STRUCTURAL DOMAINS ESSENTIAL FOR SEROTONIN RECEPTOR PHAR

5-羟色胺受体 PAR 必需的结构域

• 批准号: 2434743
• 负责人: Bryan L. Roth
• 金额: $ 22.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2434743
• 关键词: chemical models; chimeric proteins; computer simulation; neuropharmacology; protein structure function; receptor binding; receptor sensitivity; serotonin receptor; site directed mutagenesis; tissue /cell culture

Alterations in the functional activity and/or number of serotonin2 (5-HT2) and/or serotonin1C (5-HT-1c) receptors have been implicated in the pathophysiology of a large number of mental illnesses including obsessive- compulsive disorder, schizophrenia, depression, anxiety, dysthymia, suicide, aggression and eating disorders. Additionally, a number of psycho- and neuropharmacologic agents including antidepressants (mianserin, amitriptyline, imipramine), antipsychotic drugs (loxapine, clozapine), hallucinogens (lysergic acid diethylamide) and anti-dysthymic agents (ritanserin) bind to 5-HT2 and 5-HT-1c receptors. Determining the precise roles the 5-HT2 and 5-HT-1c receptors have in mediating the effects of these agents is difficult because no truly subtype selective agents are currently available. Insights we gain in understanding how drugs bind to each of these receptors should enhance our ability to design novel receptor-specific agents which can be used to treat mental illnesses. This proposal will determine how agonists and antagonists bind to 5-HT2 and 5-HT-1c receptors. We will utilize the techniques of molecular biology and receptor pharmacology to identify specific amino acids essential for specifying the ligand binding domains of each receptor. We are utilizing four major techniques. (1) chimeric protein construction (2) site directed mutagenesis, (3) molecular modelling and (4) structural biochemical measurements. Our strategy is to test three-dimensional molecular models of 5- HT2 and 5- HT-1c receptor-ligand interactions using a combination of molecular biological and structural-biochemical techniques. We will also take advantage of unique mutations we have produced to probe the molecular details responsible for hallucinogen- induced alterations of serotonin receptors in vitro. These findings will be useful for the design and synthesis of new medications to treat psychiatric diseases.

功能活性和/或羟色胺2的变化（5-HT2） 和/或羟色胺1C（5-HT-1C）受体已与 大量精神疾病的病理生理，包括强迫症 强迫症，精神分裂症，抑郁症，焦虑，心情障碍， 自杀，侵略和饮食失调。此外，许多 心理和神经药物包括抗抑郁药 （米亚梅林，阿米替林，丙咪胺），抗精神病药（柠檬蛋白，， 氯氮平），致幻剂（脂肪酸二乙酰胺）和抗疾病 剂（利坦塞蛋白）与5-HT2和5-HT-1C受体结合。确定 精确的作用5-HT2和5-HT-1C受体在介导 这些代理的影响很困难，因为没有真正的亚型选择性 代理商目前可用。我们在理解如何 药物与这些受体中的每一个结合，应增强我们的设计能力 可用于治疗心理的新型受体特异性药物 疾病。 该提议将决定激动剂和拮抗剂如何与5-HT2结合 和5-HT-1C受体。我们将利用分子生物学的技术 和受体药理学以鉴定特定的氨基酸 指定每个受体的配体结合结构域。我们正在利用 四种主要技术。 （1）嵌合蛋白结构（2）位置 定向诱变，（3）分子建模和（4）结构 生化测量。我们的策略是测试三维 使用5-HT2和5-HT-1C受体配体相互作用的分子模型使用 分子生物学和结构生物化学的结合 技术。我们还将利用我们拥有的独特突变 产生的是为了探测负责致幻蛋白原的分子细节 在体外诱导5-羟色胺受体的改变。这些发现会 对于设计和合成新药物以治疗 精神病。