5-HT2A RECEPTOR STRUCTURE--AN INTEGRATED APPROACH

5-HT2A 受体结构——综合方法

• 批准号: 6165218
• 负责人: RICHARD B WESTKAEMPER
• 金额: $ 10.98万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2001-12-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6165218
• 关键词: G protein; chemical models; computer simulation; cyclic amine; ligands; model design /development; molecular site; neurotransmitter agonist; phenylalkylamine; physical model; protein structure function; receptor binding; receptor coupling; serotonin receptor; site directed mutagenesis

DESCRIPTION (Adapted from applicant's abstract): 5-HT has been implicated in a large number of processes including the regulation of sleep, appetite, mood, aggression, perception, memory and anxiety. At least 14 separate 5-HT receptors have evolved, which are divided into seven main families. Not surprisingly, alterations of 5-HT receptor activity have been shown to occur in many psychiatric diseases including anxiety, depression, eating disorders, schizophrenia, personality disorders, and many drug-induced psychotic states. Additionally, a number of effective psychopharmacologic agents for diseases as diverse as schizophrenia and anxiety have been developed which either specifically alter brain levels of 5-HT or bind to 5-HT receptor subtypes. We propose to use a novel tripartite approach to develop an understanding of the relationships between ligand structure, neurotransmitter receptor structure, and ligand-receptor association. Specifically, we intend to elucidate the molecular determinants of the interactions between 5-HT2 receptors DOB-like phenylethylamines, and a series of tricyclic compounds using an integrated approach that combines information from site-directed mutagenesis and ligand SAR to refine hypothetical 3-dimensional (3-D) receptor models. The first and most basic event that determines the pharmacological activity of an agent is the association of a ligand with the receptor. The ultimate pharmacological outcome is a result of receptor activation or deactivation following formation of the ligand-receptor complex. Since there are no direct experimental structures for the membrane bound G-protein coupled receptor (GPCR) structures, the molecular details of ligand-receptor structure can only be investigated indirectly by examining ligand SAR, and receptor SAR by site-directed mutagenesis. Computational chemistry and molecular modeling provide means to evaluate and organize indirect data into a hypothetical 3-D framework at the atomic level of detail. Such 3-D models provide a means to not only organize experimental observations but also to generate testable hypotheses concerning ligand-receptor interactions. We will synthesize and evaluate compounds designed specifically on the basis of receptor models to test the importance of certain amino acid residues for ligand binding and receptor function, thus testing model accuracy. The affinities and functional properties of the designed target compounds will be evaluated with both the native and selected mutant receptors. This is one of the first times that a combined approach, utilizing receptor modeling, model-specific ligand design, and model-directed mutagenesis, has been applied to 5-HT receptors.

描述（根据申请人的摘要改编）：5-HT已牵涉 在大量过程中，包括睡眠调节，食欲调节， 情绪，侵略，感知，记忆和焦虑。 至少14个单独的5-HT 受体已经进化，分为七个主要家庭。 不是 令人惊讶的是，已经证明5-HT受体活性的改变 在许多精神病中，包括焦虑，抑郁，饮食 疾病，精神分裂症，人格障碍和许多药物引起的 精神病状态。 此外，许多有效的心理药物学 像精神分裂症和焦虑一样多样的疾病的药物已经 开发的，要么专门改变5-HT的大脑水平，要么结合到 5-HT受体亚型。 我们建议使用一种新颖的三方方法 了解配体结构之间的关系， 神经递质受体结构和配体受体关联。 具体而言，我们打算阐明 5-HT2受体DOB样苯甲胺和A之间的相互作用 使用集成方法结合的一系列三环化合物 来自位置定向诱变和配体SAR的信息以完善 假设的3维（3-D）受体模型。 第一个也是最基本的 确定药物药理活性的事件是 配体与受体的关联。 最终药理 结果是受体激活或失活后的结果 配体受体复合物的形成。 由于没有直接 膜结合G蛋白偶联受体的实验结构 （GPCR）结构，配体受体结构的分子细节可以 仅通过检查配体SAR和受体SAR进行间接研究 定向诱变。 计算化学和分子建模 提供评估和组织间接数据的方法 在原子能层面上的框架。 这样的3D模型提供了一种手段 不仅组织实验观察，而且还可以生成可测试的观测 有关配体 - 受体相互作用的假设。 我们将合成，并 评估专门根据受体模型设计的化合物 测试某些氨基酸残基在配体结合和 受体功能，从而测试模型的精度。 亲和力 将评估设计目标化合物的功能性能 与天然和选择的突变受体。 这是 首次使用受体建模的联合方法， 模型特异性配体设计和模型定向的诱变已是 应用于5-HT受体。