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Positive allosteric modulator

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https://www.readbyqxmd.com/read/28646511/control-of-autoimmune-inflammation-using-liposomes-to-deliver-positive-allosteric-modulators-of-metabotropic-glutamate-receptors
#1
Joshua M Gammon, Arjun R Adapa, Christopher M Jewell
Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator of metabotropic glutamate receptor 4 (mGluR4), can promote regulatory T cells by altering cytokine secretion to bias T cell differentiation...
June 24, 2017: Journal of Biomedical Materials Research. Part A
https://www.readbyqxmd.com/read/28642232/a-single-amino-acid-residue-at-transmembrane-domain-4-of-the-alpha-subunit-influences-carisoprodol-direct-gating-efficacy-at-gabaa-receptors
#2
Manoj Kumar, Manish Kumar, John Freund, Glenn H Dillon
The muscle relaxant carisoprodol (CSP, trade name Soma) has recently been controlled at the federal level as a Schedule IV drug due to its high abuse potential and consequences of misuse, such as withdrawal syndrome, delusions, seizures and even death. Recent work has shown that carisoprodol can directly gate and allosterically modulate the GABAA receptor. These actions are subunit-dependent; compared to other GABAA receptors, carisoprodol has nominal direct gating effects in α3β2γ2receptors. Here, using site-directed-mutagenesis and whole cell patch clamp electrophysiology in transiently transfected HEK293 cells, we examined the role of GABAA receptor α subunit transmembrane domain 4 (TM4) amino acids in direct gating and allosteric modulatory actions of carisoprodol...
June 22, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28640864/targeting-breast-cancer-cells-by-mrs1477-a-positive-allosteric-modulator-of-trpv1-channels
#3
Mustafa Nazıroğlu, Bilal Çiğ, Walter Blum, Csaba Vizler, Andrea Buhala, Annamária Marton, Róbert Katona, Katalin Jósvay, Beat Schwaller, Zoltán Oláh, László Pecze
There is convincing epidemiological and experimental evidence that capsaicin, a potent natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist, has anticancer activity. However, capsaicin cannot be given systemically in large doses, because of its induction of acute pain and neurological inflammation. MRS1477, a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477 evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial cells...
2017: PloS One
https://www.readbyqxmd.com/read/28630250/amplification-of-mglu5-endocannabinoid-signaling-rescues-behavioral-and-synaptic-deficits-in-a-mouse-model-of-adolescent-and-adult-dietary-polyunsaturated-fatty-acids-imbalance
#4
Antonia Manduca, Anissa Bara, Thomas Larrieu, Olivier Lassalle, Corinne Joffre, Sophie Layé, Olivier J Manzoni
Energy-dense, yet nutritionally-poor food is a high-risk factor for mental health disorders. This is of particular concern during adolescence, a period often associated with increased consumption of low nutritional content food and higher prevalence of mental health disorders. Indeed, there is an urgent need to understand the mechanisms linking unhealthy diet and mental disorders. Deficiency in n-3 polyunsaturated fatty acid (PUFAs) is a hallmark of poor nutrition and mood disorders. Here, we developed a mouse model of n-3 PUFAs deficiency lasting from adolescence into adulthood...
June 19, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28619476/brexanolone-sage-547-injection-in-post-partum-depression-a-randomised-controlled-trial
#5
Stephen Kanes, Helen Colquhoun, Handan Gunduz-Bruce, Shane Raines, Ryan Arnold, Amy Schacterle, James Doherty, C Neill Epperson, Kristina M Deligiannidis, Robert Riesenberg, Ethan Hoffmann, David Rubinow, Jeffrey Jonas, Steven Paul, Samantha Meltzer-Brody
BACKGROUND: Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. METHODS: For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA...
June 12, 2017: Lancet
https://www.readbyqxmd.com/read/28619258/rho-kinase-dependent-desensitization-of-gpr39-a-unique-mechanism-of-gpcr-downregulation
#6
Yuji Shimizu, Ryokichi Koyama, Tomohiro Kawamoto
GPR39, a G-protein-coupled receptor activated by zinc, reportedly activates multiple intracellular signaling pathways via Gs, Gq, G12/13, and β-arrestin, but little is known about downregulation of the receptor upon its activation. To our knowledge, this is the first report on the mechanism of feedback regulation of GPR39 function determined in GPR39-expressing HEK293 cells (HEK293-GPR39) as a model cell system. In HEK293-GPR39 cells, GPR39-C3, which is a positive allosteric modulator, activated cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and β-arrestin recruitment...
June 12, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28610974/positive-modulation-of-%C3%AE-5-gabaa-receptors-in-preadolescence-prevents-reduced-locomotor-response-to-amphetamine-in-adult-female-but-not-male-rats-prenatally-exposed-to-lipopolysaccharide
#7
Bojan Batinić, Anja Santrač, Ivan Jančić, Guanguan Li, Aleksandra Vidojević, Bojan Marković, James M Cook, Miroslav M Savić
We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with α5 GABAA receptors (α5GABAARs), expression of which takes place between E14 and E17...
June 10, 2017: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/28606623/the-interaction-between-alpha-7-nicotinic-acetylcholine-receptor-and-nuclear-peroxisome-proliferator-activated-receptor-%C3%AE-represents-a-new-antinociceptive-signaling-pathway-in-mice
#8
Giulia Donvito, Deniz Bagdas, Wisam Toma, Elnaz Rahimpour, Asti Jackson, Julie A Meade, Shakir AlSharari, Abhijit R Kulkarni, F Ivy Carroll, Aron H Lichtman, Roger L Papke, Ganesh A Thakur, M Imad Damaj
Recently, α7 nicotinic acetylcholine receptors (nAChRs), primarily activated by binding of orthosteric agonists, represent a target for anti-inflammatory and analgesic drug development. These receptors may also be modulated by positive allosteric modulators (PAMs), ago-allosteric ligands (ago-PAMs), and α7-silent agonists. Activation of α7 nAChRs has been reported to increase the brain levels of endogenous ligands for nuclear peroxisome proliferator-activated receptors type-α (PPAR-α), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in a Ca(2+)-dependent manner...
June 9, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28603025/the-ampa-receptor-positive-allosteric-modulator-s-47445-rescues-in%C3%A2-vivo-ca3-ca1-long-term-potentiation-and-structural-synaptic-changes-in-old-mice
#9
Albert Giralt, María Ángeles Gómez-Climent, Rafael Alcalá, Sylvie Bretin, Daniel Bertrand, José María Delgado-García, Esther Pérez-Navarro, Jordi Alberch, Agnès Gruart
Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are small molecules that decrease deactivation of AMPARs via an allosteric site. These molecules keep the receptor in an active state. Interestingly, this type of modulator has been proposed for treating cognitive decline in ageing, dementias, and Alzheimer's disease (AD). S 47445 (8-cyclopropyl-3-[2-(3-fluorophenyl)ethyl]-7,8-dihydro-3H-[1,3]oxazino[6,5-g][1,2,3]benzotriazine-4,9-dione) is a novel AMPAR positive allosteric modulator (AMPA-PAM)...
June 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28598634/design-and-synthesis-of-%C3%AE-and-%C3%AE-lactam-m1-positive-allosteric-modulators-pams-convulsion-and-cholinergic-toxicity-of-an-m1-selective-pam-with-weak-agonist-activity
#10
Jennifer E Davoren, Michelle Garnsey, Betty Pettersen, Michael A Brodney, Jeremy R Edgerton, Jean Philippe Fortin, Sarah Grimwood, Antony R Harris, Stephen Jenkinson, Terry P Kenakin, John T Lazzaro, Che-Wah Lee, Susan M Lotarski, Lisa Nottebaum, Steven V O'Neil, Michael Popiolek, Simeon Ramsey, Stefanus J Steyn, Catherine A Thorn, Lei Zhang, Damien Webb
Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were completed using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct agonism, rather than allosteric modulation, could be responsible for the adverse effects. This manuscript describes the design and synthesis of lactam-derived M1 PAMs that address this question...
June 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28596119/alterations-of-m1-and-m4-acetylcholine-receptors-in-the-genetically-dystonic-dt-sz-hamster-and-moderate-antidystonic-efficacy-of-m1-and-m4-anticholinergics
#11
Melanie Hamann, Jagoda Plank, Franziska Richter, Christoph Bode, Sinisa Smiljanic, Meaghan Creed, José N Nobrega, Angelika Richter
Striatal cholinergic dysfunction has been suggested to play a critical role in the pathophysiology of dystonia. In the dt(sz) hamster, a phenotypic model of paroxysmal dystonia, M1 antagonists exerted moderate antidystonic efficacy after acute systemic administration. In the present study, we examined the effects of the M4 preferring antagonist tropicamid and whether long-term systemic or acute intrastriatal injections of the M1 preferring antagonist trihexyphenidyl are more effective in mutant hamsters. Furthermore, M1 and M4 receptors were analyzed by autoradiography and immunohistochemistry...
June 9, 2017: Neuroscience
https://www.readbyqxmd.com/read/28587821/structural-development-of-1-2-3-4-tetrahydroisoquinoline-type-positive-allosteric-modulators-of-prostacyclin-receptor-ippams-to-improve-metabolic-stability-and-investigation-of-metabolic-fate
#12
Hiroyuki Miyachi, Toshifumi Suzuki, Riyo Imamura, Tetsuo Nagano, Takayoshi Okabe
We synthesized a series of 1,2,3,4-tetrahydroisoquinoline-type positive allosteric modulators of prostacyclin receptor (IPPAMs), aiming to improve the metabolic stability of the previously identified hit compound IPPAM-3 (2). Our results indicated that the 3-position of the 2-substituted phenyl ring in this series of IPPAM-3 derivatives is a hot spot for metabolism catalyzed by human hepatic microsomes. This conclusion was confirmed by the finding that 8, in which the 3-position is blocked by a fluorine substituent, exhibited superior metabolic stability (t1/2 21min versus 7min for parent compound 2)...
May 20, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28586221/the-structure-activity-relationship-of-a-tetrahydroisoquinoline-class-of-n-methyl-%C3%A1-aspartate-receptor-modulators-that-potentiates-glun2b-containing-n-methyl-%C3%A1-aspartate-receptors
#13
Katie L Strong, Matthew P Epplin, John Bacsa, Christopher J Butch, Pieter B Burger, David S Menaldino, Stephen F Traynelis, Dennis C Liotta
We have identified a series of positive allosteric NMDA receptor (NMDAR) modulators derived from a known class of GluN2C/D-selective tetrahydroisoquinoline analogues that includes CIQ. The prototypical compound of this series contains a single isopropoxy moiety in place of the two methoxy substituents present in CIQ. Modifications of this isopropoxy-containing scaffold led to the identification of analogues with enhanced activity at the GluN2B subunit. We identified molecules that potentiate the response of GluN2B/GluN2C/GluN2D, GluN2B/GluN2C, and GluN2C/GluN2D-containing NMDARs to maximally effective concentrations of agonist...
June 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28570708/designing-small-molecules-to-target-cryptic-pockets-yields-both-positive-and-negative-allosteric-modulators
#14
Kathryn M Hart, Katelyn E Moeder, Chris M W Ho, Maxwell I Zimmerman, Thomas E Frederick, Gregory R Bowman
Allosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible to target proteins considered "undruggable" and to develop new therapies that circumvent existing resistance. Despite growing interest in allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites in proteins. Previously, we used Markov State Models (MSMs) to identify such "cryptic pockets," and here we describe a method for identifying compounds that bind in these cryptic pockets and modulate enzyme activity...
2017: PloS One
https://www.readbyqxmd.com/read/28544993/muscarinic-receptor-m4-positive-allosteric-modulators-attenuate-central-effects-of-cocaine
#15
Camilla Dall, Pia Weikop, Ditte Dencker, Anna C Molander, Gitta Wörtwein, P Jeffrey Conn, Anders Fink-Jensen, Morgane Thomsen
BACKGROUND: Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis that specific muscarinic M4 receptor stimulation can attenuate the discriminative stimulus effects and conditioned rewarding effects of cocaine, measures believed to predict the ability of cocaine and cocaine-associated cues to elicit relapse to drug taking...
July 1, 2017: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/28536867/suppressing-effect-of-cor659-on-alcohol-sucrose-and-chocolate-self-administration-in-rats-involvement-of-the-gabab-and-cannabinoid-cb1-receptors
#16
Paola Maccioni, Giancarlo Colombo, Irene Lorrai, Alessandro Zaru, Mauro A M Carai, Gian Luigi Gessa, Antonella Brizzi, Claudia Mugnaini, Federico Corelli
RATIONALE AND OBJECTIVES: COR659 [methyl2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate] is a new, positive allosteric modulator (PAM) of the GABAB receptor. This study evaluated whether COR659 shared with previously tested GABAB PAMs the capacity to reduce alcohol self-administration in rats. RESULTS: Treatment with non-sedative doses of COR659 (2.5, 5, and 10 mg/kg; i.p.) suppressed lever-responding for alcohol (15% v/v) in Sardinian alcohol-preferring (sP) rats under the fixed ratio (FR) 4 (FR4) and progressive ratio (PR) schedules of reinforcement; COR659 was more potent and effective than the reference GABAB PAM, GS39783...
May 24, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28536523/positive-modulatory-interactions-of-nmda-receptor-glun1-2b-ligand-binding-domains-attenuate-antagonists-activity
#17
Douglas Bledsoe, Ceyhun Tamer, Ivana Mesic, Christian Madry, Bradley G Klein, Bodo Laube, Blaise M Costa
N-methyl D-aspartate receptors (NMDAR) play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A-D) and two GluN3 (A-B) subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD) and ligand binding domain (LBD), transmembrane domain (TMD) and an intracellular C-terminal domain (CTD)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28523095/therapeutic-advantage-of-the-positive-allosteric-modulators-of-the-gaba-b-receptor
#18
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
#19
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...
July 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28521115/anticonvulsant-profile-of-the-neuroactive-steroid-sge-516-in-animal-models
#20
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
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