VORONOI MAPPING OF COCAINE RECEPTORS

可卡因受体的 VORONOI 作图

• 批准号: 3213442
• 负责人: GORDON M CRIPPEN
• 金额: $ 11.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-30 至 1993-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3213442
• 关键词: X ray crystallography; brain; central nervous system; chemical binding; chemical models; cocaine; dopamine receptor; drug abuse; drug adverse effect; drug metabolism; drug receptors; mathematical model; membrane proteins; molecular dynamics; neurotransmitter receptor

Pharmacological studies on the biological action of cocaine have identified several sites of specific binding in the central nervous system associated with toxicity, self administration behavior, and other features of drug abuse. There are in vitro assays showing good correlation with physiologica effects, whereby experimentalists have measured specific binding constants to well-defined CNS receptors for a series of cocaine derivatives. Since these assays are typically done with brain homogenates, and the receptors are probably membrane bound proteins, there is little hope for a detailed X-ray crystal structure of the receptor, and we must make do with just the binding data. Can we use this limited information to deduce a detailed pic- ture of the shape of the receptor site and the energetics of drug-receptor interactions? How much detail can be deduced? What can we learn if the assa actually involves more than one type of receptor? Can this information be used to suggest cocaine antagonists or drugs with greater specificity for particular receptors? We propose to enhance our rigorous computer algorithm for receptor mapping and apply them to the available experimental data on cocaine binding to CNS receptors, in order to answer these questions.

关于可卡因生物学作用的药理研究已经证实 中枢神经系统中几个与之相关的特异性结合部位 具有毒性、自我给药行为等特点的药物 虐待。体外试验显示与生理学有很好的相关性。 效应，从而实验者测量了特定的结合常数 一系列可卡因衍生物的明确的中枢神经系统受体。自.以来 这些分析通常是用脑匀浆和受体进行的 很可能都是膜结合蛋白，希望有一个详细的 受体的X射线晶体结构，我们必须凑合使用 绑定数据。我们能不能利用这些有限的信息来推断一张详细的图片- 受体部位形状的真实性和药物受体的能量学 互动？可以推断出多少细节？我们能从阿萨身上学到什么 实际上涉及不止一种类型的受体？这条信息能不能 用于指可卡因拮抗剂或对可卡因有更强特异性的药物 特定的受体？我们建议增强我们严格的计算机算法 用于受体映射，并将它们应用于现有的实验数据 可卡因与中枢神经系统受体的结合，以回答这些问题。