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Positive allosteric modulator

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https://www.readbyqxmd.com/read/28436443/curcumol-allosterically-modulates-gaba-a-receptors-in-a-manner-distinct-from-benzodiazepines
#1
Yan-Mei Liu, Hui-Ran Fan, Jing Ding, Chen Huang, Shining Deng, Tailin Zhu, Tian-Le Xu, Wei-Hong Ge, Wei-Guang Li, Fei Li
Inhibitory A type γ-aminobutyric acid receptors (GABAARs) play a pivotal role in orchestrating various brain functions and represent an important molecular target in neurological and psychiatric diseases, necessitating the need for the discovery and development of novel modulators. Here, we show that a natural compound curcumol, acts as an allosteric enhancer of GABAARs in a manner distinct from benzodiazepines. Curcumol markedly facilitated GABA-activated currents and shifted the GABA concentration-response curve to the left in cultured hippocampal neurons...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28432359/role-of-the-ion-channel-extracellular-collar-in-ampa-receptor-gating
#2
Maria V Yelshanskaya, Samaneh Mesbahi-Vasey, Maria G Kurnikova, Alexander I Sobolevsky
AMPA subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission and are implicated in numerous neurological diseases. Ionic currents through AMPA receptor channels can be allosterically regulated via different sites on the receptor protein. We used site-directed mutagenesis and patch-clamp recordings to probe the ion channel extracellular collar, the binding region for noncompetitive allosteric inhibitors. We found position and substitution-dependent effects for introduced mutations at this region on AMPA receptor gating...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28428226/rapid-throughput-analysis-of-gabaa-receptor-subtype-modulators-and-blockers-using-disbac1-3-membrane-potential-red-dye
#3
Atefeh Mousavi Nik, Brandon Pressly, Vikrant Singh, Shane Antrobus, Susan Hulsizer, Michael A Rogawski, Heike Wulff, Isaac N Pessah
Fluorometric Imaging Plate Reader (FLIPR®) membrane potential dye (FMP-Red-Dye) is a proprietary tool for basic discovery and high throughput drug screening for G-protein coupled receptors and ion channels. We optimized and validated this potentiometric probe to assay functional modulators of heterologous expressed GABAA receptor (GABAAR) isoforms (synaptic α1β3γ2, extrasynaptic α4β3δ, and β3 homopentomers). High-resolution mass spectrometry identified FMP-Red-dye as DisSBAC1(3). GABAAR expressing cells equilibrated with FMP-Red-Dye exhibited depolarized equilibrium membrane (Em) potentials compared to GABAAR-null cells...
April 20, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28426939/high-throughput-agonist-shift-assay-development-for-the-analysis-of-m1-positive-allosteric-modulators
#4
Michelle F Homsher, Douglas C Beshore, Jason Cassaday, Brian Squadroni, Elizabeth Mohammed, Michelle Hartnett, Stephen Day, Lei Ma, David Pechter, Michelle D Smith, Fredrick Monsma, Paul Zuck, Michael F Finley, Victor N Uebele, Jeffrey D Hermes
Agonist shift assays feature cross-titrations of allosteric modulators and orthosteric ligands. Information generated in agonist shift assays can include a modulator's effect on the orthosteric agonist's potency (alpha) and efficacy (beta), as well as direct agonist activity of the allosteric ligand (tauB) and the intrinsic binding affinity of the modulator to the unoccupied receptor (KB). Because of the heavy resource demand and complex data handling, these allosteric parameters are determined infrequently during the course of a drug discovery program and on a relatively small subset of compounds...
April 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28425312/activation-of-spinal-alpha-7-nicotinic-acetylcholine-receptor-shortens-the-duration-of-remifentanil-induced-postoperative-hyperalgesia-by-upregulating-kcc2-in-the-spinal-dorsal-horn-in-rats
#5
Wei Gu, Wei Zhang, Yishan Lei, Yin Cui, Shuaishuai Chu, Xiaoping Gu, Zhengliang Ma
Background Accumulating evidence has shown that the signal from spinal brain-derived neurotrophic factor/tyrosine receptor kinase B-K(+)-Cl(-) cotransporter-2 plays a critical role in the process of pain hypersensitivity. The activation of alpha-7 nicotinic acetylcholine receptors could have an analgesic effect on remifentanil-induced postoperative hyperalgesia. Nevertheless, whether intrathecal administration of PNU-120596, an alpha-7 nicotinic acetylcholine receptors selective type II positive allosteric modulator, before surgery could affect the duration of remifentanil-induced postoperative hyperalgesia remains unknown, and the effects of alpha-7 nicotinic acetylcholine receptors activation on the brain-derived neurotrophic factor/tyrosine receptor kinase B-K(+)-Cl(-) cotransporter-2 signal in the spinal dorsal horn of rats with remifentanil-induced postoperative hyperalgesia is still enigmatic...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28424220/gababr-induced-egfr-transactivation-promotes-migration-of-human-prostate-cancer-cells
#6
Shuai Xia, Cong He, Yini Zhu, Suyun Wang, Huiping Li, Zhongling Zhang, Xinnong Jiang, Jianfeng Liu
G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been detected in human cancer tissues and cancer cell lines, but the role of GABABR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABABR hijacks RTK signaling to modulate the fates of human prostate cancer cells...
April 19, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28419415/allostery-at-opioid-receptors-modulation-with-small-molecule-ligands
#7
REVIEW
Kathryn E Livingston, John R Traynor
Opioid receptors are 7-transmembrane domain receptors that couple to heterotrimeric G proteins. The endogenous ligands for opioid receptors are peptides which bind to the orthosteric site on the receptors. The μ-opioid receptor is the target for opioid analgesics while the δ-opioid receptor has been suggested as a target for pain management, migraine, and depression. Similarly, κ-opioid receptors are involved in pain and depression and nociceptin receptors in pain and mood behaviors. However, exogenous orthosteric ligands for the opioid receptors cause a myriad of on-target side effects...
April 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28417952/investigating-the-molecular-mechanism-of-positive-and-negative-allosteric-modulators-in-the-calcium-sensing-receptor-dimer
#8
Stine Engesgaard Jacobsen, Ulrik Gether, Hans Bräuner-Osborne
Allosteric modulators that are targeting the calcium-sensing receptor (CaSR) hold great therapeutic potential, and elucidating the molecular basis for modulation would thus benefit the development of novel therapeutics. In the present study, we aimed at investigating the mechanism of allosteric modulation in CaSR by testing dimers carrying mutations in the allosteric site of one or both of the subunits. To ensure measurements on a well-defined dimer composition, we applied a trans-activation system in which only the specific heterodimer of two loss-of-function mutants responded to agonist...
April 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28416443/astrocytes-modulate-thalamic-sensory-processing-via-mglu2-receptor-activation
#9
C S Copeland, T M Wall, R E Sims, S A Neale, E Nisenbaum, H R Parri, T E Salt
Astrocytes possess many of the same signalling molecules as neurons. However, the role of astrocytes in information processing, if any, is unknown. Using electrophysiological and imaging methods, we report the first evidence that astrocytes modulate neuronal sensory inhibition in the rodent thalamus. We found that mGlu2 receptor activity reduces inhibitory transmission from the thalamic reticular nucleus to the somatosensory ventrobasal thalamus (VB): mIPSC frequencies in VB slices were reduced by the Group II mGlu receptor agonist LY354740, an effect potentiated by mGlu2 positive allosteric modulator (PAM) LY487379 co-application (30 nM LY354740: 10...
April 14, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28416442/allopregnanolone-decreases-interictal-spiking-and-fast-ripples-in-an-animal-model-of-mesial-temporal-lobe-epilepsy
#10
Maxime Lévesque, Rochelle Herrington, Leila Leclerc, Michael A Rogawski, Massimo Avoli
The objective of this study was to characterize the impact of allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, on interictal spikes and high-frequency oscillations (ripples: 80-200 Hz, fast ripples: 250-500 Hz) in the pilocarpine model of mesial temporal lobe epilepsy. Seven out of 25 Sprague-Dawley rats experiencing 1 h of pilocarpine-induced status epilepticus (SE) began treatment with allopregnanolone (9.6-12.8 mg/kg/day) on the following day...
April 14, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28407365/role-of-allopregnanolone-biosynthesis-in-acute-stress-induced-anxiety-like-behaviors-in-mice
#11
Kazumi Yoshizawa, Ayano Okumura, Kozue Nakashima, Tomoyo Sato, Tatsuya Higashi
The neurosteroid allopregnanolone (3α, 5α-tetra-hydroprogesterone: ALLO) elicits anxiolytic, anticonvulsant, and hypnotic anesthetic effects in vivo similar to those induced by other positive allosteric modulators of the GABAA receptor. Endogenous ALLO has been shown to be rapidly elevated in the brain by acute stress paradigms, such as immobilization, in animal models. The present study was designed to ascertain the role of neurosteroid biosynthesis in the anxiety-like behavior induced by immobilization stress...
April 13, 2017: Synapse
https://www.readbyqxmd.com/read/28396143/lethal-effects-of-an-insecticidal-spider-venom-peptide-involve-positive-allosteric-modulation-of-insect-nicotinic-acetylcholine-receptors
#12
Monique J Windley, Irina Vetter, Richard J Lewis, Graham M Nicholson
κ-Hexatoxins (κ-HXTXs) are a family of excitotoxic insect-selective neurotoxins from Australian funnel-web spiders that are lethal to a wide range of insects, but display no toxicity towards vertebrates. The prototypic κ-HXTX-Hv1c selectively blocks native and expressed cockroach large-conductance calcium-activated potassium (BKCa or KCa1.1) channels, but not their mammalian orthologs. Despite this potent and selective action on insect KCa1.1 channels, we found that the classical KCa1.1 blockers paxilline, charybdotoxin and iberiotoxin, which all block insect KCa1...
April 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28390229/discovery-of-4-amino-3-arylsulfoquinolines-a-novel-non-acetylenic-chemotype-of-metabotropic-glutamate-5-mglu5-receptor-negative-allosteric-modulators
#13
János Galambos, Attila Bielik, Gábor Wágner, György Domány, János Kóti, Zoltán Béni, Áron Szigetvári, Zsuzsanna Sánta, Zoltán Orgován, Amrita Bobok, Béla Kiss, Mónika L Mikó-Bakk, Mónika Vastag, Katalin Sághy, Mikhail Krasavin, Krisztina Gál, István Greiner, Zsolt Szombathelyi, György M Keserű
Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo...
March 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28389336/the-activity-of-selective-sigma-1-receptor-ligands-in-seizure-models-in-vivo
#14
Edijs Vavers, Baiba Svalbe, Lasma Lauberte, Ilmars Stonans, Ilga Misane, Maija Dambrova, Liga Zvejniece
Sigma-1 receptor (Sig1R) is a ligand-regulated protein which, since its discovery, has been widely studied as a novel target to treat neurological disorders, including seizures. However, the roles and mechanisms of Sig1R in the regulation of seizures are not fully understood. The aim of the present study was to test and compare effects of often used selective Sig1R ligands in models of experimentally induced seizures. The anti-seizure activities and interactions of selective Sig1R agonist PRE-084, selective Sig1R antagonist NE-100 and novel positive allosteric Sig1R modulator E1R were evaluated in pentylenetetrazol (PTZ) and (+)-bicuculline (BIC)-induced seizure models in mice...
April 4, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28382542/kk-92a-a-novel-gabab-receptor-positive-allosteric-modulator-attenuates-nicotine-self-administration-and-cue-induced-nicotine-seeking-in-rats
#15
Xia Li, Emmanuel Sturchler, Katarzyna Kaczanowska, Michael Cameron, M G Finn, Patrick Griffin, Patricia McDonald, Athina Markou
RATIONALE: GABAB receptors (GABABR) play a critical role in GABAergic neurotransmission in the brain and are thought to be one of the most promising targets for the treatment of drug addiction. GABABR positive allosteric modulators (PAMs) have shown promise as potential anti-addictive therapies, as they lack the sedative and muscle relaxant properties of full GABAB receptor agonists such as baclofen. OBJECTIVES: The present study was aimed at developing novel, selective, and potent GABABR PAMs with efficacy on abuse-related effects of nicotine...
April 5, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28369721/biased-agonism-and-allosteric-modulation-of-gpr183-a-7tm-receptor-also-known-as-ebv-induced-ebi2
#16
Viktorija Daugvilaite, Christian Medom Madsen, Michael Lückmann, Clara Castello Echeverria, Andreas Walter Sailer, Thomas Michael Frimurer, Mette Marie Rosenkilde, Tau Benned-Jensen
BACKGROUND AND PURPOSE: The G protein-coupled receptor Epstein Barr virus-induced gene 2 (EBI2, also known as GPR183) is activated by oxysterols and plays a pivotal role for proper B cell migration during immune responses. While the molecular basis of agonist binding has been addressed in several studies, the concept of biased agonism of EBI2 has not been explored. EXPERIMENTAL APPROACH: We investigated the effects of the EBI2 endogenous agonist 7α,25-OHC on G protein-dependent and -independent pathways as well as sodium ion allosterism using site-directed mutagenesis and functional studies...
March 29, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28365836/abuse-related-effects-of-subtype-selective-gabaa-receptor-positive-allosteric-modulators-in-an-assay-of-intracranial-self-stimulation-in-rats
#17
Kathryn L Schwienteck, Guanguan Li, Michael M Poe, James M Cook, Matthew L Banks, S Stevens Negus
RATIONALE: GABAA positive allosteric modulators (GABAA PAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse liability is a concern. Novel GABAA PAMS may have lower abuse liability while retaining clinical utility. OBJECTIVE: The present study compared abuse-related effects of the non-selective GABAA PAM diazepam, the α1-selective GABAA PAM zolpidem, and three novel GABAA PAMs (JY-XHe-053, XHe-II-053, and HZ-166) using intracranial self-stimulation (ICSS) in rats...
April 1, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28360196/epithelial-chemokine-cxcl14-synergizes-with-cxcl12-via-allosteric-modulation-of-cxcr4
#18
Paul J Collins, Michelle L McCully, Laura Martínez-Muñoz, César Santiago, James Wheeldon, Stephan Caucheteux, Sylvia Thelen, Valentina Cecchinato, Julia M Laufer, Vladimir Purvanov, Yoan R Monneau, Hugues Lortat-Jacob, Daniel F Legler, Mariagrazia Uguccioni, Marcus Thelen, Vincent Piguet, Mario Mellado, Bernhard Moser
The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100-300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone...
March 30, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28360094/identification-and-structure-function-study-of-positive-allosteric-modulators-of-kainate-receptors
#19
Anja Probst Larsen, Sabine Fievre, Karla Frydenvang, Pierre Francotte, Bernard Pirotte, Jette Sandholm Karstrup, Christophe Mulle
Kainate receptors (KARs) consist of a class of ionotropic glutamate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of AMPA receptors have been reported, no such ligands are available for KARs. In this study, we have investigated the ability of three benzothiadiazine-based modulators to potentiate glutamate-evoked currents at recombinantly expressed KARs...
March 30, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28358902/screening-for-ampa-receptor-auxiliary-subunit-specific-modulators
#20
Caleigh M Azumaya, Emily L Days, Paige N Vinson, Shaun Stauffer, Gary Sulikowski, C David Weaver, Terunaga Nakagawa
AMPA receptors (AMPAR) are ligand gated ion channels critical for synaptic transmission and plasticity. Their dysfunction is implicated in a variety of psychiatric and neurological diseases ranging from major depressive disorder to amyotrophic lateral sclerosis. Attempting to potentiate or depress AMPAR activity is an inherently difficult balancing act between effective treatments and debilitating side effects. A newly explored strategy to target subsets of AMPARs in the central nervous system is to identify compounds that affect specific AMPAR-auxiliary subunit complexes...
2017: PloS One
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