Neuroscience Research, Pfizer Worldwide Research and Development, 700 Main Street, Cambridge, MA 02139, USA.
Pharmacol Ther. 2013 Jan;137(1):22-54. doi: 10.1016/j.pharmthera.2012.08.012. Epub 2012 Aug 25.
Substantial progress in the identification of genes encoding for a large number of proteins responsible for various aspects of neurotransmitter release, postsynaptic detection and downstream signaling, has advanced our understanding of the mechanisms by which neurons communicate and interact. Nicotinic acetylcholine receptors represent a large and well-characterized family of ligand-gated ion channels that is expressed broadly throughout the central and peripheral nervous system, and in non-neuronal cells. With 16 mammalian genes identified that encode for nicotinic receptors and the ability of the subunits to form heteromeric or homomeric receptors, the repertoire of conceivable receptor subtype combinations is enormous and offers unique possibilities for the design and development of new therapeutics that target nicotinic acetylcholine receptors. The aim of this review is to provide the reader with recent insights in nicotinic acetylcholine receptors from genes, structure and function to diseases, and with the latest findings on the pharmacology of these receptors. Although so far only a few nicotinic drugs have been marketed or are in late stage development, much progress has been made in the design of novel chemical entities that are being explored for the treatment of various diseases, including addiction, depression, ADHD, cognitive deficits in schizophrenia and Alzheimer's disease, pain and inflammation. A pharmacological analysis of these compounds, including those that were discontinued, can improve our understanding of the pharmacodynamic and pharmacokinetic requirements for nicotinic 'drug-like' molecules and will reveal if hypotheses on therapies based on targeting specific nicotinic receptor subtypes have been adequately tested in the clinic.
在鉴定编码大量负责神经递质释放、突触后检测和下游信号转导等各个方面的蛋白质的基因方面取得了重大进展，这加深了我们对神经元通讯和相互作用机制的理解。烟碱型乙酰胆碱受体是一个广泛表达于中枢和外周神经系统以及非神经元细胞的大型、特征明确的配体门控离子通道家族。目前已经鉴定出 16 个编码烟碱受体的哺乳动物基因，并且这些亚基能够形成异源或同源受体，因此可以设想出的受体亚型组合是巨大的，为针对烟碱乙酰胆碱受体的新型治疗药物的设计和开发提供了独特的可能性。本综述的目的是为读者提供有关烟碱乙酰胆碱受体从基因、结构和功能到疾病的最新见解，并介绍这些受体的药理学最新发现。尽管到目前为止，只有少数几种烟碱类药物已经上市或处于后期开发阶段，但在设计新型化学实体方面已经取得了很大进展，这些实体正在探索用于治疗各种疾病，包括成瘾、抑郁症、ADHD、精神分裂症和阿尔茨海默病的认知缺陷、疼痛和炎症。对这些化合物（包括已停用的化合物）进行药理学分析可以增进我们对烟碱类“药物样”分子的药效动力学和药代动力学要求的理解，并揭示基于针对特定烟碱受体亚型的治疗假设在临床上是否得到了充分验证。
