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Positive allosteric modulator

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https://www.readbyqxmd.com/read/29046145/experimental-treatment-options-in-absence-epilepsy
#1
Gilles van Luijtelaar, Mehrnoush Zobeiri, Annika Lüttjohann, Antoine Depaulis
BACKGROUND: The benign character of absence epilepsy compared to other genetic generalized epilepsy syndromes has often hampered the search for new treatment options. Absence epilepsy is most often treated with ethosuximide or valproic acid. However, both drugs are not always well tolerated or fail, and seizure freedom for a larger proportion of patients remains to be achieved. The availability of genuine animal models of epilepsy does allow to search for new treatment options not only for absence epilepsy perse but also for other genetic - previously called idiopathic - forms of epilepsy...
October 17, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29042858/expanding-the-role-of-thyroid-stimulating-hormone-in-skeletal-physiology
#2
REVIEW
Ramkumarie Baliram, Rauf Latif, Mone Zaidi, Terry F Davies
The dogma that thyroid-stimulating hormone (TSH) solely regulates the production of thyroid hormone from the thyroid gland has hampered research on its wider physiological roles. The action of pituitary TSH on the skeleton has now been well described; in particular, its action on osteoblasts and osteoclasts. It has also been recently discovered that the bone marrow microenvironment acts as an endocrine circuit with bone marrow-resident macrophages capable of producing a novel TSH-β subunit variant (TSH-βv), which may modulate skeletal physiology...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29037946/discovery-of-a-novel-2-4-dimethylquinoline-6-carboxamide-m4-positive-allosteric-modulator-pam-chemotype-via-scaffold-hopping
#3
Madeline F Long, Julie L Engers, Sichen Chang, Xiaoyan Zhan, Rebecca L Weiner, Vincent B Luscombe, Alice L Rodriguez, Hyekyung P Cho, Colleen M Niswender, Thomas M Bridges, P Jeffrey Conn, Darren W Engers, Craig W Lindsley
This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M4 PAM activity in most M4 PAMs to date, within the thieno[2,3-b]pyridine core, as the β-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core...
October 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29033825/acute-stress-affects-the-expression-of-hippocampal-mu-oscillations-in-an-age-dependent-manner
#4
Samir Takillah, Jérémie Naudé, Steve Didienne, Claude Sebban, Brigitte Decros, Esther Schenker, Michael Spedding, Alexandre Mourot, Jean Mariani, Philippe Faure
Anxiolytic drugs are widely used in the elderly, a population particularly sensitive to stress. Stress, aging and anxiolytics all affect low-frequency oscillations in the hippocampus and prefrontal cortex (PFC) independently, but the interactions between these factors remain unclear. Here, we compared the effects of stress (elevated platform, EP) and anxiolytics (diazepam, DZP) on extracellular field potentials (EFP) in the PFC, parietal cortex and hippocampus (dorsal and ventral parts) of adult (8 months) and aged (18 months) Wistar rats...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29032104/participation-of-gabab-receptors-in-cortical-postictal-excitability-in-immature-rats
#5
Pavel Mareš
Arrest of seizures is due to an active inhibition and is followed in mature brain by period of refractoriness markedly present one min after the end of seizures. To study changes in cortical excitability after epileptic seizures we used electrical stimulation of sensorimotor cortical area in immature rats - 25-day-old ones with mature postictal refractoriness and 12-day-old where postictal potentiation of afterdischarges (ADs) is present instead of refractoriness at one minute after the end of the conditioning AD...
October 12, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29030082/adx-47273-a-mglu5-receptor-positive-allosteric-modulator-attenuates-deficits-in-cognitive-flexibility-induced-by-withdrawal-from-binge-like-ethanol-exposure-in-rats
#6
Marta Marszalek-Grabska, Ewa Gibula-Bruzda, Anna Bodzon-Kulakowska, Piotr Suder, Kinga Gawel, Sylwia Talarek, Joanna Listos, Ewa Kedzierska, Wojciech Danysz, Jolanta H Kotlinska
Repeated exposure to and withdrawal from ethanol induces deficits in spatial reversal learning. Data indicate that metabotropic glutamate 5 (mGlu5) receptors are implicated in synaptic plasticity and learning and memory. These receptors functionally interact with N-methyl-d-aspartate (NMDA) receptors, and activation of one type results in the activation of the other. We examined whether (S)-(4-fluorophenyl)(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl (ADX-47273), a positive allosteric modulator (PAM) of mGlu5 receptor, attenuates deficits in reversal learning induced by withdrawal (11-13days) from 'binge-like' ethanol input (5...
October 10, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/29025977/an-approach-to-discovering-novel-muscarinic-m1-receptor-positive-allosteric-modulators-with-potent-cognitive-improvement-and-minimized-gastrointestinal-dysfunction
#7
Emi Kurimoto, Satoru Matsuda, Yuji Shimizu, Yuu Sako, Takao Mandai, Takahiro Sugimoto, Hiroki Sakamoto, Haruhide Kimura
Activation of muscarinic M1 receptor (M1R) is a promising approach for improving cognitive impairment in Alzheimer's disease. However, an M1 selective positive allosteric modulator (PAM), benzyl quinolone carboxylic acid (BQCA), at 30 mg/kg, induced diarrhea in wild-type mice, but not in M1R knock-out mice. Moreover, BQCA (0.1-1000 nM) augmented electric field stimulation (EFS) -induced ileum contraction in an in vitro Magnus assay. Thus, we decided to establish a drug-screening strategy to discover novel M1 PAMs producing potent cognitive improvement with minimized gastrointestinal (GI) dysfunction...
October 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29024789/in-vitro-pharmacological-characterization-of-the-bispyridinium-non-oxime-compound-mb327-and-its-2-and-3-regioisomers
#8
K V Niessen, T Seeger, S Rappenglück, T Wein, G Höfner, K T Wanner, H Thiermann, F Worek
The primary toxic mechanism of organophosphorus compounds, i.e. nerve agents or pesticides, is based on the irreversible inhibition of acetylcholinesterase. In consequence of the impaired hydrolysis, the neurotransmitter acetylcholine accumulates in cholinergic synapses and disturbs functional activity of nicotinic and muscarinic acetylcholine receptors by overstimulation and subsequent desensitization. The resulting cholinergic syndrome will become acute life-threatening, if not treated adequately. The current standard treatment, consisting of administration of a competitive mAChR antagonist (e...
October 9, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28993837/gaba-receptors-and-the-pharmacology-of-sleep
#9
W Wisden, X Yu, N P Franks
Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABAA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABAA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics...
October 10, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28967122/immuno-pharmacological-characterization-of-group-ii-metabotropic-glutamate-receptors-controlling-glutamate-exocytosis-in-mouse-cortex-and-spinal-cord
#10
Guendalina Olivero, Tommaso Bonfiglio, Matteo Vergassola, Cesare Usai, Barbara Riozzi, Giuseppe Battaglia, Ferdinando Nicoletti, Anna Pittaluga
BACKGROUND AND PURPOSE: We recently proposed the existence of mGlu3-preferring autoreceptors in spinal cord terminals and of mGlu2-preferring autoreceptors in cortical terminals. This study aims to verify our previous conclusions and to extend their pharmacological characterization. EXPERIMENTAL APPROACH: We studied the effect of LY566332, an mGlu2 receptors positive allosteric modulator (PAM) and of LY2389575, a selective mGlu3 receptor negative allosteric (NAM) modulator, on the mGlu2/3 agonist LY379268-mediated inhibition of glutamate exocytosis [measured as KCl-evoked release of preloaded [(3) H]-D-aspartate ([(3) H]-D-Asp)]...
October 1, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28963038/lateral-septum-stimulation-disinhibits-dopaminergic-neurons-in-the-antero-ventral-region-of-the-ventral-tegmental-area-role-of-gaba-a-alpha-1-receptors
#11
Ignacio Vega-Quiroga, Hector E Yarur, Katia Gysling
The mechanisms commanding the activity of dopaminergic neurons of the ventral tegmental area (VTA) and the location of these neurons are relevant for the coding and expression of motivated behavior associated to reward-related signals. Anatomical evidence shows that several brain regions modulate VTA dopaminergic neurons activity via multiple mechanisms. However, there is still scarce knowledge of how the lateral septum (LS) modulates VTA activity. We performed in-vivo dual-probe microdialysis to measure VTA dopamine, glutamate and GABA extracellular levels after LS stimulation in the presence or absence of GABAergic antagonists...
September 27, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28950762/positive-modulation-of-ampa-receptors-promotes-survival-and-proliferation-of-neural-stem-progenitor-cells-from-the-adult-rat-spinal-cord
#12
Laureen D Hachem, Andrea J Mothe, Charles H Tator
Transplantation of neural stem/progenitor cells (NSPCs) following spinal cord injury (SCI) is a promising strategy to enhance regeneration but is limited by poor survival of grafted cells. Determining methods to enhance survival of NSPCs is therefore essential. Positive modulation of AMPA receptors has been shown to enhance neurogenesis in various models of brain injury. Here we examined the effect of selective AMPA receptor modulation in adult rat spinal cord-derived NSPCs using a class of allosteric AMPA receptor modulators known as ampakines...
September 26, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28945802/hbv-core-protein-allosteric-modulators-differentially-alter-cccdna-biosynthesis-from-de-novo-infection-and-intracellular-amplification-pathways
#13
Fang Guo, Qiong Zhao, Muhammad Sheraz, Junjun Cheng, Yonghe Qi, Qing Su, Andrea Cuconati, Lai Wei, Yanming Du, Wenhui Li, Jinhong Chang, Ju-Tao Guo
Hepatitis B virus (HBV) core protein assembles viral pre-genomic (pg) RNA and DNA polymerase into nucleocapsids for reverse transcriptional DNA replication to take place. Several chemotypes of small molecules, including heteroaryldihydropyrimidines (HAPs) and sulfamoylbenzamides (SBAs), have been discovered to allosterically modulate core protein structure and consequentially alter the kinetics and pathway of core protein assembly, resulting in formation of irregularly-shaped core protein aggregates or "empty" capsids devoid of pre-genomic RNA and viral DNA polymerase...
September 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28939686/species-specific-involvement-of-aldehyde-oxidase-and-xanthine-oxidase-in-the-metabolism-of-the-pyrimidine-containing-mglu5-negative-allosteric-modulator-vu0424238-auglurant
#14
Rachel D Crouch, Anna L Blobaum, Andrew S Felts, P Jeffrey Conn, Craig W Lindsley
Aldehyde oxidase (AO) and xanthine oxidase (XO) are molybdo-flavoenzymes that catalyze oxidation of aromatic azaheterocycles. Differences in AO activity have been reported among various species including rat, human, and monkey. Herein we report a species difference in the enzymes responsible for metabolism of mGlu5 NAM VU0424238 (VU238, auglurant). Hepatic S9 incubations with AO and XO specific inhibitors hydralazine and allopurinol indicated that rat and cynomolgus monkey both oxidized VU238 to the 6-oxopyrimidine metabolite M1 via an AO-mediated pathway, whereas secondary oxidation to the 2,6-dioxopyrimidine metabolite M2 was mediated predominantly by AO in monkey and XO in rat...
September 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28931433/role-of-gabaa-receptors-in-alcohol-use-disorders-suggested-by-chronic-intermittent-ethanol-cie-rodent-model
#15
REVIEW
Richard W Olsen, Jing Liang
GABAergic inhibitory transmission is involved in the acute and chronic effects of ethanol on the brain and behavior. One-dose ethanol exposure induces transient plastic changes in GABAA receptor subunit levels, composition, and regional and subcellular localization. Rapid down-regulation of early responder δ subunit-containing GABAA receptor subtypes mediating ethanol-sensitive tonic inhibitory currents in critical neuronal circuits corresponds to rapid tolerance to ethanol's behavioral responses. Slightly slower, α1 subunit-containing GABAA receptor subtypes mediating ethanol-insensitive synaptic inhibition are down-regulated, corresponding to tolerance to additional ethanol behaviors plus cross-tolerance to other GABAergic drugs including benzodiazepines, anesthetics, and neurosteroids, especially sedative-hypnotic effects...
September 20, 2017: Molecular Brain
https://www.readbyqxmd.com/read/28923470/tripodal-lipoprotein-variants-with-c-terminal-hydrophobic-residues-allosterically-modulate-activity-of-the-degp-protease
#16
Hyojin Park, Yurie T Kim, Chulwon Choi, Seokhee Kim
DegP, a member of the highly conserved HtrA family of proteases, performs a regulated proteolysis of toxic misfolded proteins in the periplasm of Gram-negative bacteria. The allosteric switch between inactive and active conformations is a central mechanism to carefully control proteolytic activity of DegP and to maintain the optimal cellular fitness, but few other molecules than substrates are known to allosterically control DegP activity. Here, we demonstrate that a mutant variant of an outer-membrane lipoprotein, Lpp(+Leu), can function as a novel allosteric effector that changes the dynamic range of DegP activity...
October 13, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28912557/a-nmda-receptor-calcium-influx-assay-sensitive-to-stimulation-by-glutamate-and-glycine-d-serine
#17
Hongqiu Guo, L Miguel Camargo, Fred Yeboah, Mary Ellen Digan, Honglin Niu, Yue Pan, Stephan Reiling, Gilberto Soler-Llavina, Wilhelm A Weihofen, Hao-Ran Wang, Y Gopi Shanker, Travis Stams, Anke Bill
N-methyl-D-aspartate-receptors (NMDARs) are ionotropic glutamate receptors that function in synaptic transmission, plasticity and cognition. Malfunction of NMDARs has been implicated in a variety of nervous system disorders, making them attractive therapeutic targets. Overexpression of functional NMDAR in non-neuronal cells results in cell death by excitotoxicity, hindering the development of cell-based assays for NMDAR drug discovery. Here we report a plate-based, high-throughput approach to study NMDAR function...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28902994/discovery-structure-activity-relationship-and-anti-parkinsonian-effect-of-a-potent-and-brain-penetrant-chemical-series-of-positive-allosteric-modulators-of-metabotropic-glutamate-receptor-4
#18
Delphine Charvin, Vincent Pomel, Millan Ortiz, Mélanie Frauli, Sophie Scheffler, Edith Steinberg, Luc Baron, Laurène Deshons, Rachel Rudigier, Delphine Thiarc, Christophe Morice, Baptiste Manteau, Stanislas Mayer, Danielle Graham, Bruno Giethlen, Nadia Brugger, Gaël Hedou, François Conquet, Stephan Schann
The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms, after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model...
September 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28900387/social-isolation-in-early-versus-late-adolescent-mice-is-associated-with-persistent-behavioral-deficits-that-can-be-improved-by-neurosteroid-based-treatment
#19
Andrea Locci, Philippe Geoffroy, Michel Miesch, Ayikoe-Guy Mensah-Nyagan, Graziano Pinna
Early trauma and stress exposure during a critical period of life may increase the risk of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) in adulthood. The first-choice treatment for MDD and PTSD are selective serotonin reuptake inhibitor (SSRI) antidepressants. Unfortunately, half of MDD and PTSD patients show resistance to the therapeutic effects of these drugs and more efficient treatments are essential. Both MDD and PTSD patients present reduced levels of allopregnanolone (Allo), a potent endogenous positive allosteric modulator of GABA action at GABAA receptors which are normalized by SSRIs in treatment responders...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28894166/flavonoid-allosteric-modulation-of-mutated-visual-rhodopsin-associated-with-retinitis-pigmentosa
#20
María Guadalupe Herrera-Hernández, Eva Ramon, Cecylia S Lupala, Mercè Tena-Campos, Juan J Pérez, Pere Garriga
Dietary flavonoids exhibit many biologically-relevant functions and can potentially have beneficial effects in the treatment of pathological conditions. In spite of its well known antioxidant properties, scarce structural information is available on the interaction of flavonoids with membrane receptors. Advances in the structural biology of a specific class of membrane receptors, the G protein-coupled receptors, have significantly increased our understanding of drug action and paved the way for developing improved therapeutic approaches...
September 11, 2017: Scientific Reports
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