Creation of a constitutively activated state of the 5-HT2A receptor by site-directed mutagenesis:: Revelation of inverse agonist activity of antagonists
Creation of a constitutively activated state of the 5-HT2A receptor by site-directed mutagenesis:: Revelation of inverse agonist activity of antagonists
复制标题
DOI：
10.1111/j.1749-6632.1998.tb10184.x
复制
发表时间：
1998-01-01
期刊：
影响因子：
--
通讯作者：
Teitler, M
中科院分区：
文献类型：
--
作者：
Egan, C;Herrick-Davis, K;Teitler, M
组成活性的GPCR揭示了药物的新特性，这些药物在GPCR的天然形式下表现出经典的竞争拮抗作用，这些药物逆转了组成活性的基础水平，表明它们具有逆激动剂活性。我们感兴趣的是确定天然5-HT2A受体的竞争性拮抗剂，特别是抗精神病药物，是否在构成活性的5-HT2A受体上表现出相反的激动剂活性。所有测试的药物都降低了组成活性5-HT2A受体的基础IP产生，表明它们都表现出逆激动剂活性。利培酮和酮色林对基础IP产生的抑制作用最大，导致C322K突变受体的基础活性降低82%和80%。分别。抗精神病药物显示出反向激动剂活性，表明稳定5-HT2A受体的非活性构象是其作用机制的关键组成部分。
Constitutively active GPCR have revealed novel properties of drugs that exhibit classical competitive antagonism at the native forms of GPCR, These drugs reverse basal levels of constitutive activity, indicating that they have inverse agonist activity. We were interested in determining if competitive antagonists of the native 5-HT2A receptor, in particular, antipsychotic drugs, exhibit inverse agonist activity at the constitutively active 5-HT2A receptor. All of the drugs tested reduced basal IP production of constitutively active 5-HT2A receptors, indicating that they all exhibited inverse agonist activity. Risperidone and ketanserin produced the greatest inhibition of basal IP production resulting in a reduction of basal activity in the C322K mutant receptor of 82% and 80%. respectively. Antipsychotic drugs display inverse agonist activity, indicating that stabilization of the inactive conformation of the 5-HT2A receptor map be a key component of their mechanism of action.