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Positive allosteric modulator

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https://www.readbyqxmd.com/read/28211669/3-aminomethyl-derivatives-of-2-phenylimidazo-1-2-a-pyridine-as-positive-allosteric-modulators-of-gabaa-receptor-with-potential-antipsychotic-activity
#1
Monika Marcinkowska, Marcin Kolaczkowski, Krzysztof Kamiński, Adam Bucki, Maciej Henryk Pawlowski, Agata Siwek, Tadeusz Karcz, Gabriela Starowicz, Karolina Sloczynska, Elżbieta Pękala, Anna Wesołowska, Jerzy Samochowiec, Paweł Mierzejewski, Przemyslaw Bienkowski
Schizophrenia is a mental illness characterized by behavioral changes as well as anatomical and neurochemical abnormalities. There has been a remarkable progress in the drug discovery for schizophrenia; however, antipsychotics that act through molecular targets, other than monoaminergic receptors, have not been developed. One of the hypotheses of schizophrenia states that GABAergic dysfunction might be implemented in the pathophysiology of this disease. Our recent findings and previous clinical observations have suggested that modulation of GABAergic system through α1-GABAA receptors would represent an original approach for the treatment of schizophrenia...
February 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28199738/orthosteric-and-allosteric-potentiation-of-heteromeric-neuronal-nicotinic-acetylcholine-receptors
#2
REVIEW
Jingyi Wang, Jon Lindstrom
Heteromeric nicotinic acetylcholine receptors (nAChRs) were thought to have two orthodox agonist binding sites at two α/β subunit interfaces. Highly selective ligands are hard to achieve by targeting orthodox agonist sites because of high sequence similarity of this binding pocket among different subunits. Recently, unorthodox acetylcholine (ACh) binding sites have been discovered at some α/α and β/α subunit interfaces, such as α4/α4, α5/α4 and β3/α4. Targeting unorthodox sites may yield subtype-selective ligands which are otherwise hard to develop, such as those for (α4β2)2 α5, (α4β2)2 β3 and (α6β2)2 β3 nAChRs...
February 15, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28197318/discovery-of-vu0467485-az13713945-an-m4-pam-evaluated-as-a-preclinical-candidate-for-the-treatment-of-schizophrenia
#3
Michael R Wood, Meredith J Noetzel, Bruce J Melancon, Michael S Poslusney, Kellie D Nance, Miguel A Hurtado, Vincent B Luscombe, Rebecca L Weiner, Alice L Rodriguez, Atin Lamsal, Sichen Chang, Michael Bubser, Anna L Blobaum, Darren W Engers, Colleen M Niswender, Carrie K Jones, Nicholas J Brandon, Michael W Wood, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28196863/conformational-changes-in-the-activation-loop-of-mitochondrial-glutaminase-c-a-direct-fluorescence-read-out-that-distinguishes-the-binding-of-allosteric-inhibitors-from-activators
#4
Clint A Stalnecker, Jon W Erickson, Richard A Cerione
The first step in glutamine catabolism is catalyzed by the mitochondrial enzyme glutaminase, with a specific isoform, glutaminase C (GAC), being highly expressed in cancer cells. GAC activation requires the formation of homo-tetramers, promoted by anionic allosteric activators such as inorganic phosphate. This leads to the proper orientation of a flexible loop proximal to the dimer-dimer interface that is essential for catalysis (i.e. the activation loop). A major class of allosteric inhibitors of GAC, with the prototype being BPTES (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide), and the related molecule CB-839, binds to the activation loop and induces the formation of an inactive tetramer (2 inhibitors bound per active tetramer)...
February 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28196430/first-in-human-trial-of-a-type-i-positive-allosteric-modulator-of-alpha7-nicotinic-acetylcholine-receptors-pharmacokinetics-safety-and-evidence-for-neurocognitive-effect-of-avl-3288
#5
Kelvin W Gee, Ann Olincy, Richard Kanner, Lynn Johnson, Derk Hogenkamp, Josette Harris, Minhtam Tran, Stephen A Edmonds, William Sauer, Ryan Yoshimura, Timothy Johnstone, Robert Freedman
Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects...
February 1, 2017: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/28188265/the-kinase-cipk23-inhibits-ammonium-transport-in-arabidopsis-thaliana
#6
Tatsiana Straub, Uwe Ludewig, Benjamin Neuhaeuser
Ion transport in plants is not only strictly regulated on a transcriptional level, but it is also regulated posttranslationally. Enzyme modifications such as phosphorylation provide rapid regulation of many plant ion transporters and channels. Upon exposure to high ammonium concentrations in the rhizosphere, the high-affinity AMmonium Transporters (AMT) in Arabidopsis thaliana are efficiently inactivated by phosphorylation to avoid toxic accumulation of cytoplasmic ammonium. External ammonium stimulates the phosphorylation of a conserved threonine in the cytosolic AMT1 C-terminus, which allosterically inactivates AMT1 trimers...
February 10, 2017: Plant Cell
https://www.readbyqxmd.com/read/28182309/propagation-of-the-allosteric-modulation-induced-by-sodium-in-the-%C3%AE-opioid-receptor
#7
Xianqiang Sun, Genevieve Laroche, Xu Wang, Hans Ågren, Greg Bowman, Patrick M Giguère, Yaoquan Tu
Allosteric sodium in the helix bundle of a G protein-coupled receptor (GPCR) can modulate the receptor activation on the intracellular side. This phenomenon has confounded the GPCR community for decades. In this work, we present a theoretical model that reveals the mechanism of the allosteric modulation induced by sodium in the δ opioid receptor. We found that the allosteric sodium ion exploits a distinct conformation of the key residue Trp2746.48 to propagate the modulation to helixes 5 and 6, which further transmits along the helixes and regulates their positions on the intracellular side...
February 9, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28168926/stimulation-of-nicotinic-acetylcholine-alpha7-receptors-rescue-schizophrenia-like-cognitive-impairments-in-rats
#8
Agnieszka Potasiewicz, Agnieszka Nikiforuk, Małgorzata Hołuj, Piotr Popik
Alpha7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction plays an important role in schizophrenia. Positive allosteric modulators of α7 nAChR have emerged as a promising therapeutic approach to manage cognitive deficits that are inadequately treated in schizophrenic patients. The aim of the present study was to evaluate the ability of type I (CCMI) and type II (PNU120596) α7 nAChR positive allosteric modulators to counteract MK-801-induced cognitive and sensorimotor gating deficits. The activity of these compounds was compared with the action of the α7 nAChR agonist A582941...
February 2017: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/28167741/a-new-molecular-mechanism-to-engineer-protean-agonism-at-a-g-protein-coupled-receptor
#9
Anna De Min, Carlo Matera, Andreas Bock, Janine Holze, Jessica Kloeckner, Mathias Muth, Christian Traenkle, Marco De Amici, Terry Kenakin, Ulrike Holzgrabe, Clelia Dallanoce, Evi Kostenis, Klaus Mohr, Ramona Schrage
Protean agonists are of great pharmacological interest as their behavior may change in magnitude and direction depending on the constitutive activity of a receptor. Yet, this intriguing phenomenon has been poorly described and understood, due to the lack of stable experimental systems and design strategies. Here, we overcome both limitations: First, we demonstrate that modulation of the ionic strength in a defined experimental set-up allows for analysis of GPCR activation in the absence and presence of a specific amount of spontaneous receptor activity using the muscarinic M2 acetylcholine receptor as a model...
February 6, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28166368/efficacy-of-mglu2-positive-allosteric-modulators-alone-and-in-combination-with-levetiracetam-in-the-mouse-6-hz-model-of-psychomotor-seizures
#10
Cameron S Metcalf, Brian D Klein, Misty D Smith, Tim Pruess, Marc Ceusters, Hilde Lavreysen, Stefan Pype, Nancy Van Osselaer, Roy Twyman, H Steve White
OBJECTIVE: The metabotropic glutamate receptor subtype 2 (mGlu2 ) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2 is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2 -acting compounds. METHODS: The anticonvulsant efficacy of two selective mGlu2 -positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3 receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model...
February 6, 2017: Epilepsia
https://www.readbyqxmd.com/read/28163934/enhancing-nmda-receptor-function-recent-progress-on-allosteric-modulators
#11
REVIEW
Lulu Yao, Qiang Zhou
The N-methyl-D-aspartate receptors (NMDARs) are subtype glutamate receptors that play important roles in excitatory neurotransmission and synaptic plasticity. Their hypo- or hyperactivation are proposed to contribute to the genesis or progression of various brain diseases, including stroke, schizophrenia, depression, and Alzheimer's disease. Past efforts in targeting NMDARs for therapeutic intervention have largely been on inhibitors of NMDARs. In light of the discovery of NMDAR hypofunction in psychiatric disorders and perhaps Alzheimer's disease, efforts in boosting NMDAR activity/functions have surged in recent years...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28162648/-401-brain-alpha-7-nicotinic-acetylcholine-receptor-positive-allosteric-modulator-attenuates-mechanical-allodynia-and-hyperalgesia-in-a-mouse-model-of-neuroinflammatory-pain
#12
M Abbas, S Rahman
No abstract text is available yet for this article.
April 2016: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/28161890/homology-guided-mutational-analysis-reveals-the-functional-requirements-for-antinociceptive-specificity-of-crmp2-derived-peptides
#13
Aubin Moutal, Wennan Li, Yue Wang, Weina Ju, Shizhen Luo, Song Cai, Liberty François-Moutal, Samantha Perez-Miller, Jackie Hu, Erik T Dustrude, Todd W Vanderah, Vijay Gokhale, May Khanna, Rajesh Khanna
BACKGROUND AND PURPOSE: N-type voltage-gated calcium (CaV2.2) channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Despite CaV2.2 antagonism being recommended as first-line treatment for neuropathic pain, calcium-current blocking gabapentinoids inadequately alleviate chronic pain symptoms and are often mired by numerous side-effects. Collapsin response mediator protein 2 (CRMP2) targets CaV2.2 to the sensory neuron membrane, and allosterically modulates Cav2...
February 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28150939/antinociceptive-effects-of-a-novel-%C3%AE-2-%C3%AE-3-subtype-selective-gabaa-receptor-positive-allosteric-modulator
#14
Lakeisha A Lewter, Janet L Fisher, Justin N Siemian, Kashi Reddy Methuku, Michael M Poe, James M Cook, Jun-Xu Li
Pain remains a challenging clinical condition and spinal GABAA receptors are crucial modulators of pain processing. α2/α3-subtype GABAA receptors mediate the analgesic actions of benzodiazepines. Positive allosteric modulators (PAMs) at α2/α3-subtype GABAA receptors may have analgesic potential. Here we report a new selective α2/α3-subtype GABAA receptor PAM in in vitro and in vivo pain assays. KRM-II-81 demonstrated similar efficacy at α1/α2/α3 GABAA receptors and negligible efficacy at α4/α5/α6 GABAA receptors, with α2 and α3-subtypes being 17- and 28-fold more potent than α1 subtypes in HEK-293T cells expressing GABAA receptors with different α subunits...
February 2, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28139681/attenuating-nicotine-reinforcement-and-relapse-by-enhancing-endogenous-brain-levels-of-kynurenic-acid-in-rats-and-squirrel-monkeys
#15
Maria E Secci, Alessia Auber, Leigh V Panlilio, Godfrey H Redhi, Eric B Thorndike, Charles W Schindler, Robert Schwarcz, Steven R Goldberg, Zuzana Justinova
Currently-available antismoking medications have limited efficacy and often fail to prevent relapse. Thus, there is a pressing need for newer, more effective treatment strategies. Recently, we demonstrated that enhancing endogenous levels of kynurenic acid (KYNA, a neuroinhibitory product of tryptophan metabolism) counteracts the rewarding effects of cannabinoids by acting as a negative allosteric modulator of α7 nicotinic receptors (α7nAChRs). Since the effects of KYNA on cannabinoid reward involve nicotinic receptors, in the present study we used rat and squirrel monkey models of reward and relapse to examine the possibility that enhancing KYNA can counteract the effects of nicotine...
January 31, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28135635/recent-advances-in-drug-discovery-of-gpcr-allosteric-modulators-for-neurodegenerative-disorders
#16
REVIEW
Robert Lütjens, Jean-Philippe Rocher
The activation or the inhibition of G-protein coupled receptors (GPCRs) implicated in the pathophysiology of neurodegenerative disorders is considered as a relevant approach for the treatment of these diseases. The modulation of the relevant GPCRs targets by positive or by negative allosteric modulators appears to be promising, the major challenge remaining the discovery of these molecules. In this review, we highlight the recent development in this field and the therapeutic potential of selected GPCRs allosteric modulators...
January 27, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28132910/b-973-a-novel-piperazine-positive-allosteric-modulator-of-the-%C3%AE-7-nicotinic-acetylcholine-receptor
#17
Debra J Post-Munson, Rick L Pieschl, Thaddeus F Molski, John D Graef, Adam W Hendricson, Ronald J Knox, Ivar M McDonald, Richard E Olson, John E Macor, Michael R Weed, Linda J Bristow, Laszlo Kiss, Michael K Ahlijanian, James Herrington
The alpha7 (α7) nicotinic acetylcholine receptor is a therapeutic target for cognitive disorders. Here we describe 3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propanamide (B-973), a novel piperazine-containing molecule that acts as a positive allosteric modulator of the α7 receptor. We characterize the action of B-973 on the α7 receptor using electrophysiology and radioligand binding. At 0.1mM acetylcholine, 1μM B-973 potentiated peak acetylcholine-induced currents 6-fold relative to maximal acetylcholine (3mM) and slowed channel desensitization, resulting in a 6900-fold increase in charge transfer...
January 26, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28131622/perinatal-nicotine-treatment-induces-transient-increases-in-nacho-protein-levels-in-the-rat-frontal-cortex
#18
Franziska Wichern, Majbrit M Jensen, Ditte Z Christensen, Jens D Mikkelsen, Marjorie C Gondré-Lewis, Morten S Thomsen
The nicotinic acetylcholine receptor (nAChR) regulator chaperone (NACHO) was recently identified as an important regulator of nAChR maturation and surface expression. Here we show that NACHO levels decrease during early postnatal development in rats. This decrease occurs earlier and to a greater degree in the frontal cortex (FC) compared with the hippocampus (HIP). We further show that rats exposed to nicotine during pre- and postnatal development exhibit significantly higher NACHO levels in the FC at postnatal day (PND) 21, but not at PND60...
January 25, 2017: Neuroscience
https://www.readbyqxmd.com/read/28130813/prediction-of-consensus-binding-mode-geometries-for-related-chemical-series-of-positive-allosteric-modulators-of-adenosine-and-muscarinic-acetylcholine-receptors
#19
Leon A Sakkal, Kyle Z Rajkowski, Roger S Armen
Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A1 R, A2A R, A3 R) and muscarinic acetylcholine (M1 R, M5 R) receptors were modeled using both rigid and flexible receptor CHARMM-based molecular docking. Studies of adenosine receptors investigated the molecular basis of the probe-dependence of PAM activity by modeling in complex with specific agonist radioligands...
January 28, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28128474/mimicking-the-regulation-step-of-fe-monooxygenases-allosteric-modulation-of-fe-iv-oxo-formation-by-guest-binding-in-a-dinuclear-zn-ii-fe-ii-calix-6-arene-based-funnel-complex
#20
Nathalie Ségaud, Constance De Thomasson, Caroline Daverat, Katell Sénéchal-David, Amandine Dos Santos, Vincent Steinmetz, Philippe Maître, Jean-Noël Rebilly, Frédéric Banse, Olivia Reinaud
A heteroditopic ligand associated with a calix[6]arene scaffold bearing a tris(imidazole) coordinating site at its small rim and an amine/pyridine ligand at its large rim has been prepared, and its regioselective coordination to Zn(II) at the small rim and Fe(II) in the amine/pyridine ligand has been achieved. The heterodinuclear complex obtained displays an overall cone conformation capped by the tris(imidazole)Zn(II) moiety and bears a non-heme Fe(II) complex at its base. Each of the metal centers exhibits one labile position, allowing the coordination inside the cavity of a guest alkylamine at Zn(II) and the generation of reaction intermediates (Fe(III) (OOH) and Fe(IV) O) at the large rim...
January 27, 2017: Chemistry: a European Journal
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