ACTIVATION OF THE 5-HT1C RECEPTOR EXPRESSED IN XENOPUS OOCYTES BY THE BENZAZEPINES SCH-23390 AND SKF-38393
ACTIVATION OF THE 5-HT1C RECEPTOR EXPRESSED IN XENOPUS OOCYTES BY THE BENZAZEPINES SCH-23390 AND SKF-38393
复制标题
DOI：
10.1111/j.1476-5381.1991.tb12546.x
复制
发表时间：
1991-12-01
影响因子：
7.3
通讯作者：
KEBABIAN, JW
中科院分区：
文献类型：
--
作者：
BRIGGS, CA;POLLOCK, NJ;KEBABIAN, JW
1利用非洲爪蟾卵母细胞中表达的克隆的5-HT 1C受体来表征四种多巴胺D1选择性苯并氮杂卓对5-HT 1C受体的作用。 此外，在猪的脉络丛中测量了D1-选择性苯并氮杂卓与5-HT 1C受体的表观结合。2在表达克隆的5-HT 1C受体的电压钳位卵母细胞中，5-羟色胺（5-HT）引起特征性内向电流反应，EC 50为13 nM。 SCH 23390是一种立体选择性激动剂（或部分激动剂），EC 50约为550 nM。 SKF 38393（1 μ M-1 mM）、SKF 77434（100 μ M）和SKF 82958（100 μ M）也可作为克隆的5-HT 1C受体的激动剂（或部分激动剂）。 SKF 38393对5-HT 1C受体没有立体选择性。3对SCH 23390的反应激活缓慢，尽管反应包含磷脂酰肌醇信号转导系统激活的许多振荡特征，但SCH 23390很少引起5-HT反应中常见的快速尖峰样反应。 然而，对SKF 38393、SKF 77434和SKF 82958的反应在外观上与对5-HT的反应相同，只是对苯并氮杂卓的反应较小。 通过对表达克隆的5-HT 1C受体的各单个卵母细胞同时应用苯并氮杂卓和5-HT进行这些比较。4与卵母细胞中测量的反应一致，SCH 23390立体选择性结合猪脉络丛中的5-HT 1C受体（K（i）= 6.3 nM），和SKF 38393以较低的亲和力（K（i）= 2.0-2.2 μ M）非立体选择性地结合。5可以得出结论：虽然这些苯并氮杂卓表现出对多巴胺D1受体的选择性，它们还可以作为5-HT 1C受体的激动剂或部分激动剂在原位和在爪蟾卵母细胞中表达。 卵母细胞表达系统可用于研究这些5-HT 1C受体的功能药理学。 多巴胺和5-HT受体之间的立体选择性的药理作用和变化的信息应该是感兴趣的建模配体与这些G-蛋白偶联受体的相互作用，并在测试这样的模型通过受体诱变。
1 A cloned 5-HT1C receptor expressed in Xenopus laevis oocytes was used to characterize the action of four dopamine D1-selective benzazepines at the 5-HT1C receptor. Additionally, the apparent binding of the D1-selective benzazepines to 5-HT1C receptors was measured in the choroid plexus of the pig.2 In voltage-clamped oocytes expressing the cloned 5-HT1C receptor, 5-hydroxytryptamine (5-HT) elicited a characteristic inward current response with an EC50 of 13 nM. SCH 23390 acted as a stereoselective agonist (or partial agonist) with an EC50 of about 550 nM. SKF 38393 (1-mu-M-1 mM), SKF 77434 (100-mu-M), and SKF 82958 (100-mu-M) also acted as agonists (or partial agonists) at the cloned 5-HT1C receptor. SKF 38393 was not stereoselective at the 5-HT1C receptor.3 The response to SCH 23390 activated slowly and, although the response contained many oscillations characteristic of the activation of the phosphatidylinositol signal transduction system, SCH 23390 rarely elicited the rapid spike-like response seen routinely in response to 5-HT. However, the responses to SKF 38393, SKF 77434, and SKF 82958 were identical in appearance to the response to 5-HT, except that the responses to the benzazepines were smaller. These comparisons were made by applying both a benzazepine and 5-HT to each individual oocyte expressing the cloned 5-HT1C receptor.4 Consistent with the responses measured in oocytes, SCH 23390 bound stereoselectively to 5-HT1C receptors in the choroid plexus of the pig (K(i) = 6.3 nM), and SKF 38393 bound non-stereoselectively with lower affinity (K(i) = 2.0-2.2-mu-M).5 It is concluded that while these benzazepines demonstrate selectivity for the dopamine D1 receptor, they also can act as agonists or partial agonists at the 5-HT1C receptor in situ and as expressed in Xenopus oocytes. The oocyte expression system is useful for studies of the functional pharmacology of these 5-HT1C receptors. Information about the pharmacological actions and variations in stereoselectivity among dopamine and 5-HT receptors should be of interest in modelling the interactions of ligands with these G-protein coupled receptors, and in the testing of such models through receptor mutagenesis.