5-HT2A RECEPTOR STRUCTURE--AN INTEGRATED APPROACH

5-HT2A 受体结构——综合方法

基本信息

批准号：
2883464
负责人：
RICHARD B WESTKAEMPER
金额：
$ 10.66万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-03-01 至 2001-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2883464
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

项目摘要

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（改编自申请人的摘要）：涉及 5-HT 在许多过程中，包括睡眠、食欲的调节，情绪、攻击性、感知、记忆和焦虑。至少 14 个独立的 5-HT 受体已经进化，分为七个主要家族。不是令人惊讶的是，5-HT 受体活性的改变已被证明发生许多精神疾病，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，一些有效的精神药理学治疗精神分裂症和焦虑症等多种疾病的药物已被开发出特异性改变大脑 5-HT 水平或结合 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。具体来说，我们打算阐明的分子决定因素 5-HT2受体DOB样苯乙胺和a之间的相互作用系列三环化合物采用综合方法，结合来自定点诱变和配体 SAR 的信息可进行精炼假设的 3 维 (3-D) 受体模型。第一个也是最基本的决定药物药理活性的事件是配体与受体的结合。终极药理结果是受体激活或失活的结果配体-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只能通过检查配体 SAR 和受体 SAR 来间接研究定点诱变。计算化学和分子建模提供评估间接数据并将其组织成假设的 3D 的方法原子级别细节的框架。这种 3D 模型提供了一种方法不仅组织实验观察，而且生成可测试的关于配体-受体相互作用的假设。我们将综合并评估基于受体模型专门设计的化合物测试某些氨基酸残基对于配体结合的重要性和受体功能，从而测试模型的准确性。亲和力和将评估设计的目标化合物的功能特性与天然和选定的突变受体。这是其中之一首次采用联合方法，利用受体建模，模型特异性配体设计和模型定向诱变已被应用于5-HT受体。