Advances in the In vitro and In vivo pharmacology of Alpha4beta2 nicotinic receptor positive allosteric modulators.
Advances in the In vitro and In vivo pharmacology of Alpha4beta2 nicotinic receptor positive allosteric modulators.
复制标题
Alpha4beta2烟碱受体正变构调节剂的体外和体内药理学进展。
DOI：
10.1016/j.neuropharm.2020.108008
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发表时间：
2020
影响因子：
4.7
通讯作者：
McMahon,LanceR
中科院分区：
文献类型：
--
作者：
Wilkerson,JennyL;Deba,Farah;Crowley,MorganL;Hamouda,AymanK;McMahon,LanceR
含有α-4和β-2亚基的受体是脑内主要的神经元型烟碱型乙酰胆碱受体。这种受体在尼古丁成瘾中起着关键作用，潜在的戒烟疗法产生了对α4β2nAChR的调节。此外，在α4β2nAChR上作为激动剂的化合物可能对病理性疼痛的治疗有用。此外，由于α4β2nAChR与认知有关，作为α4β2nAChR激动剂的疗法也被研究为治疗认知障碍和影响认知功能的神经疾病，如阿尔茨海默病和精神分裂症。本文综述了α4β2神经元nAChR的变构调节剂比传统的α4β2nAChR正构配体具有优势的分子体外证据。具体地说，我们探索了nAChR变构调节剂的概念，即nAChR变构调节剂允许更大的药理选择性，同时最大限度地减少潜在的有害非靶标效应。此外，我们在这里讨论了α4β2神经元nAChR上变构调节剂的开发和临床前临床行为评估，作为戒烟、病理性疼痛以及影响认知功能的认知障碍和神经疾病的治疗方法。这篇文章是《尼古丁神经药理学的当代进展》特刊的一部分。
Receptors containing α4 and β2 subunits are a major neuronal nicotinic acetylcholine receptor (nAChR) subtype in the brain. This receptor plays a critical role in nicotine addiction, with potential smoking cessation therapeutics producing modulation of α4β2 nAChR. In addition, compounds that act as agonists at α4β2 nAChR may be useful for the treatment of pathological pain. Further, as the α4β2 nAChR has been implicated in cognition, therapeutics that act as α4β2 nAChR agonists are also being examined as treatments for cognitive disorders and neurological diseases that impact cognitive function, such as Alzheimer's disease and schizophrenia. This review will cover the molecularin vitroevidence that allosteric modulators of the α4β2 neuronal nAChR provide several advantages over traditional α4β2 nAChR orthosteric ligands. Specifically, we explore the concept that nAChR allosteric modulators allow for greater pharmacological selectivity, while minimizing potential deleterious off-target effects. Further, here we discuss the development and preclinicalin vivobehavioral assessment of allosteric modulators at the α4β2 neuronal nAChR as therapeutics for smoking cessation, pathological pain, as well as cognitive disorders and neurological diseases that impact cognitive function.This article is part of the special issue on ‘Contemporary Advances in Nicotine Neuropharmacology’.