CONSTITUTIVELY ACTIVE SEROTONIIN RECEPTORS

典型非典型药物氯氮平的作用机制 抗精神病药物，一直是密集研究的目标 在揭示这种药物的关键属性时，它允许它具有 与更经典的药物相比，抗精神病药物的活性更高 抗精神病药物。有证据表明，氯氮平的药效很高 与5HT-2A受体的亲和力相互作用可能是一个关键因素。 此外，氯氮平对5-羟色胺-2C、5-羟色胺-6和 5羟色胺-7受体。直到最近，人们还一直认为 氯氮平是5HT-2A的经典竞争性拮抗剂 受体。不过，这项提案中的初步数据显示， 氯氮平是一种成分激活形式的反向激动剂。 通过定点突变产生的5-羟色胺-2A受体。在……里面 为了探索氯氮平的非典型活性的可能性 可能与其在5-羟色胺-2 A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物的作用 在结构性激活的5HT-2A受体上的药物将是 下定决心。预计如果5HT-2A反向激动剂 活性是非典型药物特性的关键因素，这种相关性 会发现在反向激动剂活性和非典型 抗精神病活性。为了确定该病毒的特异性 氯氮平在5-羟色胺-2A受体上的反向激动剂活性 氯氮平等非典型抗精神病药物的临床疗效 5-羟色胺-2C、5-羟色胺-6和5-羟色胺-7的构成活性形式 受体将被确定。预计这些研究 应该证实或驳斥5HT-2A受体的假说 反向激动剂活性是非典型抗精神病药物活性的关键， 并可能揭示5HT-2C、5HT-6或 5HT-7在非典型药物作用中的作用。还预计， 激动剂药理作用的异同 被研究的四种5-羟色胺受体的状态将被揭示：这 信息在未来的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。

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.