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Positive allosteric modulator

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https://www.readbyqxmd.com/read/28327612/endogenous-opioids-regulate-moment-to-moment-neuronal-communication-and-excitability
#1
Bryony L Winters, Gabrielle C Gregoriou, Sarah A Kissiwaa, Oliver A Wells, Danashi I Medagoda, Sam M Hermes, Neil T Burford, Andrew Alt, Sue A Aicher, Elena E Bagley
Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster. Endogenously released opioids inhibit glutamate release through the δ-opioid receptor (DOR), an effect potentiated by a DOR-positive allosteric modulator. Postsynaptically, the opioids activate a potassium conductance through the μ-opioid receptor (MOR), suggesting for the first time that endogenously released opioids directly regulate neuronal excitability...
March 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/28323850/ligand-guided-homology-modelling-of-the-gabab2-subunit-of-the-gabab-receptor
#2
Thibaud Freyd, Dawid Warszycki, Stefan Mordalski, Andrzej J Bojarski, Ingebrigt Sylte, Mari Gabrielsen
γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and disturbances in the GABAergic system have been implicated in numerous neurological and neuropsychiatric diseases. The GABAB receptor is a heterodimeric class C G protein-coupled receptor (GPCR) consisting of GABAB1a/b and GABAB2 subunits. Two GABAB receptor ligand binding sites have been described, namely the orthosteric GABA binding site located in the extracellular GABAB1 Venus fly trap domain and the allosteric binding site found in the GABAB2 transmembrane domain...
2017: PloS One
https://www.readbyqxmd.com/read/28320841/prefrontal-cortex-kca2-channels-regulate-mglu5-dependent-plasticity-and-extinction-of-alcohol-seeking-behavior
#3
Reginald Cannady, Justin T McGonigal, Ryan J Newsom, John J Woodward, Patrick J Mulholland, Justin T Gass
Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu5 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (KCa2) channels have also been implicated in extinction learning of fear memories, and mGlu5 receptor activation can reduce KCa2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined KCa2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats...
March 20, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28306151/the-quantitative-characterization-of-functional-allosteric-effects
#4
Terry Kenakin
Seven-transmembrane receptors (7TMRs or GPCRs [G protein-coupled receptors]) are nature's prototypic allosteric proteins in that they mediate the interaction between ligand binding to the receptor and the receptor interacting with another cell signaling protein. A growing class of potential drugs acting through 7TMRs are allosteric in nature in that they bind to a separate site on the receptor protein to modify the interactions between the receptor, natural binding/orthosteric ligand, and signaling proteins...
March 17, 2017: Current Protocols in Pharmacology
https://www.readbyqxmd.com/read/28300546/cocaine-self-administration-specifically-increases-a2ar-d2r-and-d2r-sigma1r-heteroreceptor-complexes-in-the-rat-nucleus-accumbens-shell-relevance-for-cocaine-use-disorder
#5
Dasiel O Borroto-Escuela, Manuel Narváez, Karolina Wydra, Julia Pintsuk, Luca Pinton, Antonio Jimenez-Beristain, Michael Di Palma, Joanna Jastrzębska, Malgorzata Filip, Kjell Fuxe
Adenosine 2A receptor (A2AR) agonists were indicated to reduce cocaine reward and cocaine seeking mainly through activation of antagonistic allosteric A2AR-dopamine D2R (D2R) interactions in A2AR-D2R heteroreceptor complexes. Furthermore, it was shown that modulation of cocaine reward involves antagonistic A2AR-D2R interactions in the ventral but not the dorsal striatum in rats. In the current work the proximity ligation assay (PLA) was used to further study the A2AR-D2R heteroreceptor complexes in the nucleus accumbens shell and core as well as the dorsal striatum under the influence of cocaine self-administration in rats...
March 12, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28294133/the-gabab-positive-allosteric-modulator-adx71441-attenuates-alcohol-self-administration-and-relapse-to-alcohol-seeking-in-rats
#6
Eric Augier, Russell S Dulman, Ruslan Damadzic, Andrew Pilling, J Paul Hamilton, Markus Heilig
GABAergic signaling is involved in modulating the reinforcing properties of alcohol, and GABAB receptors have been proposed as a potential target for clinical treatment of alcoholism. The orthosteric GABAB receptor agonist baclofen has been shown to suppress operant self-administration of alcohol in animals and alcohol use in alcohol dependent patients, but its utility is limited by a narrow therapeutic index. We tested the effects of ADX71441, a novel GABAB receptor positive allosteric modulator on alcohol-related behaviors in rats...
March 15, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28292762/gpr40-reduces-food-intake-and-body-weight-through-glp-1
#7
Judith N Gorski, Michele J Pachanski, Joel Mane, Christopher W Plummer, Sarah Souza, Brande S Thomas-Fowlkes, Aimie M Ogawa, Adam B Weinglass, Jerry Di Salvo, Boonlert Cheewatrakoolpong, Andrew D Howard, Steven L Colletti, Maria E Trujillo
GPR40 partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose independent insulin secretagogues. The class of small molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and GLP-1 (17)...
March 14, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28289374/discovery-of-compounds-that-positively-modulate-the-high-affinity-choline-transporter
#8
Parul Choudhary, Emma J Armstrong, Csilla C Jorgensen, Mary Piotrowski, Maria Barthmes, Rubben Torella, Sarah E Johnston, Yuya Maruyama, John S Janiszewski, R Ian Storer, Sarah E Skerratt, Caroline L Benn
Cholinergic hypofunction is associated with decreased attention and cognitive deficits in the central nervous system in addition to compromised motor function. Consequently, stimulation of cholinergic neurotransmission is a rational therapeutic approach for the potential treatment of a variety of neurological conditions. High affinity choline uptake (HACU) into acetylcholine (ACh)-synthesizing neurons is critically mediated by the sodium- and pH-dependent high-affinity choline transporter (CHT, encoded by the SLC5A7 gene)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28286129/fret-based-sensors-unravel-activation-and-allosteric-modulation-of-the-gabab-receptor
#9
Nathalie Lecat-Guillet, Carine Monnier, Xavier Rovira, Julie Kniazeff, Laurent Lamarque, Jurriaan M Zwier, Eric Trinquet, Jean-Philippe Pin, Philippe Rondard
The main inhibitory neurotransmitter, γ-aminobutyric acid (GABA), modulates many synapses by activating the G protein-coupled receptor GABAB, which is a target for various therapeutic applications. It is an obligatory heterodimer made of GB1 and GB2 that can be regulated by positive allosteric modulators (PAMs). The molecular mechanism of activation of the GABAB receptor remains poorly understood. Here, we have developed FRET-based conformational GABAB sensors compatible with high-throughput screening. We identified conformational changes occurring within the extracellular and transmembrane domains upon receptor activation, which are smaller than those observed in the related metabotropic glutamate receptors...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28285325/mglu1-receptor-as-a-drug-target-for-treatment-of-substance-use-disorders-time-to-gather-stones-together
#10
REVIEW
Olga A Dravolina, Edwin Zvartau, Wojciech Danysz, Anton Y Bespalov
Modulation of the mGlu1 receptor was repeatedly shown to inhibit various phenomena associated with exposure to abused drugs. Efficacy in preclinical models was observed with both positive and negative allosteric modulators (PAMs and NAMs, respectively) using essentially non-overlapping sets of experimental methods. Taken together, these data indicate that the mGlu1 receptor certainly plays a significant role in the plasticity triggered by the exposure to abused drugs and is involved in the maintenance of drug-seeking and drug-taking behaviors...
March 11, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28273868/pharmacological-potential-and-synthetic-approaches-of-imidazo-4-5-b-pyridine-and-imidazo-4-5-c-pyridine-derivatives
#11
REVIEW
Malwina Krause, Henryk Foks, Katarzyna Gobis
The structural resemblance between the fused imidazopyridine heterocyclic ring system and purines has prompted biological investigations to assess their potential therapeutic significance. They are known to play a crucial role in numerous disease conditions. The discovery of their first bioactivity as GABAA receptor positive allosteric modulators divulged their medicinal potential. Proton pump inhibitors, aromatase inhibitors, and NSAIDs were also found in this chemical group. Imidazopyridines have the ability to influence many cellular pathways necessary for the proper functioning of cancerous cells, pathogens, components of the immune system, enzymes involved in carbohydrate metabolism, etc...
March 4, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28270751/understanding-the-role-of-gpcr-heteroreceptor-complexes-in-modulating-the-brain-networks-in-health-and-disease
#12
REVIEW
Dasiel O Borroto-Escuela, Jens Carlsson, Patricia Ambrogini, Manuel Narváez, Karolina Wydra, Alexander O Tarakanov, Xiang Li, Carmelo Millón, Luca Ferraro, Riccardo Cuppini, Sergio Tanganelli, Fang Liu, Malgorzata Filip, Zaida Diaz-Cabiale, Kjell Fuxe
The introduction of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28267561/pharmacological-and-antihyperalgesic-properties-of-the-novel-%C3%AE-2-3-preferring-gabaa-receptor-ligand-mp-iii-024
#13
Bradford D Fischer, Raymond J Schlitt, Bryan Z Hamade, Sabah Rehman, Margot Ernst, Michael M Poe, Guanguan Li, Revathi Kodali, Leggy A Arnold, James M Cook
γ-Aminobutyric acid type A (GABAA) receptors are located in spinal nociceptive circuits where they modulate the transmission of pain sensory signals from the periphery to higher centers. Benzodiazepine-type drugs bind GABAA, receptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAA, and α5GABAA receptors, respectively) through which they inhibit the transmission of these signals. However, the role of these different GABAA receptor subtypes in the antihyperalgisic properties of benzodiazepine-type drugs has not been characterized fully and is limited by currently available compounds...
March 3, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28260499/regulatory-role-of-g-protein-coupled-receptors-in-pancreatic-cancer-development-and-progression
#14
Hildegard M Schuller
BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer deaths with incidence rising and a high mortality rate. Smoking, psychological stress, diabetes, pancreatitis and alcohol abuse are known risk factors for pancreatic cancer. OBJECTIVE: Targeting G protein-coupled receptor signaling for the prevention and therapy of pancreatic cancer. METHOD: Review of published literature. RESULTS AND CONCLUSION: All known risk factors for pancreatic cancer cause hyperactive cyclic adenosine monophosphate (cAMP) signaling via cancer stimulating Gαs-coupled beta-adrenergic and prostaglandin E2 receptors and/or by suppressing signaling via inhibitory Gαi-coupled GABAB-receptors...
March 3, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28259560/4-chlorophenylguanidine-is-an-asic3-agonist-and-positive-allosteric-modulator
#15
Amruta S Agharkar, Eric B Gonzales
Acid-sensing ion channels (ASICs) are proton-sensitive sodium channels that open in response to lowered extracellular pH and are expressed in the central and peripheral nervous systems. The ASIC3 subtype is found primarily in the periphery where the channel mediates pain signals caused by ischemia and inflammation. Here, we provide identify 4-chlorophenylguanidine (4-CPG) as an ASIC3 positive allosteric modulator and newest member of the growing group of guanidine modulators of ASICs. Furthermore, the 4-CPG reversed the effects of ASIC3 desensitization...
February 17, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28257822/characterization-of-6-methoxyflavanone-as-a-novel-anxiolytic-agent-a-behavioral-and-pharmacokinetic-approach
#16
Shehla Akbar, Fazal Subhan, Nasiara Karim, Urooj Aman, Sami Ullah, Muhammad Shahid, Nisar Ahmad, Khwaja Fawad, Robert D E Sewell
Benzodiazepines are regularly prescribed for treatment of anxiety though there are side effects. Flavonoids have selective affinity for GABAA receptors implicated in anxiolytic-like activity in rodents, but are devoid of the unwanted side effects of benzodiazepines. In this study, 6-methoxyflavanone (6-MeOF), a positive allosteric modulator of γ-amino butyric acid (GABA) responses at human recombinant GABAA receptors, was evaluated for its behavioral profile in the elevated plus-maze as well as the staircase- plus and open-field tests in mice...
February 28, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28252105/the-human-two-pore-channel-1-is-modulated-by-cytosolic-and-luminal-calcium
#17
Laura Lagostena, Margherita Festa, Michael Pusch, Armando Carpaneto
Two-pore channels (TPC) are intracellular endo-lysosomal proteins with only recently emerging roles in organellar signalling and involvement in severe human diseases. Here, we investigated the functional properties of human TPC1 expressed in TPC-free vacuoles from Arabidopsis thaliana cells. Large (20 pA/pF) TPC1 currents were elicited by cytosolic addition of the phosphoinositide phosphatidylinositol-(3,5)-bisphosphate (PI(3,5)P2) with an apparent binding constant of ~15 nM. The channel is voltage-dependent, activating at positive potentials with single exponential kinetics and currents are Na(+) selective, with measurable but low permeability to Ca(2+)...
March 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28249817/the-direct-actions-of-cannabidiol-and-2-arachidonoyl-glycerol-at-gabaa-receptors
#18
T Bakas, P S van Nieuwenhuijzen, S O Devenish, I S McGregor, J C Arnold, M Chebib
Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties. The mechanism of action of CBD in producing such effects remains unclear. Despite evidence that some endogenous and synthetic cannabinoids interact with GABAA receptors, no-one has yet investigated the effects of CBD. Here we used two-electrode voltage clamp electrophysiology to compare the actions of CBD with those of the major central endocannabinoid, 2-arachidonoyl glycerol (2-AG) on human recombinant GABAA receptors (synaptic α1-6βγ2 and extrasynaptic α4β2δ) expressed on Xenopus oocytes...
February 27, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28246638/evolutionary-fine-tuning-of-conformational-ensembles-in-fimh-during-host-pathogen-interactions
#19
Vasilios Kalas, Jerome S Pinkner, Thomas J Hannan, Michael E Hibbing, Karen W Dodson, Alex S Holehouse, Hao Zhang, Niraj H Tolia, Michael L Gross, Rohit V Pappu, James Janetka, Scott J Hultgren
Positive selection in the two-domain type 1 pilus adhesin FimH enhances Escherichia coli fitness in urinary tract infection (UTI). We report a comprehensive atomic-level view of FimH in two-state conformational ensembles in solution, composed of one low-affinity tense (T) and multiple high-affinity relaxed (R) conformations. Positively selected residues allosterically modulate the equilibrium between these two conformational states, each of which engages mannose through distinct binding orientations. A FimH variant that only adopts the R state is severely attenuated early in a mouse model of uncomplicated UTI but is proficient at colonizing catheterized bladders in vivo or bladder transitional-like epithelial cells in vitro...
February 2017: Science Advances
https://www.readbyqxmd.com/read/28242877/epilepsy-associated-grin2a-mutations-reduce-nmda-receptor-trafficking-and-agonist-potency-molecular-profiling-and-functional-rescue
#20
L Addis, J K Virdee, L R Vidler, D A Collier, D K Pal, D Ursu
Mutations in the N-methyl-D-aspartate receptor (NMDAR) gene GRIN2A cause epilepsy-aphasia syndrome (EAS), a spectrum of epileptic, cognitive and language disorders. Using bioinformatic and patient data we shortlisted 10 diverse missense mutations for characterisation. We used high-throughput calcium-flux assays and patch clamp recordings of transiently transfected HEK-293 cells for electrophysiological characterization, and Western blotting and confocal imaging to assay expression and surface trafficking. Mutations P79R, C231Y, G483R and M705V caused a significant reduction in glutamate and glycine agonist potency, whilst D731N was non-responsive...
December 2017: Scientific Reports
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