Agonist actions of "β-blockers" provide evidence for two agonist activation sites or conformations of the human β1-adrenoceptor
Agonist actions of "β-blockers" provide evidence for two agonist activation sites or conformations of the human β1-adrenoceptor
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DOI：
10.1124/mol.63.6.1312
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发表时间：
2003-06-01
影响因子：
3.6
通讯作者：
Hill, SJ
中科院分区：
文献类型：
--
作者：
Baker, JG;Hall, IP;Hill, SJ
以前对4-[3-[(1，1-二甲基乙基)氨基]2-羟丙氧基]1，3-二氢-2H-苯并咪唑-2-酮(CGP 12177)的研究表明，人的β(1)-肾上腺素受体有两种不同的激动剂构象：1)经典激动剂(儿茶酚胺)和β-拮抗剂作用；2)CGP 12177是激动剂，相对抵抗β-肾上腺素能受体拮抗剂的抑制。在本研究中，我们利用cAMP反应元件调节基因转录的研究来证实这两个β(1)-肾上腺素受体位点/构象的存在，并提供强有力的证据表明，一系列临床使用的β-肾上腺素能受体阻滞剂(β-受体阻滞剂)在这两个部位显示出不同的激动剂和/或拮抗剂作用。[2-(3-Carbamoyl-4-hydroxyphenoxy)-ethylamino]-3[4-(1-methyl-4-trifluormethyl-2-imidazolyl)-phenoxy]-2-propanolmethanesulphonate(CGP20712A)和阿替洛尔是儿茶酚胺结合位点的经典拮抗剂，但对次级CGP20712A位点的亲和力要低得多。CgP 12177和卡维地洛是儿茶酚胺位点的有效拮抗剂，但在较高浓度时通过次级拮抗剂抗性位点介导对基因转录的实质性激动剂作用。然而，β-受体阻滞剂的兴奋作用并不局限于这个次要部位，我们发现一些(特别是乙酰丁洛尔和拉贝洛尔)主要通过儿茶酚胺部位起作用，而另一些(吲哚洛尔和阿普洛尔)可以同时刺激两者。因此，临床上看到的对β受体阻滞剂的不同反应可能部分是由这些β受体激动剂反应和两个部位或构象的不同激活引起的。
Previous work with 4-[3-[(1,1-dimethylethyl) amino] 2-hydroxypropoxy]1,3- dihydro-2H-benzimidazol-2-one (CGP 12177) has led to the suggestion that there are two different agonist conformations of the human beta(1)-adrenoceptor: 1) where classic agonists (catecholamines) and beta-antagonists act, and 2) where CGP 12177 is an agonist and relatively resistant to inhibition by beta-adrenoceptor antagonists. In the present study, we have used studies of cAMP response element-regulated gene transcription to confirm the presence of these two beta(1)-adrenoceptor sites/ conformations and to provide strong evidence that a range of clinically used beta-adrenoceptor blockers (beta-blockers) exhibit differential agonists and/or antagonist actions at the two sites. [2-(3-Carbamoyl-4-hydroxyphenoxy)-ethylamino]-3[ 4-(1-methyl-4-trifluormethyl-2-imidazolyl)-phenoxy]-2-propanolmethanesulphonate (CGP 20712A) and atenolol act as classic antagonists at the catecholamine binding site but have much lower affinity for the secondary CGP 12177 site. CGP 12177 and carvedilol are potent antagonists at the catecholamine site but mediate substantial agonist actions on gene transcription via the secondary antagonist-resistant site at higher concentrations. Agonist effects of beta-blockers are not, however, confined to this secondary site, and we show that some ( particularly acebutolol and labetolol) act primarily via the catecholamine site, whereas others ( pindolol and alprenolol) can stimulate both. The different responses to beta-blockers seen in the clinic may therefore be caused in part by these beta-blocker agonist responses and the differential activation of the two sites or conformations.