Inverse agonism and neutral antagonism at α1a- and α1b-adrenergic receptor subtypes
Inverse agonism and neutral antagonism at α1a- and α1b-adrenergic receptor subtypes
复制标题
DOI：
10.1124/mol.56.5.858
复制
发表时间：
1999-11-01
影响因子：
3.6
通讯作者：
Cotecchia, S
中科院分区：
文献类型：
--
作者：
Rossier, O;Abuin, L;Cotecchia, S
我们已经表征了药理学拮抗作用，即，中性拮抗作用或反向激动作用，由多种α-受体阻滞剂在两种α 1-肾上腺素能受体（AR）亚型（α（1a）-和α（1b）-AR）上显示。在与α（1b）-AR的A293同源的位置将组成性激活突变引入α（1a）-AR，其中先前描述了激活突变。最初测试了24种化学结构不同的α-受体阻滞剂对由COS-7细胞中表达的组成型活性A271 E和A293 E突变体介导的激动剂非依赖性磷酸肌醇反应的影响。还测试了选定数量的药物对COS-7细胞中表达的野生型α（1a）-和α（1b）-AR的小但可测量的自发活性的影响。我们的研究结果表明，大量结构不同的α-受体阻滞剂对α（1a）-和α（1b）-AR亚型均显示出显著的负效应。对于其他药物，在不同的组成型活性突变体中，阴性疗效不同。最显著的差异涉及一组N-芳基哌嗪，包括8-[2-[4-（5-氯-2-甲氧基苯基）-1-哌嗪基]乙基]-8-氮杂螺[4，5]癸烷-7，9-二酮（REC 15/3039）、REC 15/2739和REC 15/3011，它们是对野生型α（1b）-AR具有显著负效应的反向激动剂，但对α（1a）-AR没有。
We have characterized the pharmacological antagonism, i.e., neutral antagonism or inverse agonism, displayed by a number of alpha-blockers at two alpha 1-adrenergic receptor (AR) subtypes, alpha(1a)- and alpha(1b)-AR. Constitutively activating mutations were introduced into the alpha(1a)-AR at the position homologous to A293 of the alpha(1b)-AR where activating mutations were previously described. Twenty-four alpha-blockers differing in their chemical structures were initially tested for their effect on the agonist-independent inositol phosphate response mediated by the constitutively active A271E and A293E mutants expressed in COS-7 cells. A selected number of drugs also were tested for their effect on the small, but measurable spontaneous activity of the wild-type alpha(1a)- and alpha(1b)-AR expressed in COS-7 cells. The results of our study demonstrate that a large number of structurally different alpha-blockers display profound negative efficacy at both the alpha(1a)- and alpha(1b)-AR subtypes. For other drugs, the negative efficacy varied at the different constitutively active mutants. The most striking difference concerns a group of N-arylpiperazines, including 8-[2-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (REC 15/3039), REC 15/2739, and REC 15/3011, which are inverse agonists with profound negative efficacy at the wild-type alpha(1b)-AR, but not at the alpha(1a)-AR.