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Muscarinic receptors

Juliana C C Dallagnol, Elham Khajehali, Emma T van der Westhuizen, Manuela Jörg, Celine Valant, Alan G Goncalves, Ben Capuano, Arthur Christopoulos, Peter J Scammells
Targeting allosteric sites at M1 muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators may not only potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh), but may also possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles...
March 15, 2018: Journal of Medicinal Chemistry
Carmen Scheibenbogen, Madlen Loebel, Helma Freitag, Anne Krueger, Sandra Bauer, Michaela Antelmann, Wolfram Doehner, Nadja Scherbakov, Harald Heidecke, Petra Reinke, Hans-Dieter Volk, Patricia Grabowski
INTRODUCTION: Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases...
2018: PloS One
Gian Marco Rosa, Danilo Baccino, Alberto Valbusa, Carolina Scala, Fabio Barra, Claudio Brunelli, Simone Ferrero
Overactive bladder (OAB) syndrome is common in the general population, particularly in elderly patients. Antimuscarinic drugs (AMs) are considered the mainstay pharmaceutical treatment of OAB whereas β3-adrenoceptor agonists, such as mirabegron, represent a good alternative. Owing to the important role of muscarinic and β3 receptors in cardiovascular (CV) tissue and to the fact that OAB patients often have CV comorbidities, the safety-profile of these drugs constitute an important challenge. Area covered: The aim of this review is to evaluate the CV effects of AMs and mirabegron in OAB...
March 15, 2018: Expert Opinion on Drug Safety
Mario Malerba, Matteo Nardin, Giuseppe Santini, Nadia Mores, Alessandro Radaeli, Paolo Montuschi
Maintenance pharmacological treatment for stable chronic obstructive pulmonary disease (COPD) is based on inhaled drugs, including long-acting muscarinic receptor antagonists (LAMA), long-acting β2 -adrenoceptor agonists (LABA) and inhaled corticosteroids (ICS). Inhaled pharmacological treatment can improve patients' daily symptoms and reduce decline of pulmonary function and acute exacerbation rate. Treatment with all three inhaled drug classes is reserved for selected, more severe, patients with COPD when symptoms are not sufficiently controlled by dual LABA/LAMA therapy and exacerbations are frequent...
January 2018: Therapeutic Advances in Respiratory Disease
Li-Yuan Chen, Maxime Lévesque, Mauro Cataldi, Massimo Avoli
The muscarinic receptor agonist carbachol (CCh) can induce activity in the theta range (4 - 15 Hz) in the entorhinal cortex (EC), but the underlying network mechanisms remain unclear. Here, we investigated the interplay between interneurons and principal cells in the EC during CCh-induced theta-like field oscillations in an in vitro brain slice preparation using tetrodes. Field oscillations at 10.1 Hz (IQR = 9.5 - 10.9 Hz) occurred during bath application of CCh (100 μM; n = 32 experiments) and were associated with single-unit (n = 189) firing...
March 10, 2018: Neuroscience
V Hepnarova, J Korabecny, L Matouskova, P Jost, L Muckova, M Hrabinova, N Vykoukalova, M Kerhartova, T Kucera, R Dolezal, E Nepovimova, K Spilovska, E Mezeiova, N L Pham, D Jun, F Staud, D Kaping, K Kuca, O Soukup
Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line...
March 2, 2018: European Journal of Medicinal Chemistry
Vivek Krishna Pulakazhi Venu, Mahmoud Saifeddine, Koichiro Mihara, Mahmoud El-Daly, Darrell Belke, Jonathan L E Dean, Edward R O'Brien, Simon A Hirota, Morley D Hollenberg
BACKGROUND AND PURPOSE: Previously, we demonstrated that exogenous Heat Shock Protein 27 (HSP27/gene, HSPB1) treatment of human endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re-endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 could also affect mature endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on eNOS/NO-dependent relaxation caused by acetylcholine and the coagulation pathway-activated receptor, proteinase-activated receptor-2 (PAR2)...
March 12, 2018: British Journal of Pharmacology
Li-Min Mao, Hunter J Faris, John Q Wang
The Src family kinase (SFK) is a subfamily of non-receptor tyrosine kinases. SFK members, Src and especially Fyn, are expressed in the striatum. These SFK members are involved in the regulation of neuronal and synaptic activities and are linked to the pathogenesis of a variety of neuropsychiatric and neurodegenerative disorders. Given the fact that muscarinic acetylcholine (mACh) receptors are highly expressed in striatal neurons and are critical for the regulation of striatal function, we investigated the role of mACh receptors in the regulation of SFKs in the adult rat striatum in vivo...
March 12, 2018: Journal of Molecular Neuroscience: MN
Allie J Widman, Lori L McMahon
Low-dose ketamine, an open-channel N -methyl d-aspartate receptor (NMDAR) antagonist, mediates rapid antidepressant effects in humans that are mimicked in preclinical rodent models. Disinhibition of pyramidal cells via decreased output of fast-spiking GABAergic interneurons has been proposed as a key mechanism that triggers the antidepressant response. Unfortunately, to date, disinhibition has not been directly demonstrated. Furthermore, whether disinhibition is a common mechanism shared among other antagonists with rapid antidepressant properties in humans has not been investigated...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Daniel Giglio, Lucie Podmolikova, Gunnar Tobin
Currently, we have assessed the neuronal control of the urinary bladder in radiation cystitis and whether interstitial cells contribute to the condition. Fourteen days following bladder irradiation (20 Gy) rats were sedated and the urinary bladder was cut in two sagittal halves where electrical field stimulation (EFS; 5-20 Hz) was applied on the pelvic nerve afferents or stretch (80 mN) on one half of the urinary bladder, while contractions were registered on the contralateral half of the urinary bladder in the absence and presence of increasing doses of imatinib (1-10 mg/kg; inhibitor of c-kit+ interstitial cells), atropine (1 mg/kg; to block muscarinic M3 receptors) or PPADS (2 mg/kg; to block P2X1 purinoceptors)...
March 12, 2018: Journal of Pharmacology and Experimental Therapeutics
Ariel A Batallán-Burrowes, C Andrew Chapman
Persistent firing in layer III entorhinal cortex neurons that can be evoked during muscarinic receptor activation may contribute to mechanisms of working memory. The entorhinal cortex receives strong dopaminergic inputs which may modulate working memory for motivationally significant information. We used whole cell recordings in in vitro rat brain slices to assess the effects of dopamine on persistent firing in layer III neurons initiated by depolarizing current injection. Persistent firing during pharmacological block of ionotropic excitatory and inhibitory synaptic transmission, and in the presence of the cholinergic agonist carbachol (10 μM), was observed in 39% of layer III pyramidal cells...
March 7, 2018: Neuroscience Letters
Rocco Gogliotti, Nicole Fisher, Branden Stansley, Carrie Jones, Craig Lindsley, Jeffrey Conn, Colleen Niswender
Mutations in the Methyl CpG Binding Protein 2 (MECP2) gene are responsible for the neurodevelopmental disorder Rett syndrome (RTT). MeCP2 is a DNA-binding protein whose abundance and ability to complex with HDAC3 is linked to the regulation of chromatin structure. Consequently, loss-of-function mutations in MeCP2 are predicted to have broad effects on gene expression. However, to date, studies in mouse models of RTT have identified a limited number of gene or pathway-level disruptions, and even fewer genes have been identified that could be considered amenable to classical drug discovery approaches...
March 9, 2018: Journal of Pharmacology and Experimental Therapeutics
J F Golding, K A Wesnes, B R Leaker
AIMS: The aim of this study was to compare the effects of the selective M3 muscarinic acetylcholine receptor antagonist Darifenacin, oral Hyoscine hydrobromide and Placebo on motion sickness induced by cross-coupled stimulation. METHODS: The effects of Darifenacin 10 mg or 20 mg, Hyoscine hydrobromide 0.6 mg and Placebo were assessed in a randomised, double-blind, 4-way cross over trial of 16 healthy subjects. Motion sickness, skin conductance (a measure of sweating) and psychomotor cognitive function tests were investigated...
March 9, 2018: British Journal of Clinical Pharmacology
Agostinho Lemos, Rita Meloc, Antonio J Preto, Jose G Almeida, Irina S Moreira, M Natalia D S Cordeiro
Parkinson's Disease (PD) is a long-term neurodegenative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel anti-parkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD...
March 8, 2018: Current Neuropharmacology
Yu-Li Liu, Li-de Zhang, Tie-Ming Ma, Si-Tong Song, Hai-Tao Liu, Xu Wang, Ning Li, Chang Yang, Song Yu
Acupuncture was proven beneficial in treating allergic inflammation. We aimed to explore the regulation underlying the effects of acupuncture on Feishu, an acupoint most commonly used in the acupuncture therapy for respiratory diseases, with respect to the system of sympathetic nerve neurotransmitter acetylcholine (Ach). Male Wistar rats were randomly grouping. No treatment was taken in the normal group. Allergic asthma was induced using ovalbumin on the model, Feishu acupuncture, and sham acupuncture groups; then control or acupuncture treatment lasting for 3 weeks was performed...
March 8, 2018: Inflammation
Panos Zanos, Scott M Thompson, Ronald S Duman, Carlos A Zarate, Todd D Gould
Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites...
March 7, 2018: CNS Drugs
Paulina Valuskova, Vladimir Farar, Sandor Forczek, Iva Krizova, Jaromir Myslivecek
Autoradiography helps to determine the distribution and density of muscarinic receptor (MR) binding sites in the brain. However, it relies on the selectivity of radioligands toward their target.3 H-Pirenzepine is commonly believed to label predominantly M1 MR,3 H-AFDX-384 is considered as M2 MR selective ligand. Here we performed series of autoradiographies with3 H-AFDX-384 (2 nM), and3 H-pirenzepine (5 nM) in WT, M1 KO, M2 KO, and M4 KO mice to address the ligand selectivity. Labeling with3 H-pirenzepine using M1 KO, M2 KO, and M4 KO brain sections showed the high selectivity toward M1 MR...
2018: Frontiers in Pharmacology
Toshio Takahashi, Akira Shiraishi, Jun Murata
Cholinergic signaling, which modulates cell activities via nicotinic and muscarinic acetylcholine receptors (n- and mAChRs) in response to internal or external stimuli, has been demonstrated in mammalian non-neuronal cells that synthesize acetylcholine (ACh). One of the major pathways of excitatory transmission in the enteric nervous system (ENS) is mediated by cholinergic transmission, with the transmitter ACh producing excitatory potentials in postsynaptic effector cells. In addition to ACh-synthesizing and ACh-metabolizing elements in the ENS, the presence of non-neuronal ACh machinery has been reported in epithelial cells of the small and large intestines of rats and humans...
March 5, 2018: International Journal of Molecular Sciences
Lan-Xue Zhao, Yan-Hui Ge, Cai-Hong Xiong, Ling Tang, Ying-Hui Yan, Ping-Yee Law, Yu Qiu, Hong-Zhuan Chen
M1 muscarinic acetylcholine receptors (M1 mAChRs) are the most abundant muscarinic receptors in the hippocampus and have been shown to have procognitive effects. AMPA receptors (AMPARs), an important subtype of ionotropic glutamate receptors, are key components in neurocognitive networks. However, the role of AMPARs in procognitive effects of M1 mAChRs and how M1 mAChRs affect the function of AMPARs remain poorly understood. Here, we found that basal expression of GluA1, a subunit of AMPARs, and its phosphorylation at Ser845 were maintained by M1 mAChR activity...
March 6, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Yinglong Miao, J Andrew McCammon
Protein-protein binding is key in cellular signaling processes. Molecular dynamics (MD) simulations of protein-protein binding, however, are challenging due to limited timescales. In particular, binding of the medically important G-protein-coupled receptors (GPCRs) with intracellular signaling proteins has not been simulated with MD to date. Here, we report a successful simulation of the binding of a G-protein mimetic nanobody to the M2 muscarinic GPCR using the robust Gaussian accelerated MD (GaMD) method...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
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