operates cation channels (SOC) and receptor-operated channels (ROC)), CaR negative allosteric modulator Calhex231 (blocking SOC, activating ROC) and ROC analogue TPA (activating ROC, blocking SOC), protein kinase C (PKC) inhibitor Ro31-8220, PKCs and PKCμ inhibitor Go6967(activate SOC, blocking ROC), respectively...
November 24, 2017: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/29163035/npas2-regulation-of-anxiety-like-behavior-and-gabaa-receptors
#18
Angela R Ozburn, Joseph Kern, Puja K Parekh, Ryan W Logan, Zheng Liu, Edgardo Falcon, Darius Becker-Krail, Kush Purohit, Nicole M Edgar, Yanhua Huang, Colleen A McClung
Abnormal circadian rhythms and circadian genes are strongly associated with several psychiatric disorders. Neuronal PAS Domain Protein 2 (NPAS2) is a core component of the molecular clock that acts as a transcription factor and is highly expressed in reward- and stress-related brain regions such as the striatum. However, the mechanism by which NPAS2 is involved in mood-related behaviors is still unclear. We measured anxiety-like behaviors in mice with a global null mutation in Npas2 (Npas2 null mutant mice) and found that Npas2 null mutant mice exhibit less anxiety-like behavior than their wild-type (WT) littermates (in elevated plus maze, light/dark box and open field assay)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29159020/the-current-agonists-and-positive-allosteric-modulators-of-%C3%AE-7-nachr-for-cns-indications-in-clinical-trials
#19
REVIEW
Taoyi Yang, Ting Xiao, Qi Sun, Kewei Wang
The alpha-7 nicotinic acetylcholine receptor (α7 nAChR), consisting of homomeric α7 subunits, is a ligand-gated Ca(2+)-permeable ion channel implicated in cognition and neuropsychiatric disorders. Enhancement of α7 nAChR function is considered to be a potential therapeutic strategy aiming at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Currently, a number of α7 nAChR modulators have been reported and several of them have advanced into clinical trials...
November 2017: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/29158584/ketamine-enhances-structural-plasticity-in-mouse-mesencephalic-and-human-ipsc-derived-dopaminergic-neurons-via-ampar-driven-bdnf-and-mtor-signaling
#20
L Cavalleri, E Merlo Pich, M J Millan, C Chiamulera, T Kunath, P F Spano, G Collo
Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons...
November 21, 2017: Molecular Psychiatry
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