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Positive allosteric modulator

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https://www.readbyqxmd.com/read/27920723/sex-dependent-anti-stress-effect-of-an-%C3%AE-5-subunit-containing-gabaa-receptor-positive-allosteric-modulator
#1
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
#2
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
#3
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
#4
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...
November 14, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908761/discovery-of-dual-positive-allosteric-modulators-pams-of-the-metabotropic-glutamate-2-receptor-and-cyslt1-antagonists-for-treating-migraine-headache
#5
Maria-Jesus Blanco, Dana R Benesh, James A Knobelsdorf, Albert Khilevich, Guillermo S Cortez, Fese Mokube, Thomas D Aicher, Todd M Groendyke, Fredrik P Marmsater, Tony P Tang, Kirk W Johnson, Amy Clemens-Smith, Mark A Muhlhauser, Steven Swanson, John Catlow, Renee Emkey, Michael P Johnson, Jeffrey M Schkeryantz
Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold...
November 18, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27908269/levamisole-a-positive-allosteric-modulator-for-the-%C3%AE-3%C3%AE-4-nicotinic-acetylcholine-receptors-prevents-weight-gain-in-cd-1-mice-on-a-high-fat-diet
#6
Jeanne A Lewis, Jerrel L Yakel, Anshul A Pandya
Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the function of multiple neurotransmitter pathways throughout the central nervous system. This includes nAChRs found on the proopiomelanocortin neurons in the hypothalamus. Activation of these nAChRs by nicotine causes a decrease in consumption of food in rodents. In this study, we tested the effect of subtype selective allosteric modulators for nAChRs on the body weight of CD-1 mice. Levamisole, an allosteric modulator for the α3β4 subtype of nAChRs, prevented weight gain in mice that were fed a high fat diet...
December 1, 2016: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/27891077/presynaptic-g-protein-coupled-receptors-gatekeepers-of-addiction
#7
REVIEW
Kari A Johnson, David M Lovinger
Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses and G protein-coupled receptors (GPCRs) that have slower neuromodulatory actions...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27889489/the-drug-candidate-adx71441-is-a-novel-potent-and-selective-positive-allosteric-modulator-of-the-gabab-receptor-with-a-potential-for-treatment-of-anxiety-pain-and-spasticity
#8
Mikhail Kalinichev, Françoise Girard, Hasnaà Haddouk, Mélanie Rouillier, Eric Riguet, Isabelle Royer-Urios, Vincent Mutel, Robert Lütjens, Sonia Poli
Positive allosteric modulation of the GABAB receptor is a promising alternative to direct activation of the receptor as a therapeutic approach for treatment of addiction, chronic pain, anxiety, epilepsy, autism, Fragile X syndrome, and psychosis. Here we describe in vitro and in vivo characterization of a novel, potent and selective GABAB positive allosteric modulator (PAM) N-(5-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide (ADX71441). In vitro, Schild plot and reversibility tests at the target confirmed PAM properties of the compound...
November 23, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27879006/allosteric-modulation-an-alternate-approach-targeting-the-cannabinoid-cb1-receptor
#9
REVIEW
Thuy Nguyen, Jun-Xu Li, Brian F Thomas, Jenny L Wiley, Terry P Kenakin, Yanan Zhang
The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions. A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years. In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators. A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists...
November 23, 2016: Medicinal Research Reviews
https://www.readbyqxmd.com/read/27876620/the-gabab-positive-allosteric-modulators-cgp7930-and-gs39783-stimulate-erk1-2-signalling-in-cells-lacking-functional-gabab-receptors
#10
Maria C Olianas, Simona Dedoni, Pierluigi Onali
The present study shows that the GABAB positive allosteric modulators (PAMs) CGP7930 and GS39783 stimulate extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signalling in cells that do not express functional GABAB receptors. In human SH-SY5Y neuroblastoma cells, CGP7930 and GS39783 induced a time- and concentration-dependent increase in ERK1/2 phosphorylation with potencies similar to those displayed as GABAB PAMs. Conversely, γ-aminobutyric acid and the GABAB receptor agonists (-)baclofen and SKF97541 were completely inactive...
November 19, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27872019/metabotropic-glutamate-receptors-and-neurodegenerative-diseases
#11
REVIEW
Fabiola M Ribeiro, Luciene B Vieira, Rita G W Pires, Roenick P Olmo, Stephen S G Ferguson
Glutamate is the most important excitatory neurotransmitter of the mammalian central nervous system (CNS), playing an important role in memory, synaptic plasticity and neuronal development. However, glutamate overstimulation is also implicated in neuronal cell death. There are two major types of glutamate receptors: ionotropic and metabotropic. Thus far, eight metabotropic glutamate receptors (mGluRs) subtypes have been characterized and are divided into three subgroups based on sequence homology and cell signaling activation...
November 19, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27864368/role-of-the-cys-loop-and-transmembrane-domain-in-the-allosteric-modulation-of-%C3%AE-4%C3%AE-2-nicotinic-acetylcholine-receptors
#12
Constanza Alcaino, Maria Musgaard, Teresa Minguez, Simone Mazzaferro, Manuel Faundez, Patricio Iturriaga-Vasquez, Philip C Biggin, Isabel Bermudez
Allosteric modulators of pentameric ligand gated ion channels (pLGICs) are thought to act on elements of the pathways that couple agonist binding to channel gating. Using α4β2 nicotinic acetylcholine receptors (nAChRs) and the α4β2-selective positive modulators 17β-estradiol (βEST) and desformylflustrabromine (dFBr), we have identified pathways that link the binding sites for these modulators to the Cys loop, a region that is critical for channel gating in all pLGICs. Previous studies have shown that the binding site for potentiating βEST is in the C-terminal (post-M4 region) of the α4 subunit...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27864339/development-of-a-platform-to-enable-fully-automated-cross-titration-experiments
#13
Jason Cassaday, Michael Finley, Brian Squadroni, Sylvie Jezequel-Sur, Albert Rauch, Bharti Gajera, Victor Uebele, Jeffrey Hermes, Paul Zuck
In the triage of hits from a high-throughput screening campaign or during the optimization of a lead compound, it is relatively routine to test compounds at multiple concentrations to determine potency and maximal effect. Additional follow-up experiments, such as agonist shift, can be quite valuable in ascertaining compound mechanism of action (MOA). However, these experiments require cross-titration of a test compound with the activating ligand of the receptor requiring 100-200 data points, severely limiting the number tested in MOA assays in a screening triage...
November 18, 2016: Journal of Laboratory Automation
https://www.readbyqxmd.com/read/27856084/difluorocyclobutylacetylenes-as-positive-allosteric-modulators-of-mglur5-with-reduced-bioactivation-potential
#14
Andrew P Degnan, Darrell Maxwell, Anand Balakrishnan, Jeffrey M Brown, Amy Easton, Michael Gulianello, Umesh Hanumegowda, Melissa Hill-Drzewi, Regina Miller, Kenneth S Santone, Arun Senapati, Eric E Shields, Digavalli V Sivarao, Ryan Westphal, Valerie J Whiterock, Xiaoliang Zhuo, Joanne J Bronson, John E Macor
Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-d-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype...
December 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27853832/old-drugs-with-new-skills-fenoprofen-as-an-allosteric-enhancer-at-melanocortin-receptor-3
#15
Trinidad Montero-Melendez, Rachel A E Forfar, Jennifer M Cook, Jeffrey C Jerman, Debra L Taylor, Mauro Perretti
The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC3, MC4, and MC5 receptors...
November 16, 2016: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/27848106/allosteric-effect-of-adenosine-triphosphate-on-peptide-recognition-by-3-5-cyclic-adenosine-monophosphate-dependent-protein-kinase-catalytic-subunits
#16
Rait Kivi, Karina Solovjova, Tõiv Haljasorg, Piret Arukuusk, Jaak Järv
The allosteric influence of adenosine triphosphate (ATP) on the binding effectiveness of a series of peptide inhibitors with the catalytic subunit of 3'5'-cyclic adenosine monophosphate dependent protein kinase was investigated, and the dependence of this effect on peptide structure was analyzed. The allosteric effect was calculated as ratio of peptide binding effectiveness with the enzyme-ATP complex and with the free enzyme, quantified by the competitive inhibition of the enzyme in the presence of ATP excess, and by the enzyme-peptide complex denaturation assay, respectively It was found that the principle "better binding-stronger allostery" holds for interactions of the studied peptides with the enzyme, indicating that allostery and peptide binding with the free enzyme are governed by the same specificity pattern...
December 2016: Protein Journal
https://www.readbyqxmd.com/read/27845713/novel-approaches-to-investigate-one-carbon-metabolism-and-related-b-vitamins-in-blood-pressure
#17
REVIEW
Amy McMahon, Helene McNulty, Catherine F Hughes, J J Strain, Mary Ward
Hypertension, a major risk factor for heart disease and stroke, is the world's leading cause of preventable, premature death. A common polymorphism (677C→T) in the gene encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) is associated with increased blood pressure, and there is accumulating evidence demonstrating that this phenotype can be modulated, specifically in individuals with the MTHFR 677TT genotype, by the B-vitamin riboflavin, an essential co-factor for MTHFR. The underlying mechanism that links this polymorphism, and the related gene-nutrient interaction, with hypertension is currently unknown...
November 11, 2016: Nutrients
https://www.readbyqxmd.com/read/27844094/attenuation-of-nicotine-taking-and-seeking-in-rats-by-the-stoichiometry-selective-alpha4beta2-nicotinic-acetylcholine-receptor-positive-allosteric-modulator-ns9283
#18
John J Maurer, Karin Sandager-Nielsen, Heath D Schmidt
RATIONALE: The rewarding and reinforcing effects of nicotine are produced, in large part, by activation of neuronal α4β2* nicotinic acetylcholine receptors (nAChRs), pentameric protein complexes comprised of different stoichiometries of α4 and β2 subunits. However, little is known about the functional role of distinct subtypes of α4β2* nAChRs in nicotine addiction. OBJECTIVES: NS9283 represents a new class of stoichiometry-selective positive allosteric modulators (PAMs) that selectively bind to α4β2 nAChRs containing three α4 and two β2 subunits (3(α4)2(β2) nAChRs)...
November 14, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/27834679/molecular-mechanism-of-action-for-allosteric-modulators-and-agonists-in-cc-chemokine-receptor-5-ccr5
#19
Stefanie Karlshøj, Roxana Maria Amarandi, Olav Larsen, Viktorija Daugvilaite, Anne Steen, Matjaž Brvar, Aurel Pui, Thomas Michael Frimurer, Trond Ulven, Mette Marie Rosenkilde
The small molecule metal-ion chelators bipyridine and terpyridine complexed with Zn(2+) (ZnBip and ZnTerp) act as CCR5 agonists and strong positive allosteric modulators of CCL3-binding to CCR5, weak modulators of CCL4-binding, and as competitors for CCL5-binding. Here we describe their binding site using computational modeling, binding and functional studies on WT and mutated CCR5. The metal-ion Zn(2+) is anchored to the chemokine receptor-conserved E283(VII:06/7.39) Both chelators interact with aromatic residues in the transmembrane receptor domain...
November 10, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27831563/tissue-type-plasminogen-activator-controls-neuronal-death-by-raising-surface-dynamics-of-extrasynaptic-nmda-receptors
#20
Flavie Lesept, Arnaud Chevilley, Julie Jezequel, Laurent Ladépêche, Richard Macrez, Margaux Aimable, Sophie Lenoir, Thomas Bertrand, Laëtitia Rubrecht, Pascale Galea, Laurent Lebouvier, Karl-Uwe Petersen, Yannick Hommet, Eric Maubert, Carine Ali, Laurent Groc, Denis Vivien
N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood...
November 10, 2016: Cell Death & Disease
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