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Positive allosteric modulator

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https://www.readbyqxmd.com/read/28059509/pyrimidinyl-biphenylureas-identification-of-new-lead-compounds-as-allosteric-modulators-of-the-cannabinoid-receptor-cb1
#1
Leepakshi Khurana, Boqiao Fu, Anantha L Duddupudi, Yu-Hsien Liao, Sri Sujana Immadi, Debra A Kendall, Dai Lu
The allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB1) and antagonized G protein coupling. This compound demonstrated potent anorectic effects similar to the CB1 antagonist rimonabant that once was marketed for the treatment of obesity suggesting a new chemical entity for the discovery of anti-obesity drugs. To increase structural diversity of this class of CB1 ligands, we designed and synthesized two classes of novel analogs, in which the pyridine ring of 2 was replaced by a pyrimidine ring...
January 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28049619/synthesis-and-evaluation-of-1-cyclopropylmethyl-4-4-11-c-methoxyphenyl-piperidin-1-yl-2-oxo-1-2-dihydropyridine-3-carbonitrile-11-c-cmdc-for-pet-imaging-of-metabotropic-glutamate-receptor-2-in-the-rat-brain
#2
Yufei Ma, Katsushi Kumata, Joji Yui, Yiding Zhang, Tomoteru Yamasaki, Akiko Hatori, Masayuki Fujinaga, Nobuki Nengaki, Lin Xie, Hui Wang, Ming-Rong Zhang
Brain metabotropic glutamate receptor 2 (mGluR2) has been proposed as a therapeutic target for the treatment of schizophrenia-like symptoms arising from increased glutamate transmission in the forebrain. However, there does not exist a reliable tool for the study of mGluR2 in human neuroimaging. The purpose of this study was to radiosynthesize 1-(cyclopropylmethyl)-4-(4-[(11)C]methoxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([(11)C]CMDC) and evaluate its potential as a positron emission tomography (PET) radiotracer for imaging mGluR2 in the rat brain...
December 23, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28018173/positive-allosteric-modulation-of-insect-olfactory-receptor-function-by-orco-agonists
#3
Panagiota Tsitoura, Kostas Iatrou
Insect olfactory receptors (ORs) are heteromeric ligand-gated cation channels composed of a common olfactory receptor subunit (ORco) and a variable subunit (ORx) of as yet unknown structures and undetermined stoichiometries. In this study, we examined the allosteric modulation exerted on Anopheles gambiae heteromeric ORx/ORco olfactory receptors in vitro by a specific class of ORco agonists (OAs) comprising ORcoRAM2 and VUAA1. High OA concentrations produced stronger functional responses in cells expressing heteromeric receptor channels relative to cells expressing ORco alone...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28011766/structural-insight-to-mutation-effects-uncover-a-common-allosteric-site-in-class-c-gpcrs
#4
Kasper Harpsøe, Michael W Boesgaard, Christian Munk, Hans Bräuner-Osborne, David E Gloriam
MOTIVATION: Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry. Combining pharmacological site-directed mutagenesis data with the recent class C GPCR experimental structures will provide a foundation for rational design of new therapeutics. RESULTS: We uncover one common site for both positive and negative modulators with different amino acid layouts that can be utilized to obtain selectivity...
December 22, 2016: Bioinformatics
https://www.readbyqxmd.com/read/28009705/positive-allosteric-modulation-of-gabaa-receptors-attenuates-high-blood-pressure-in-schlager-hypertensive-mice
#5
Emily R Stevenson, Esther M C Johns, Francine Z Marques, Kristy L Jackson, Pamela J Davern, Roger G Evans, Geoffrey A Head
OBJECTIVE: Blood pressure high Schlager (BPH/2J) mice have neurogenic hypertension associated with differences in hypothalamic GABAA receptors compared with their normotensive counterparts (BPN/3J). Allopregnanolone is an endogenous neurosteroid reduced in chronic stress, and when administered, decreases anxiety by positive allosteric modulation of GABAA receptors. METHODS: To determine if allopregnanolone could be a viable therapeutic for neurogenic hypertension, male BPH/2J (n = 6-7) and BPN/3J (n = 8-9) mice were equipped with radiotelemetry probes to compare cardiovascular variables before and after implantation of subcutaneous minipumps delivering allopregnanolone (5 mg/kg per day), or its vehicle, for a period of 2 weeks...
December 22, 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/28009436/pharmacological-characterisation-of-n-2s-5-6-fluoro-3-pyridinyl-2-3-dihydro-1h-inden-2-yl-2-propanesulfonamide-a-novel-clinical-ampa-receptor-positive-allosteric-modulator
#6
Simon E Ward, Paul Beswick, Novella Calcinaghi, Lee A Dawson, Jane Gartlon, Francesca Graziani, Declan N C Jones, Laurent Lacroix, M H Selina Mok, Beatrice Oliosi, Joanne Pardoe, Kathryn Starr, Marie L Woolley, Mark H Harries
BACKGROUND AND PURPOSE: AMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the pre-clinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application. EXPERIMENTAL APPROACH: [N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro 1H-inden-2-yl]-2-propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent...
December 23, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28001356/diverse-effects-on-m1-signaling-and-adverse-effect-liability-within-a-series-of-m1-ago-pams
#7
Jerri M Rook, Masahito Abe, Hyekyung P Cho, Kellie D Nance, Vincent B Luscombe, Jeffrey J Adams, Jonathan W Dickerson, Daniel H Remke, Pedro M Garcia-Barrantes, Darren W Engers, Julie L Engers, Sichen Chang, Jarrett J Foster, Anna L Blobaum, Colleen M Niswender, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley
Both historical clinical and recent preclinical data suggest that the M1 muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer's disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M1 activation. Efforts then shifted to focus on selective activation of M1 via either allosteric agonists or positive allosteric modulators (PAMs). While M1 PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility...
January 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27995279/from-bench-to-bedside-mglur2-positive-allosteric-modulators-as-medications-to-treat-substance-use-disorders
#8
REVIEW
Jane B Acri, Alan J Cross, Phil Skolnick
OBJECTIVE: This paper provides an overview of the role of type 2 metabotropic glutamate receptors (mGluR2) in addiction and behaviors reflecting addictive processes. RESULTS: AZD8529, an mGluR2 positive allosteric modulator (PAM), failed to separate from placebo in a phase II schizophrenia trial. The demonstration by Athina Markou's laboratory that AZD8529 attenuated both nicotine self-administration and cue-induced reinstatement was a key factor in the decision to move this compound into a smoking cessation study...
December 20, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/27994742/development-of-1h-pyrazolo-3-4-b-pyridines-as-metabotropic-glutamate-receptor-5-positive-allosteric-modulators
#9
Matthew D Hill, Haiquan Fang, Jeffrey M Brown, Thaddeus Molski, Amy Easton, Xiaojun Han, Regina Miller, Melissa Hill-Drzewi, Lizbeth Gallagher, Michele Matchett, Michael Gulianello, Anand Balakrishnan, Robert L Bertekap, Kenneth S Santone, Valerie J Whiterock, Xiaoliang Zhuo, Joanne J Bronson, John E Macor, Andrew P Degnan
The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with the N-methyl-d-aspartate receptor (NMDAR). We describe the synthesis of 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile and convergent synthetic route provided access to a structurally diverse set of analogues that contain neither the aryl-acetylene-aryl nor aryl-methyleneoxy-aryl elements, the predominant structural motifs described in the literature...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27994221/dynamic-modulation-of-inflammatory-pain-related-affective-and-sensory-symptoms-by-optical-control-of-amygdala-metabotropic-glutamate-receptor-4
#10
C Zussy, X Gómez-Santacana, X Rovira, D De Bundel, S Ferrazzo, D Bosch, D Asede, F Malhaire, F Acher, J Giraldo, E Valjent, I Ehrlich, F Ferraguti, J-P Pin, A Llebaria, C Goudet
Contrary to acute pain, chronic pain does not serve as a warning signal and must be considered as a disease per se. This pathology presents a sensory and psychological dimension at the origin of affective and cognitive disorders. Being largely refractory to current pharmacotherapies, identification of endogenous systems involved in persistent and chronic pain is crucial. The amygdala is a key brain region linking pain sensation with negative emotions. Here, we show that activation of a specific intrinsic neuromodulatory system within the amygdala associated with type 4 metabotropic glutamate receptors (mGlu4) abolishes sensory and affective symptoms of persistent pain such as hypersensitivity to pain, anxiety- and depression-related behaviors, and fear extinction impairment...
December 20, 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27991902/crystal-structures-of-human-glycine-receptor-%C3%AE-3-bound-to-a-novel-class-of-analgesic-potentiators
#11
Xin Huang, Paul L Shaffer, Shawn Ayube, Howard Bregman, Hao Chen, Sonya G Lehto, Jason A Luther, David J Matson, Stefan I McDonough, Klaus Michelsen, Matthew H Plant, Stephen Schneider, Jeffrey R Simard, Yohannes Teffera, Shuyan Yi, Maosheng Zhang, Erin F DiMauro, Jacinthe Gingras
Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2...
December 19, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27991860/m1-muscarinic-allosteric-modulators-slow-prion-neurodegeneration-and-restore-memory-loss
#12
Sophie J Bradley, Julie-Myrtille Bourgognon, Helen E Sanger, Nicholas Verity, Adrian J Mogg, David J White, Adrian J Butcher, Julie A Moreno, Colin Molloy, Timothy Macedo-Hatch, Jennifer M Edwards, Jurgen Wess, Robert Pawlak, David J Read, Patrick M Sexton, Lisa M Broad, Joern R Steinert, Giovanna R Mallucci, Arthur Christopoulos, Christian C Felder, Andrew B Tobin
The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging...
December 19, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27986596/effects-of-the-synthetic-neurosteroid-ganaxolone-on-seizure-activity-and-behavioral-deficits-in-an-angelman-syndrome-mouse-model
#13
Stephanie L Ciarlone, Xinming Wang, Michael A Rogawski, Edwin J Weeber
Angelman syndrome (AS) is a rare neurogenetic disorder characterized by severe developmental delay, motor impairments, and epilepsy. GABAergic dysfunction is believed to contribute to many of the phenotypic deficits seen in AS. We hypothesized that restoration of inhibitory tone mediated by extrasynaptic GABAA receptors could provide therapeutic benefit. Here, we report that ganaxolone, a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, was anxiolytic, anticonvulsant, and improved motor deficits in the Ube3a-deficient mouse model of AS when administered by implanted mini-pump for 3 days or 4 weeks...
December 13, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27965032/molecular-insights-into-allosteric-modulation-of-class-c-g-protein-coupled-receptors
#14
REVIEW
Katie Leach, Karen J Gregory
Class C G protein-coupled receptors (GPCRs) recognise diverse extracellular stimuli and are highly tractable drug targets for a host of different psychiatric, neurological and metabolic disorders. Discovery efforts focussed on allosteric modulators for Class C GPCRs have been highly fruitful, with diverse chemotypes identified for multiple Class C members. Indeed, a positive allosteric modulator of the calcium-sensing receptor, cinacalcet, was one of the first GPCR allosteric ligands to enter the clinic. Despite this success, allosteric modulator discovery and development remains challenging...
December 11, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27958713/inositol-phosphate-accumulation-in-vivo-provides-a-measure-of-muscarinic-m1-receptor-activation
#15
Michael Popiolek, David P Nguyen, Veronica Reinhart, Jeremy R Edgerton, John Harms, Susan M Lotarski, Stefanus J Steyn, Jennifer E Davoren, Sarah Grimwood
The rationale for using M1 selective muscarinic acetylcholine receptor activators for the treatment of cognitive impairment associated with psychiatric and neurodegenerative disease is well-established in the literature. Here, we investigate measurement of inositol phosphate accumulation, an end point immediately downstream of the M1 muscarinic acetylcholine receptor signaling cascade, as an in vivo biochemical readout for M1 muscarinic acetylcholine receptor activation. Five brain penetrant M1-subtype selective activators from three structurally distinct chemical series were pharmacologically profiled for functional activity in vitro using recombinant cell calcium mobilization and inositol phosphate assays, and a native tissue hippocampal slice electrophysiology assay, to show that all five compounds presented a positive allosteric modulator agonist profile, within a narrow range of potencies...
December 27, 2016: Biochemistry
https://www.readbyqxmd.com/read/27939174/challenges-in-the-development-of-an-m4-pam-in-vivo-tool-compound-the-discovery-of-vu0467154-and-unexpected-dmpk-profiles-of-close-analogs
#16
Michael R Wood, Meredith J Noetzel, Michael S Poslusney, Bruce J Melancon, James C Tarr, Atin Lamsal, Sichen Chang, Vincent B Luscombe, Rebecca L Weiner, Hyekyung P Cho, Michael Bubser, Carrie K Jones, Colleen M Niswender, Michael W Wood, Darren W Engers, Nicholas J Brandon, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration)...
January 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27920723/sex-dependent-anti-stress-effect-of-an-%C3%AE-5-subunit-containing-gabaa-receptor-positive-allosteric-modulator
#17
Sean C Piantadosi, Beverly J French, Michael M Poe, Tamara Timić, Bojan D Marković, Mohan Pabba, Marianne L Seney, Hyunjung Oh, Beverley A Orser, Miroslav M Savić, James M Cook, Etienne Sibille
Rationale: Current first-line treatments for stress-related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "α5-PAM"), a positive allosteric modulator selective for α5-subunit containing GABAA receptors found predominantly on cortical pyramidal cell dendrites, has anti-stress effects...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27918283/muscarinic-acetylcholine-receptors-act-in-synergy-to-facilitate-learning-and-memory
#18
Katherine Leaderbrand, Helen J Chen, Kevin A Corcoran, Anita L Guedea, Vladimir Jovasevic, Jurgen Wess, Jelena Radulovic
Understanding how episodic memories are formed and retrieved is necessary if we are to treat disorders in which they malfunction. Muscarinic acetylcholine receptors (mAChR) in the hippocampus and cortex underlie memory formation, but there is conflicting evidence regarding their role in memory retrieval. Additionally, there is no consensus on which mAChR subtypes are critical for memory processing. Using pharmacological and genetic approaches, we found that (1) encoding and retrieval of contextual memory requires mAChR in the dorsal hippocampus (DH) and retrosplenial cortex (RSC), (2) memory formation requires hippocampal M3 and cooperative activity of RSC M1 and M3, and (3) memory retrieval is more impaired by inactivation of multiple M1-M4 mAChR in DH or RSC than inactivation of individual receptor subtypes...
November 2016: Learning & Memory
https://www.readbyqxmd.com/read/27916555/adx71943-and-adx71441-novel-positive-allosteric-modulators-of-the-gabab-receptor-with-distinct-central-peripheral-profiles-show-efficacy-in-the-monosodium-iodoacetate-model-of-chronic-osteoarthritis-pain-in-the-rat
#19
Mikhail Kalinichev, Tansy Donovan-Rodriguez, Françoise Girard, Hasnaá Haddouk, Isabelle Royer-Urios, Manfred Schneider, Simon T Bate, Cheryl Marker, James D Pomonis, Sonia Poli
We tested novel positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB), ADX71943 and ADX71441in the monosodium iodoacetate model of chronic osteoarthritis pain in rats with the objective to delineate the role of peripheral versus central GABAB receptor populations in modulation of chronic pain. Anesthetized Sprague-Dawley rats received an injection of monosodium iodoacetate into the knee and were tested for hyperalgesia starting post-MIA day 14. Effects of compounds on ipsilateral joint compression threshold were evaluated on post-MIA day 14 (after acute treatment), as well as after repeated, daily treatment on days 21 and 28 (ADX71943 only) and were compared to those of celecoxib (30mg/kg, p...
December 1, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27914948/triazolopyridine-ethers-as-potent-orally-active-mglu2-positive-allosteric-modulators-for-treating-schizophrenia
#20
Mendi A Higgins, Lawrence R Marcin, F Christopher Zusi, Robert Gentles, Min Ding, Bradley C Pearce, Amy Easton, Walter A Kostich, Matthew A Seager, Clotilde Bourin, Linda J Bristow, Kim A Johnson, Regina Miller, John Hogan, Valerie Whiterock, Michael Gulianello, Meredith Ferrante, Yanling Huang, Adam Hendricson, Andrew Alt, John E Macor, Joanne J Bronson
Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p...
January 15, 2017: Bioorganic & Medicinal Chemistry
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