CONSTITUTIVELY ACTIVE SEROTONIIN RECEPTORS

组成型活性血清素受体

• 批准号: 2675594
• 负责人: Milton Teitler
• 金额: $ 23.06万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2675594
• 关键词: antipsychotic agents; chlorpromazine; clozapine; cyclic AMP; haloperidol; morpholine; neuropharmacology; pimozide; prochlorperazine; protein structure function; receptor binding; risperidone; serotonin receptor; site directed mutagenesis; thioridazine; tissue /cell culture; transfection

The mechanism-of-action of clozapine, the prototypical atypical anti-psychotic drug, has been the subject of intense research aimed at revealing the key property of this drug that allows it to have superior antipsychotic activity relative to the more classical antipsychotic drugs. Evidence indicates that clozapine's high affinity interactions with the 5HT-2A receptor may be a key factor. In addition, clozapine has high affinity for the 5HT-2C, 5HT-6, and 5HT-7 receptors. Until recently it has been assumed that clozapine is a classical competitive antagonist at the 5HT-2A receptor. However, preliminary data in this proposal reveal that clozapine is an inverse agonist at the constitutively activated form of the 5HT-2A receptor, created by site-specific mutagenesis. In order to explore the possibility that clozapine's atypical activity may be related to its inverse agonist activity at the 5HT-2A receptor, the effects of a group of typical and atypical antipsychotic drugs on the constitutively activated 5HT-2A receptor will be determined. It is anticipated that if 5HT-2A inverse agonist activity is a critical factor in atypical drug properties, a correlation will be found between inverse agonist activity and atypical antipsychotic activity. In order to ascertain the specificity of the inverse agonist activity of clozapine at the 5HT-2A receptor, the effects of clozapine and other atypical antipsychotic drugs at constitutively activated forms of the 5HT-2C, 5HT-6 and 5HT-7 receptors will be determined. It is anticipated that these studies should confirm or refute the hypothesis that 5HT-2A receptor inverse agonist activity is critical to atypical antipsychotic activity, and may reveal a possible involvement of the 5HT-2C, 5HT-6 or 5HT-7 in atypical drug actions. It is also anticipated that similarities and differences in the pharmacology of the activated state of the four 5HT receptors studied will be revealed: this information may be important in future drug development aimed at developing inverse agonists for therapeutic purposes.

氯氮平的作用机制，典型的非典型 抗精神病药物，一直是紧张的研究对象，旨在 揭示了这种药物的关键特性， 相对于更经典的抗精神病药物， 抗精神病药物 有证据表明氯氮平的含量很高 与5 HT-2A受体的亲和力相互作用可能是关键因素。 此外，氯氮平对5 HT-2C、5 HT-6和5 HT-2C具有高亲和力。 5 HT-7受体。 直到最近，人们一直认为， 氯氮平是5 HT-2A的经典竞争性拮抗剂， 受体的 然而，该提案中的初步数据显示， 氯氮平是一种组成性激活形式的反向激动剂 5 HT-2A受体，通过位点特异性诱变产生。 在 探讨氯氮平的非典型活性 可能与其对5 HT-2A的反向激动剂活性有关 受体，一组典型和非典型抗精神病药的作用 对组成性激活的5 HT-2A受体的药物将被 测定 预计如果5 HT-2A反向激动剂 活性是非典型药物性质的关键因素， 将在反向激动剂活性和非典型激动剂活性之间发现 抗精神病活性。 为了确定 氯氮平对5 HT-2A受体的反向激动剂活性， 氯氮平和其他非典型抗精神病药物的作用. 5 HT-2C、5 HT-6和5 HT-7的组成型活化形式 将确定受体。 预计这些研究 应该证实或反驳5 HT-2A受体 反向激动剂活性对于非典型抗精神病活性是关键的， 并可能揭示可能涉及的5 HT-2C，5 HT-6或 5 HT-7在非典型药物作用中的作用。 我们还估计到 在药理学的相似性和差异的激活 研究的四种5 HT受体的状态将被揭示：这 这些信息在未来药物开发中可能是重要的， 开发用于治疗目的的反向激动剂。