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 molecular in vitro evidence 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 preclinical in vivo behavioral 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.

中文翻译：

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Alpha4beta2烟碱受体阳性变构调节剂的体外和体内药理学研究进展。

含有α4和β2亚基的受体是大脑中主要的神经元烟碱型乙酰胆碱受体（nAChR）亚型。该受体在尼古丁成瘾中起关键作用，潜在的戒烟治疗药物可调节α4β2nAChR。另外，在α4β2nAChR上起激动剂作用的化合物可用于治疗病理性疼痛。此外，由于已经将α4β2nAChR与认知联系起来，因此也正在研究充当α4β2nAChR激动剂的治疗剂作为影响认知功能的认知障碍和神经系统疾病的疗法，例如阿尔茨海默氏病和精神分裂症。这篇综述将涵盖分子体外证据，即α4β2神经元nAChR的变构调节剂相对于传统α4β2nAChR正构配体具有多种优势。特别，我们探讨了nAChR变构调节剂可实现更大的药理选择性，同时将潜在的有害脱靶效应降至最低的概念。此外，在这里我们讨论在α4β2神经元nAChR处的变构调节剂的开发和临床前体内行为评估，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系统疾病的治疗方法。