CONSTITUTIVELY ACTIVE SEROTONIN RECEPTORS

描述(由申请人提供)：我们已经证明氯氮平和 利培酮，非典型抗精神病药物，具有强大的反向激动剂 大鼠5SHT2a和5SHT2a的成分激活突变(CAM)形式的性质 5HT2C受体。反向激动剂活性可能是 抗精神病药物，给出修正的G-蛋白三元复合体模型 偶联受体(GPCR)，它预测了一种稳定的激活水平 受体在没有配体刺激的情况下。关于的进一步研究 抗精神病药物对氯氮平敏感的人SHT CAM形式的作用 受体是决定反向激动剂活性是否是关键的关键 非典型抗精神病药物的财产。为了将研究扩展到 人类5HT6和5HT7受体我们已经尝试制作这些受体的CAM形式 通过突变GPCR构成的两个已知区域来识别受体 活动。涉及这些区域突变的初步实验已经产生了 受体的形式要么缺乏强健的结构性活性，要么产生 受体(5HT6)的明显零突变形式。虽然这些结果已经 抗精神病药物反向激动剂活性测定进展缓慢 这些受体上的药物开辟了有趣的研究途径 GPCR家族和5-羟色胺受体内结构的变异性 很特别。 因此，我们建议追求三个具体目标：1)我们将继续测试 典型和非典型抗精神病药物在人类CAM形式的5HT2a和 5HT2C受体；2)我们将继续突变人类5HT6和5HT7 受体产生这些受体的CAM形式并测试抗精神病药物 对于这些受体的反向激动剂活性；3)我们将检查 对氯氮平敏感的5-羟色胺受体细胞的结构性激活 以及反向激动剂对人口贩运的影响 突变的受体。这些研究的结果应该会揭示角色的反转 抗精神病药物的激动剂活性在非典型特性中发挥作用 氯氮平，并可能表明一个或多个 氯氮平非典型特性中的氯氮平敏感受体。这 信息应该对设计新一代非典型 抗精神病药物具有氯氮平独特的抗精神病特性，但 没有有害的血液学影响。有关以下内容的信息 CAM受体的细胞处理的改变也应该是即将到来的， 包括有关分子结构域的信息 间隔化，被认为在细胞受体中起关键作用 敏感状态。

DESCRIPTION (provided by applicant): We have shown that clozapine and risperidone, atypical antipsychotic drugs, have potent inverse agonist properties at constitutively activated mutant (CAM) forms of the rat 5SHT2A and 5HT2C receptors. Inverse agonist activity may be a significant property of antipsychotic drugs, given the revised ternary complex model of G-protein coupled receptors (GPCR), which predicts a steady-state level of activation of receptors in the absence of ligand stimulation. Further studies of antipsychotic drug actions at CAM forms of clozapine-sensitive human SHT receptors are necessary to determine if inverse agonist activity is a key property of atypical antipsychotic drugs. In order to expand the studies to the human 5HT6 and 5HT7 receptors we have attempted to make CAM forms of these receptors by mutating two well-documented regions of GPCR constitutive activity. Initial experiments involving mutations in these areas have produced forms of the receptor either lacking robust constitutive activity or producing apparently null mutant forms of the receptor (5HT6). While these results have slowed progress on determining the inverse agonist activity of antipsychotic drugs on these receptors they open up interesting avenues of research on the variability in structure within the GPCR family and within 5HT receptors in particular. Therefore we propose to pursue three specific aims: 1) we will continue to test typical and atypical antipsychotic drugs at human CAM forms of the 5HT2A and 5HT2C receptors; 2) we will continue to mutate the human 5HT6 and 5HT7 receptors to produce CAM forms of these receptors and test antipsychotic drugs for inverse agonist activity at these receptors; 3) we will examine effects of constitutive activation on clozapine-sensitive 5HT receptor cellular trafficking, and the effects of inverse agonists on the trafficking of the mutated receptors. The results of these studies should reveal the role inverse agonist activity of antipsychotic drugs plays in the atypical properties of clozapine, and may indicate a major role for one or more of the clozapine-sensitive receptors in the atypical properties of clozapine. This information should be very helpful in designing a new generation of atypical antipsychotic drugs sharing clozapine's unique antipsychotic properties, but lacking its deleterious hematological effects. Information concerning alterations in cellular processing of CAM receptors should also be forthcoming, including information on the molecular domains involved in directing cellular compartmentalization, believed to play a key role in cellular receptor sensitivity states.