keyword
MENU ▼
Read by QxMD icon Read
search

Positive allosteric modulator

keyword
https://www.readbyqxmd.com/read/28820325/small-alarmone-synthetases-as-novel-bacterial-rna-binding-proteins
#1
Vasili Hauryliuk, Gemma C Atkinson
The alarmone nucleotides guanosine pentaphosphate (pppGpp) and tetraphosphate (ppGpp), collectively referred to as (p)ppGpp, are key regulators of bacterial growth, stress adaptation, antibiotic tolerance and pathogenicity. We have recently shown that the Small Alarmone Synthetase (SAS) RelQ from the Gram-positive pathogen Enterococcus faecalis has an RNA-binding activity (Beljantseva et al. 2017). RelQ's activities as an enzyme and as a RNA-binding protein are mutually incompatible: binding of single-stranded RNA potently inhibits (p)ppGpp synthesis in a sequence-specific manner, and RelQ's enzymatic activity destabilizes the RNA:RelQ complex...
August 18, 2017: RNA Biology
https://www.readbyqxmd.com/read/28814546/mglu7-potentiation-rescues-cognitive-social-and-respiratory-phenotypes-in-a-mouse-model-of-rett-syndrome
#2
Rocco G Gogliotti, Rebecca K Senter, Nicole M Fisher, Jeffrey Adams, Rocio Zamorano, Adam G Walker, Anna L Blobaum, Darren W Engers, Corey R Hopkin, J Scott Daniels, Carrie K Jones, Craig W Lindsley, Zixiu Xiang, P Jeffrey Conn, Colleen M Niswender
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)-CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu7) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in MECP2 reduce mGlu7 protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models...
August 16, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28814238/structural-insights-for-drugs-developed-for-phospholipase-d-enzymes
#3
Kimberly Stieglitz
BACKGROUND: In recent years human phospholipase D enzymes (PLD1 and PLD2 isozymes) have emerged as drug targets for various diseases such as cardiovascular disease, cancer, infectious diseases and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. The interest in PLD as a drug target is due to the fact that PLD enzymes belong to a superfamily of phospholipases that are essential to intracellular and extracellular signaling. Many bioactive lipid signaling molecules are generated by these enzymes including phosphatidic and lysophosphatidic acid, arachidonic acid, and diacylglycerol (DAG)...
August 15, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28813418/mechanism-of-intracellular-allosteric-%C3%AE-2ar-antagonist-revealed-by-x-ray-crystal-structure
#4
Xiangyu Liu, Seungkirl Ahn, Alem W Kahsai, Kai-Cheng Meng, Naomi R Latorraca, Biswaranjan Pani, A J Venkatakrishnan, Ali Masoudi, William I Weis, Ron O Dror, Xin Chen, Robert J Lefkowitz, Brian K Kobilka
G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28809075/allosteric-modulation-of-%C3%AE-4%C3%AE-2-nicotinic-acetylcholine-receptors-desformylflustrabromine-potentiates-antiallodynic-response-of-nicotine-in-a-mouse-model-of-neuropathic-pain
#5
D Bagdas, D Ergun, A Jackson, W Toma, M K Schulte, M I Damaj
BACKGROUND: Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The α4β2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of α4β2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for α4β2 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain...
August 14, 2017: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/28803966/a-chimeric-prokaryotic-eukaryotic-pentameric-ligand-gated-ion-channel-reveals-interactions-between-the-extracellular-and-transmembrane-domains-shape-neurosteroid-modulation
#6
Borna Ghosh, Tzu-Wei Tsao, Cynthia Czajkowski
Pentameric ligand-gated ion channels (pLGICs) are the targets of several clinical and endogenous allosteric modulators including anesthetics and neurosteroids. Molecular mechanisms underlying allosteric drug modulation are poorly understood. Here, we constructed a chimeric pLGIC by fusing the extracellular domain (ECD) of the proton-activated, cation-selective bacterial channel GLIC to the transmembrane domain (TMD) of the human ρ1 chloride-selective GABAAR, and tested the hypothesis that drug actions are regulated locally in the domain that houses its binding site...
August 10, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28803965/the-great-divide-separation-between-in%C3%A2-vitro-and-in%C3%A2-vivo-effects-of-psncbam-based-cb1-receptor-allosteric-modulators
#7
Thomas F Gamage, Charlotte E Farquhar, Timothy W Lefever, Brian F Thomas, Thuy Nguyen, Yanan Zhang, Jenny L Wiley
While allosteric modulators of the cannabinoid type-1 receptor (CB1) continue to be developed and characterized, the gap between the in vitro and in vivo data is widening, raising questions regarding translatability of their effects and biological relevance. Among the CB1 allosteric modulators, PSNCBAM-1 has received little attention regarding its effects in vivo. Recently, pregnenolone was reported to act as an allosteric modulator of CB1, blocking THC's effects in vitro and in vivo, highlighting the potential of CB1 allosteric modulators for treatment of cannabis intoxication...
August 10, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28795803/identification-and-characterization-of-the-first-selective-y4-receptor-positive-allosteric-modulator
#8
Mario Schubert, Jan Stichel, Yu Du, Iain R Tough, Gregory Sliwoski, Jens Meiler, Helen M Cox, C David Weaver, Annette G Beck-Sickinger
The human Y4 receptor (Y4R) and its cognate ligand, pancreatic polypeptide (PP), are involved in the regulation of energy exposure, satiety and food intake. This system represents a potential target for the treatment of metabolic diseases and has been extensively investigated and validated in vivo. Here, we present the compound tBPC (tertbutyl-phenoxy-cyclohexanol), a novel and selective Y4R positive allosteric modulator that potentiates Y4R activation in G-protein signaling and arrestin 3 recruitment experiments...
August 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28794944/potent-prearranged-positive-allosteric-modulators-of-the-glucagon-like-peptide-1-receptor
#9
Ben J Jones, Rosario Scopelliti, Alejandra Tomas, Stephen R Bloom, David J Hodson, Johannes Broichhagen
Drugs that allosterically modulate G protein-coupled receptor (GPCR) activity display higher specificity and may improve disease treatment. However, the rational design of compounds that target the allosteric site is difficult, as conformations required for receptor activation are poorly understood. Guided by photopharmacology, a set of prearranged positive allosteric modulators (PAMs) with restricted degrees of freedom was designed and tested against the glucagon-like peptide-1 receptor (GLP-1R), a GPCR involved in glucose homeostasis...
August 2017: ChemistryOpen
https://www.readbyqxmd.com/read/28791431/glycine-receptors-and-glycine-transporters-targets-for-novel-analgesics
#10
REVIEW
Hanns Ulrich Zeilhofer, Mario A Acuña, Jacinthe Gingras, Gonzalo E Yévenes
Glycinergic neurotransmission has long been known for its role in spinal motor control. During the last two decades, additional functions have become increasingly recognized-among them is a critical contribution to spinal pain processing. Studies in rodent pain models provide proof-of-concept evidence that enhancing inhibitory glycinergic neurotransmission reduces chronic pain symptoms. Apparent strategies for pharmacological intervention include positive allosteric modulators of glycine receptors and modulators or inhibitors of the glial and neuronal glycine transporters GlyT1 and GlyT2...
August 8, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28780872/oxazepam-dopamine-conjugates-increase-dopamine-delivery-into-striatum-of-intact-rats
#11
Tommaso Cassano, Antonio Lopalco, Modesto de Candia, Valentino Laquintana, Angela Lopedota, Annalisa Cutrignelli, Mara Perrone, Rosa M Iacobazzi, Gaurav Bedse, Massimo Franco, Nunzio Denora, Cosimo D Altomare
The neurotransmitter dopamine (DA) was covalently linked to oxazepam (OXA), a well-known positive allosteric modulator of γ-aminobutyric acid type-A (GABAA) receptor, through a carbamate linkage (4) or a succinic spacer (6). These conjugates were synthesized with the aim of improving the delivery of DA into the brain and enhancing GABAergic transmission, which may be useful for the long-term treatment of Parkinson disease (PD). Structure-based permeability properties, in vitro stability and blood-brain barrier (BBB) permeability studies led to identify the OXA-DA carbamate conjugate 4a as the compound better combining sufficient stability and ability to cross BBB...
August 5, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28769796/s-47445-produces-antidepressant-and-anxiolytic-like-effects-through-neurogenesis-dependent-and-independent-mechanisms
#12
Indira Mendez-David, Jean-Philippe Guilloux, Mariusz Papp, Laurent Tritschler, Elisabeth Mocaer, Alain M Gardier, Sylvie Bretin, Denis J David
Glutamatergic dysfunctions are observed in the pathophysiology of depression. The glutamatergic synapse as well as the AMPA receptor's (AMPAR) activation may represent new potential targets for therapeutic intervention in the context of major depressive disorders. S 47445 is a novel AMPARs positive allosteric modulator (AMPA-PAM) possessing procognitive, neurotrophic properties and enhancing synaptic plasticity. Here, we investigated the antidepressant/anxiolytic-like effects of S 47445 in a mouse model of anxiety/depression based on chronic corticosterone administration (CORT) and in the Chronic Mild Stress (CMS) model in rats...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28764646/a-randomized-double-blind-placebo-controlled-trial-of-ganaxolone-in-children-and-adolescents-with-fragile-x-syndrome
#13
Andrew Ligsay, Anke Van Dijck, Danh V Nguyen, Reymundo Lozano, Yanjun Chen, Erika S Bickel, David Hessl, Andrea Schneider, Kathleen Angkustsiri, Flora Tassone, Berten Ceulemans, R Frank Kooy, Randi J Hagerman
BACKGROUND: Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABAA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. METHODS: This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years. RESULTS: Sixty-one participants were assessed for eligibility, and 59 were randomized to the study...
August 2, 2017: Journal of Neurodevelopmental Disorders
https://www.readbyqxmd.com/read/28761055/a-single-channel-mechanism-for-pharmacological-potentiation-of-glun1-glun2a-nmda-receptors
#14
Divyan A Chopra, Kiran Sapkota, Mark W Irvine, Guangyu Fang, David E Jane, Daniel T Monaghan, Shashank M Dravid
NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on GluN1/GluN2A receptors. We found that UBP684 potentiated the whole-cell currents observed under perforated-patch conditions and slowed receptor deactivation. At the single channel level, UBP684 produced a dramatic reduction in long shut times and a robust increase in mean open time...
July 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28756462/effects-of-gaba-b-receptor-positive-modulator-on-ketamine-induced-psychosis-relevant-behaviors-and-hippocampal-electrical-activity-in-freely-moving-rats
#15
Jingyi Ma, L Stan Leung
RATIONALE: Decreased GABAB receptor function is proposed to mediate some symptoms of schizophrenia. OBJECTIVES: In this study, we tested the effect of CGP7930, a GABAB receptor positive allosteric modulator, on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in behaving rats. METHODS: Electrodes were bilaterally implanted into the hippocampus, and cannulae were placed into the lateral ventricles of Long-Evans rats...
July 29, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28753313/neuroactive-steroids-2-3%C3%AE-hydroxy-3%C3%AE-methyl-21-4-cyano-1h-pyrazol-1-yl-19-nor-5%C3%AE-pregnan-20-one-sage-217-a-clinical-next-generation-neuroactive-steroid-positive-allosteric-modulator-of-the-%C3%AE-aminobutyric-acid-a-receptor
#16
Gabriel Martinez Botella, Francesco G Salituro, Boyd L Harrison, Richard T Beresis, Zhu Bai, Maria-Jesus Blanco, Gabriel M Belfort, Jing Dai, Carlos M Loya, Michael A Ackley, Alison L Althaus, Scott J Grossman, Ethan Hoffmann, James J Doherty, Albert J Robichaud
Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA receptors. Herein, we report new SAR insights in a series of 5β-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one (SAGE-217, 3), a potent GABAA receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties...
August 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28750809/assessing-allosteric-modulation-of-cb1-at-the-receptor-and-cellular-levels
#17
Caitlin E Scott, Debra A Kendall
The cannabinoid CB1 receptor is abundant in the central nervous system and regulates neuronal transmission and other key physiological processes including those leading to pain, inflammation, memory, and feeding behavior. CB1 is activated by the endogenous ligands, arachidonoyl ethanolamine and 2-arachidonoyl glycerol, by various synthetic ligands (e.g., CP55940), and by Δ(9)-tetrahydrocannabinol, the psychoactive component of Cannabis sativa. These CB1 ligands are orthosteric and transduce downstream signals by binding CB1 and primarily inducing Gi coupling, but Gs and β-arrestin coupling are also possible...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28750808/design-and-synthesis-of-cannabinoid-1-receptor-cb1r-allosteric-modulators-drug-discovery-applications
#18
Abhijit R Kulkarni, Sumanta Garai, David R Janero, Ganesh A Thakur
Also expressed in various peripheral tissues, the type-1 cannabinoid receptor (CB1R) is the predominant G protein-coupled receptor (GPCR) in brain, where it is responsible for retrograde control of neurotransmitter release. Cellular signaling mediated by CB1R is involved in numerous physiological processes, and pharmacological CB1R modulation is considered a tenable therapeutic approach for diseases ranging from substance-use disorders and glaucoma to metabolic syndrome. Despite the design and synthesis of a variety of bioactive small molecules targeted to the CB1R orthosteric ligand-binding site, the potential of CB1R as a therapeutic GPCR has been largely unrealized due to adverse events associated with typical orthosteric CB1R agonists and antagonists/inverse agonists...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28749200/mm-gbsa-and-mm-pbsa-performance-in-activity-evaluation-of-ampa-receptor-positive-allosteric-modulators
#19
Dmitry S Karlov, Mstislav I Lavrov, Vladimir A Palyulin, Nikolay S Zefirov
No abstract text is available yet for this article.
July 27, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28743598/decrease-in-endogenous-brain-allopregnanolone-induces-autism-spectrum-disorder-asd-like-behavior-in-mice-a-novel-animal-model-of-asd
#20
Ken Ebihara, Hironori Fujiwara, Suresh Awale, Dya Fita Dibwe, Ryota Araki, Takeshi Yabe, Kinzo Matsumoto
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABAA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis...
July 22, 2017: Behavioural Brain Research
keyword
keyword
94230
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"