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Positive allosteric modulator

Roger L Papke, Can Peng, Ashok Kumar, Clare Stokes
Long-term potentiation (LTP) in the dentate gyrus was previously shown to be enhanced by nicotine, an effect dependent on both homomeric α7 and heteromeric α2β2 nicotinic acetylcholine receptors (nAChR). In our experiments, bath-applied nicotine produced no significant enhancement of LTP. The α7 nAChR silent agonist NS6740, a weak activator of α7 nAChR ion channels but an effective modulator of the cholinergic anti-inflammatory pathway, decreased LTP and, additionally, produced a substantial reduction in the baseline synaptic function prior to the high frequency stimulation used to induce LTP...
April 18, 2018: Neuroscience Letters
Mireia Jiménez-Rosés, Minos-Timotheos Matsoukas, Gianluigi Caltabiano, Arnau Cordomí
Τhe muscarinic M2 acetylcholine receptor, one of the few G protein-coupled receptors that has not only been crystallized in both active and inactive conformations, but also in the presence of a positive allosteric modulator, is an interesting system to study the molecular mechanisms of GPCR activation and ligand allosterism. Here, we have employed molecular dynamics (MD) simulations (adding to 14μs in total) to study conformational changes triggered by the inverse agonist R-(-)-3-quinuclidinyl-benzilate (QNB) in the structure of the active M2 muscarinic (PBD id 4MQS) after replacement of the agonist iperoxo by the inverse agonist QNB...
April 19, 2018: Journal of Chemical Information and Modeling
Natalia M Kowal, Philip K Ahring, Vivian W Y Liao, Dinesh C Indurti, Benjamin S Harvey, Susan M O'Connor, Mary Chebib, Elin S Olafsdottir, Thomas Balle
BACKGROUND AND PURPOSE: The alkaloid galantamine was originally isolated from the green snowdrop Galanthus woronowii and is currently marketed as a drug for treatment of mild to moderate dementia in Alzheimer's disease patients. In addition to a well-documented proficiency of inhibiting the acetylcholinesterase enzyme, galantamine has been reported to increase neuronal nicotinic acetylcholine (nACh) receptor function by acting as a positive allosteric modulator. Yet, there remains controversy regarding these findings in the literature...
April 18, 2018: British Journal of Pharmacology
Mehdi Farokhnia, Mikela B Sheskier, Mary R Lee, April N Le, Erick Singley, Sofia Bouhlal, Timmy Ton, Zhen Zhao, Lorenzo Leggio
Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA-B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA-B receptor, in combination with alcohol intake, may affect feeding- and stress-related neuroendocrine pathways remains unknown...
April 14, 2018: Neuropharmacology
Rachael L Sumner, Rebecca L McMilllan, Alexander D Shaw, Krish D Singh, Fred Sundram, Suresh D Muthukumaraswamy
Fluctuations in gonadal hormones over the course of the menstrual cycle are known to cause functional brain changes and are thought to modulate changes in the balance of cortical excitation and inhibition. Animal research has shown this occurs primarily via the major metabolite of progesterone, allopregnanolone, and its action as a positive allosteric modulator of the GABAA receptor. Our study used EEG to record gamma oscillations induced in the visual cortex using stationary and moving gratings. Recordings took place during twenty females' mid-luteal phase when progesterone and estradiol are highest, and early follicular phase when progesterone and estradiol are lowest...
April 17, 2018: Human Brain Mapping
Tayler D Sheahan, Manouela V Valtcheva, Lisa A McIlvried, Melanie Y Pullen, David A A Baranger, Robert W Gereau
The use of human tissue to validate putative analgesic targets identified in rodents is a promising strategy for improving the historically poor translational record of preclinical pain research. We recently demonstrated that in mouse and human sensory neurons, agonists for metabotropic glutamate receptors 2 and 3 (mGluR2/3) reduce membrane hyperexcitability produced by the inflammatory mediator prostaglandin E2 (PGE2 ). Previous rodent studies indicate that mGluR2/3 can also reduce peripheral sensitization by suppressing inflammation-induced sensitization of TRPV1...
March 2018: ENeuro
Valentina Vengeliene, Tatiane T Takahashi, Olga A Dravolina, Irina Belozertseva, Edwin Zvartau, Anton Y Bespalov, Rainer Spanagel
RATIONALE: Preclinical studies suggest that the GABAB receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABAB receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained? OBJECTIVE: To test efficacy and adverse effects of baclofen and the novel GABAB positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM...
April 12, 2018: Psychopharmacology
Natasha C Pflanz, Anna W Daszkowski, Garrett L Cornelison, James R Trudell, S John Mihic
Benzodiazepines are positive allosteric modulators of the GABAA receptor (GABAA R), acting at the α-γ subunit interface to enhance GABAA R function. GABA or benzodiazepine binding induces distinct conformational changes in the GABAA R. The molecular rearrangements in the GABAA R following benzodiazepine binding remain to be fully elucidated. Using two molecular models of the GABAA R, we identified electrostatic interactions between specific amino acids at the α-γ subunit interface which were broken by, or formed after, benzodiazepine binding...
April 5, 2018: Journal of Biological Chemistry
Christopher T Wild, Joanna M Miszkiel, Eric A Wold, Claudia A Soto, Chunyong Ding, Rachel M Hartley, Mark Andrew White, Noelle C Anastasio, Kathryn A Cunningham, Jia Zhou
An impaired signaling capacity of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT2CR signaling through positive allosteric modulation presents a novel therapeutic approach. Various new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of several 5-HT2CR positive allosteric modulators (PAMs)...
April 5, 2018: Journal of Medicinal Chemistry
Daniel J Drucker
Glucagon-like peptide-1 (GLP-1) released from gut enteroendocrine cells controls meal-related glycemic excursions through augmentation of insulin and inhibition of glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, actions maximizing nutrient absorption while limiting weight gain. Here I review the circuits engaged by endogenous versus pharmacological GLP-1 action, highlighting key GLP-1 receptor (GLP-1R)-positive cell types and pathways transducing metabolic and non-glycemic GLP-1 signals...
April 3, 2018: Cell Metabolism
Maarten L J Doornbos, Ilse Van der Linden, Liesbeth Vereyken, Gary Tresadern, Adriaan P IJzerman, Hilde Lavreysen, Laura H Heitman
Label-free cellular assays using a biosensor provide new opportunities for studying G protein-coupled receptor (GPCR) signaling. As opposed to conventional in vitro assays, integrated receptor-mediated cellular responses are determined in real-time rather than a single downstream signaling pathway. In this study, we examined the potential of a label-free whole cell impedance-based biosensor system (i.e. xCELLigence) to study the pharmacology of one GPCR in particular, the mGlu2 receptor. This receptor is a target for the treatment of several psychiatric diseases such as schizophrenia and depression...
March 29, 2018: Biochemical Pharmacology
Shu-Hui Chuang, Doodipala Samba Reddy
Neurosteroids are powerful modulators of GABA-A receptors. Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one, GX) and synthetic analogs of the neurosteroid allopregnanolone (AP) are designed to treat epilepsy and related conditions. However, their precise mechanism of action in native neurons remains unclear. Here, we sought to determine the mode of action of GX and its analogs at GABA-A receptors in native hippocampal neurons by analyzing extrasynaptic receptor-mediated tonic currents and synaptic receptor-mediated phasic currents...
March 30, 2018: Journal of Pharmacology and Experimental Therapeutics
Mark J Benvenga, Stephen F Chaney, Melvyn Baez, Thomas C Britton, William J Hornback, James A Monn, Gerard J Marek
There is substantial evidence that glutamate can modulate the effects of 5-hydroxytryptamine2A (5-HT2A ) receptor activation through stimulation of metabotropic glutamate2/3 (mGlu2/3 ) receptors in the prefrontal cortex. Here we show that constitutive deletion of the mGlu2 gene profoundly attenuates an effect of 5-HT2A receptor activation using the mouse head twitch response (HTR). MGlu2 and mGlu3 receptor knockout (KO) as well as age-matched ICR (CD-1) wild type (WT) mice were administered (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and observed for head twitch activity...
2018: Frontiers in Pharmacology
Sebahattin Karabulut, Ruslan Bayramov, Keziban Korkmaz Bayramov, Ahmet K Filiz, Ahmet S Taskiran, Ercan Ozdemir
Absence epilepsy is a generalized nonconvulsive type of epilepsy that is characterized by spike-wave discharges (SWD) with a frequency of 2.5-4 Hz in the EEG. The activation of the GABAergic system in central nervous system suppresses convulsive seizures but exacerbates absence seizures. Endogenous neuroactive steroids such as 3α-hydroxy-5α-pregnan-20-one (3α,5α-THPROG; allopregnanolone) and 3α,21-dihydroxy-5α-pregnan-20-one (3α,5α-THDOC, allotetrahydrodeoxycorticosteron) are GABA-A receptor-positive allosteric modulators...
March 2018: General Physiology and Biophysics
Justin R King, Aman Ullah, Ellen Bak, Saleet Jafri, Nadine Kabbani
The pharmacological targeting of the α7 nicotinic acetylcholine receptor (α7) is a promising strategy in the development of new drugs for neurological diseases Because α7 receptors regulate cellular calcium, we investigated how the prototypical type II positive allosteric modulator PNU120596 affects α7 mediated calcium signaling. Live imaging experiments show that PNU120596 augments ryanodine receptor driven calcium-induced calcium release (CICR), IP3 induced calcium release (IICR), and PLC activation by the α7 receptor...
March 27, 2018: Molecular Pharmacology
Yuanheng Li, Lilan Sun, Taoyi Yang, Wenxuan Jiao, Jingshu Tang, Xiaomin Huang, Zongze Huang, Ying Meng, Laichun Luo, Xintong Wang, Xiling Bian, Fang Zhang, Kewei Wang, Qi Sun
A series of novel thiazolo[4,5-d]pyrimidin-7(6H)-ones (3aa-3ep) were designed, synthesized and evaluated as the type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus ooctyes by two-electrode voltage clamp. The structure-activity relationship (SAR) analysis identified the compound 3ea as a potent and efficacious PAM with the maximum activation effect of the α7 current of over 1633% in the presence of acetylcholine (100 μM) and an EC50 = 1.26 μM. It is highly specific to α7 nAChR over other subtypes of nAChR, 5-HT3A, NMDA and GABAA receptors...
March 28, 2018: Journal of Medicinal Chemistry
Doodipala Samba Reddy, Ryan F Yoshimura, Gunasekaran Ramanathan, Chase Carver, Timothy B Johnstone, Derk J Hogenkamp, Kelvin W Gee
OBJECTIVE: Subunit-specific positive allosteric modulators (PAMs) of gamma-aminobutyric acid-A (GABA-A) receptors are commonly used to uncover the role of GABA-A receptor isoforms in brain function. Recently, we have designed novel PAMs selective for β2/3 -subunit containing GABA-A receptors (β2/3 -selective PAMs) that are nonbenzodiazepine site-mediated and do not show an α-subunit isoform selectivity, yet exhibit anxiolytic efficacy with reduced potential for sedation, cognitive impairment, and tolerance...
March 24, 2018: Epilepsy & Behavior: E&B
Sean P Moran, Jonathan W Dickerson, Hyekyung P Cho, Zixiu Xiang, James Maksymetz, Daniel H Remke, Xiaohui Lv, Catherine A Doyle, Deepa H Rajan, Colleen M Niswender, Darren W Engers, Craig W Lindsley, Jerri M Rook, P Jeffrey Conn
Highly selective positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for improving cognitive function in patients suffering from Alzheimer's disease and schizophrenia. However, excessive activation of M1 is known to induce seizure activity and have actions in the prefrontal cortex (PFC) that could impair cognitive function. We now report a series of pharmacological, electrophysiological, and behavioral studies in which we find that recently reported M1 PAMs, PF-06764427 and MK-7622, have robust agonist activity in cell lines and agonist effects in the mouse PFC, and have the potential to overactivate the M1 receptor and disrupt PFC function...
March 14, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Gloria S Forkuo, Amanda N Nieman, Revathi Kodali, Nicolas M Zahn, Guanguan Li, Shadiqur Rashid Roni, Michael Rajesh Stephen, Ted William Harris, Rajwana Jahan, Margaret L Guthrie, Olivia B Yu, Janet L Fisher, Gene T Yocum, Charles W Emala, Douglas A Steeber, Douglas C Stafford, James M Cook, Leggy A Arnold
We describe lead compound MIDD0301 for the oral treatment of asthma based on previously developed positive allosteric α5β3γ2 selective GABA(A) receptor (GABA(A)R) modulators. MIDD0301 relaxed airway smooth muscle at single micromolar concentrations as demonstrated with ex vivo guinea pig tracheal rings. MIDD0301 also attenuated airway hyperresponsiveness (AHR) in an ovalbumin murine model of asthma by oral administration. Reduced numbers of eosinophils and macrophages were observed in mouse broncho-alveolar lavage fluid without changing mucous metaplasia...
March 26, 2018: Molecular Pharmaceutics
Delphine Charvin
2017 is the 200th anniversary of the first published description of Parkinson's disease (PD). Fifty years ago, the clinical benefit of levodopa was first documented, representing the most important advance in the treatment of PD so far. Among the novel targets identified in the last decade, positive allosteric modulators (PAM) of mGlu4 receptors show great promise, with the potential to change the paradigm of the PD treatment approach. mGlu4 PAMs have shown consistent efficacy in various preclinical models of PD, and entered clinical trials for the first time in 2017...
March 23, 2018: Neuropharmacology
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