毒蕈碱乙酰胆碱受体
耐受性
神经科学
肌张力障碍
毒蕈碱乙酰胆碱受体M3
乙酰胆碱
毒蕈碱乙酰胆碱受体M4
药理学
毒蕈碱乙酰胆碱受体M1
神经递质
神经递质受体
医学
受体
生物
不利影响
中枢神经系统
内科学
作者
Mark S. Moehle,Aaron M. Bender,Jonathan W. Dickerson,Daniel W. Foster,Yuping Donsante,Weimin Peng,Zoey Bryant,Thomas M. Bridges,Sichen Chang,Katherine D. Watson,John S. O’Neill,Julie L. Engers,Li Ning Peng,Alice L. Rodriguez,Colleen M. Niswender,Craig W. Lindsley,Ellen J. Hess,P. Jeffrey Conn,Jerri M. Rook
标识
DOI:10.1101/2020.10.12.324152
摘要
Abstract Non-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson disease and dystonia. Despite their efficacy in these and other central nervous system disorders, anti-muscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the anti-parkinsonian and anti-dystonic efficacy observed with the use of non-selective anti-muscarinic therapeutics. Our recent work has indicated that the M 4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M 4 may recapitulate the efficacy of non-selective anti-muscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M 4 . Here we utilize genetic mAChR knockout animals in combination with non-selective mAChR antagonists to confirm that the M 4 receptor underlies the locomotor-stimulating and anti-parkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M 4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have anti-parkinsonian and anti-dystonic efficacy in pharmacological and genetic models of movement disorders.
科研通智能强力驱动
Strongly Powered by AbleSci AI