BINDING SITE STRUCTURE OF NEURONAL NICOTINIC RECEPTORS

神经元烟碱乙酰胆碱受体（nAChRs）是近年来研究的热点 因为它们是乙酰胆碱必须发挥作用的关键部位 前脑这些受体特别令人感兴趣，因为它们是 尼古丁发挥其精神作用和成瘾作用的部位。 神经元nAChRs的药物干预有望治疗 中枢神经系统疾病的影响， 了解和治疗成瘾过程。一个特别重要 治疗靶点是nAChR结合乙酰胆碱的位点。 不幸的是，我们对这一结构基础的理解 互动是有限的。此外，为了使治疗剂有效，它们 必须能够区分多种功能亚型 nAChRs的基因。该研究项目 我在本申请中所描述的将识别特定的氨基酸 确定药物药理学特性的残留物 神经元nAChR的神经递质结合位点。实验 战略是利用成员之间的药理学差异， 受体家族作为受体结构的探针。这将使用 分子生物学技术。嵌合受体亚基将是 通过将一个亚基的特定序列片段替换为 两个不同亚单位的类似序列片段。 通过确定由以下物质形成的受体的药理学性质， 嵌合亚基，决定药理学作用的序列片段 将确定特异性。根据这些结果， 在实验中，将进行单个氨基酸的改变， 不同的受体。这些实验将确定 确定药理学特异性的特定氨基酸。的 这些实验的结果将有助于治疗剂的设计 对个体受体亚型具有选择性。具体药物将由 在治疗和探索尼古丁的机制方面有很大的用途， 成瘾

Neuronal nicotinic acetylcholine receptors (nAChRs) are of great interest because they are critical sites at which acetylcholine must act to excite the forebrain. These receptors are of particular interest because they are the sites at which nicotine exerts its psychoactive and addictive effects. Pharmacologic intervention at neuronal nAChRs holds promise for treating the effects of diseases of the central nervous system and for understanding and treating addictive processes. A particularly important therapeutic target is the site at which nAChRs bind acetylcholine. Unfortunately, our understanding of the structural basis for this interaction is limited. Also, for therapeutic agents to be effective, they must be capable of distinguishing among the multiple functional subtypes of nAChRs that are present in the nervous system. The research project that I describe in this application will identify the specific amino acid residues that determine the pharmacological properties of the neurotransmitter binding sites of neuronal nAChRs. The experimental strategy is to use the pharmacological differences between members of this receptor family as probes of receptor structure. This will be done using the techniques of molecular biology. Chimeric receptor subunits will be constructed by replacing specific sequence segments of one subunit with the analogous sequence segment of a pharmacologically distinct subunit. By determining the pharmacological properties of receptors formed by chimeric subunits, the sequence segments that determine pharmacological specificity will be identified. Drawing on the results of these experiments, individual amino acid changes will be made between pharmacologically distinct receptors. These experiments will identify the specific amino acids that determine pharmacological specificity. The results of these experiments will aid in the design of therapeutic agents selective for individual receptor subtypes. Specific drugs will be of great use in treating, as well as probing the mechanism of, nicotine addiction.