Knight A R, Bowery N G
Department of Pharmacology, School of Pharmacy, London, U.K.
Neuropharmacology. 1996 Jun;35(6):703-12. doi: 10.1016/0028-3908(96)84642-9.
GABAB receptor activation inhibits forskolin-stimulated adenylyl cyclase activity but augments noradrenaline-stimulated adenylyl cyclase activity. The present study investigated the pharmacology of these two GABAB 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 (pEC50 = 6.07 +/- 0.29 and 5.04 +/- 0.17, respectively (p < 0.05)), and CGP47656 (pEC50 = 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, CGP45397, CGP36742) were also tested for their ability to antagonize 10 microM (-)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.
GABAB受体激活可抑制福斯高林刺激的腺苷酸环化酶活性，但增强去甲肾上腺素刺激的腺苷酸环化酶活性。本研究调查了这两种由GABAB受体介导的反应的药理学特性。在大鼠脑皮质切片交叉切碎标本中，证实( - )巴氯芬抑制福斯高林刺激的腺苷酸环化酶活性并增强去甲肾上腺素刺激的腺苷酸环化酶活性。还研究了另外五种激动剂（SKF97541、CGP47656、CGP44533、3 - APA和CGP44532）的效力。在这些激动剂中，有两种化合物作为福斯高林刺激的腺苷酸环化酶抑制剂的效力明显高于作为去甲肾上腺素刺激的腺苷酸环化酶活性增强剂的效力，它们是( - )巴氯芬（pEC50分别为6.07±0.29和5.04±0.17（p < 0.05））和CGP47656（pEC50分别为6.44±0.05和4.48±0.26（p < 0.05））。可以通过提出这些化合物具有低内在效力且去甲肾上腺素刺激的腺苷酸环化酶增强具有低受体储备来解释这种效力差异。此外，还测试了六种拮抗剂（CGP49311A、CGP46381、CGP45024 CGP45397、CGP36742）在这两种试验中拮抗10微摩尔( - )巴氯芬的能力。这些拮抗剂作为福斯高林刺激的腺苷酸环化酶活性抑制剂的效力范围从CGP49311A（pEC50 = 5.45±0.30）到CGP36742（pEC50 = 3.87±0.16）。每种拮抗剂在两种试验中的效力相似，表明这两种反应由药理学上相似的受体介导。
