5-HT2A RECEPTOR STRUCTURE: AN INTEGRATED APPROACH

5-HT2A 受体结构：综合方法

• 批准号: 6830811
• 负责人: RICHARD B WESTKAEMPER
• 金额: $ 22.5万
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830811
• 关键词: chemical models; computer simulation; intermolecular interaction; ligands; model design /development; molecular dynamics; molecular site; mutant; physical model; protein structure function; receptor binding; rhodopsin; serotonin inhibitor; serotonin receptor; site directed mutagenesis

DESCRIPTION (provided by applicant): Serotonin 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 serotonin 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 and a series of novel tricyclic antagonists using an integrated approach that combines information from site-directed mutagenesis and ligand structure-activity relationships (SAR) to refine hypothetical three-dimensional (3D) 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 receptors, 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 3D framework at the atomic level of detail. Such 3D 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（由申请人提供）： 血清素与许多过程有关，包括 睡眠、食欲、情绪、攻击性、知觉、记忆力的调节 焦虑。至少有 14 个独立的 5-HT 受体已经进化，它们被分为 分为七个主要家庭。毫不奇怪，5-HT 受体的改变 活性已被证明发生在许多精神疾病中，包括 焦虑症、抑郁症、饮食失调、精神分裂症、人格障碍、 以及许多药物引起的精神病状态。此外，还有一些有效的 用于治疗精神分裂症和焦虑症等多种疾病的精神药物 已开发出专门改变大脑血清素水平的药物 或与 5-HT 受体亚型结合。我们建议使用新颖的三方 加深对配体之间关系的理解的方法 结构、神经递质受体结构和配体-受体 协会。具体来说，我们打算阐明的分子决定因素 5-HT2受体与一系列新型三环化合物之间的相互作用 对抗者使用综合方法，结合来自 定点诱变和配体构效关系（SAR） 完善假设的三维 (3D) 受体模型。第一个也是最 决定药物药理活性的基本事件是 配体与受体的结合。最终药理结果 是受体激活或失活形成后的结果 配体-受体复合物。由于没有直接的实验结构 膜结合 G 蛋白偶联受体，分子细节 配体-受体结构只能通过检查来间接研究 通过定点诱变形成配体 SAR 和受体 SAR。 计算化学和分子建模提供了评估和 在原子级别将间接数据组织到假设的 3D 框架中 细节。这种 3D 模型不仅提供了组织实验的方法 观察，还可以生成有关以下方面的可检验假设 配体-受体相互作用。我们将合成和评估化合物 根据受体模型专门设计，以测试其重要性 某些氨基酸残基用于配体结合和受体功能，因此 测试模型的准确性。的亲和力和功能特性 设计的目标化合物将使用天然化合物和选定的化合物进行评估 突变受体。这是第一次采用组合方法， 利用受体建模、模型特异性配体设计和模型导向 诱变，已应用于5-HT受体。