The pharmacology of adenylyl cyclase modulation by GABA(B) receptors in rat brain slices
The pharmacology of adenylyl cyclase modulation by GABA(B) receptors in rat brain slices
复制标题
DOI：
10.1016/0028-3908(96)84642-9
复制
发表时间：
1996-06-01
影响因子：
4.7
通讯作者：
Bowery, NG
中科院分区：
文献类型：
--
作者：
Knight, AR;Bowery, NG
GABA(B)受体激活抑制Forsklin刺激的腺酰环化酶活性，但增强去甲肾上腺素刺激的腺酰环化酶活性。本研究对这两种GABA(B)受体介导的反应进行了药理学研究。在交叉切碎的大鼠皮质切片制剂中，(-)巴氯芬被证实抑制了Forsklin刺激的腺酰环化酶活性，增强了去甲肾上腺素刺激的腺酰环化酶活性。对另外5种激动剂(SKF97541、CGP47656、CGP44533、3-APA和CGP44532)的效力进行了研究。在这些激动剂中，有两个化合物对Forsklin刺激的腺酰环化酶有明显的抑制作用，而对去甲肾上腺素刺激的腺酰环化酶有明显的增强作用，它们是(-)巴氯芬(PEC(50)=6.07+/-0.29和5.04+/-0.17(p<；0.05))和CG47656(PEC(50)=6.44+/-0.05和4.48+/-0.26(p<；0.05))。有可能解释这种效力的差异，提出这些化合物具有较低的内在效力，并且去甲肾上腺素刺激的腺酰环化酶的增强具有较低的受体储备。此外，还测定了6种拮抗剂(CGP49311A、CGP46381、CGP45024、CGP35348、CGP45397、CGP36742)对30亩M(-)巴氯芬的拮抗能力。从CGP49311A(pEC50=5.45+/-0.30)到CGP36742(pEC50=3.87+/-0.16)。每种拮抗剂在两种测定中都有相似的效力，表明这两种反应是由药理上相似的受体介导的。版权所有(C)1996爱思唯尔科学有限公司。
GABA(B) receptor activation inhibits forskolin-stimulated adenylyl cyclase activity but augments noradrenaline-stimulated adenylyl cyclase activity. The present study investigated the pharmacology of these two GABA(B) receptor mediated responses. In a cross-chopped rat cortical slice preparation, it was confirmed that (-)baclofen inhibited forskolin-stimulated adenylyl cyclase activity and augmented noradrenaline-stimulated adenylyl cyclase activity. The potency of five further agonists was investigated (SKF97541, CGP47656, CGP44533, 3-APA and CGP44532). Of these agonists two compounds were significantly more potent as inhibitors of forskolin-stimulated adenylyl cyclase than as augmenters of noradrenaline-stimulated adenylyl cyclase activity, these were (-)baclofen (PEC(50) = 6.07 +/- 0.29 and 5.04 +/- 0.17, respectively (p < 0.05)), and CG47656 (PEC(50) = 6.44 +/- 0.05 and 4.48 +/- 0.26, respectively (p < 0.05)). It is possible to explain this difference in potency by proposing that these compounds have low intrinsic efficacy, and the augmentation of noradrenaline-stimulated adenylyl cyclase has a low receptor reserve. In addition six antagonists (CGP49311A, CGP46381, CGP45024, CGP35348, CGP45397, CGP36742) were also tested for their ability to antagonize 30 mu M (-)baclofen in these two assays. These antagonists ranged in potency as inhibitors of forskolin-stimulated adenylyl cyclase activity from CGP49311A (pEC50 = 5.45 +/- 0.30) to CGP36742 (pEC50 = 3.87 +/- 0.16). Each antagonist had similar potency in the two assays, suggesting that these two responses are mediated by pharmacologically similar receptors. Copyright (C) 1996 Elsevier Science Ltd.