CGP 20712 dihydrochloride

CGP 20712 dihydrochloride is a potent and selective antagonist of β1-adrenoceptor with IC50 value of 0.7 nM [1].

β1-adrenoceptor is a G-protein coupled receptor and mediates uncoupling protein-1 (UCP1) gene expression induced by norepinephrine (NE) [2].

CGP 20712 dihydrochloride is a potent and selective β1-adrenoceptor antagonist. In neocortical membranes, CGP 20712 A exhibited affinity for β1-adrenoceptor and β2-adrenoceptor with IC50 values of 0.7 and 6700 nM, respectively [1]. In brown adipocytes, CGP-20712A significantly inhibited UCP1 gene expression induced by NE. However, CGP-20712A had no effect on lipolysis. These results suggested that β1-adrenoceptor mediated UCP1 gene expression [2]. In ventricular membranes from rats, CGP 20712A (300 nM) completely occupied its high-affinity binding sites. In ventricular myocytes isolated from rats, CGP 20712A (10, 100, 1000 nM) didn’t cause the activation of adenylate cyclase mediated by β2-adrenoceptors, which suggested that β2-adrenoceptors were not present on rat ventricular myocytes [3]. In adult rat cardiac myocytes, CGP 20712A inhibited β1-AR-stimulated apoptosis, which was mediated by a cAMP-dependent mechanism [4].

References:
[1].  Dooley DJ, Bittiger H, Reymann NC. CGP 20712 A: a useful tool for quantitating beta 1- and beta 2-adrenoceptors. Eur J Pharmacol, 1986, 130(1-2): 137-139.
[2].  Chaudhry A, Granneman JG. Differential regulation of functional responses by beta-adrenergic receptor subtypes in brown adipocytes. Am J Physiol, 1999, 277(1 Pt 2): R147-153.
[3].  Kitagawa Y, Adachi-Akahane S, Nagao T. Determination of beta-adrenoceptor subtype on rat isolated ventricular myocytes by use of highly selective beta-antagonists. Br J Pharmacol. 1995, 116(1): 1635-1643.
[4].  Communal C, Singh K, Sawyer DB, et al. Opposing effects of beta(1)- and beta(2)-adrenergic receptors on cardiac myocyte apoptosis : role of a pertussis toxin-sensitive G protein. Circulation, 1999, 100(22): 2210-2212.

Determination of beta-adrenoceptor subtype on rat isolated ventricular myocytes by use of highly selective beta-antagonists.[Pubmed:8564230]

Br J Pharmacol. 1995 Sep;116(1):1635-43.

1. The relative proportions of beta 1- and beta 2-adrenoceptors were determined by radioligand binding studies in three different rat myocardial preparations: membranes prepared from rat ventricle (ventricular membranes), membranes prepared from rat isolated ventricular myocytes (myocyte membranes), and myocytes isolated from rat ventricle (myocytes). 2. Competition experiments using CGP 20712A or ICI 118,551 with [125I]-iodocyanopindolol ([125I]-ICYP) revealed high- and low-affinity binding sites in ventricular membranes. The concentration at which each beta-antagonist occupied 100% of its high-affinity binding sites was 300 nM for CGP 20712A (beta 1-adrenoceptor) and 50 nM for ICI 118,551 (beta 2-adrenoceptor). 3. The density of high-affinity (beta 1-adrenoceptor) and low-affinity (beta 2-adrenoceptor) binding sites for CGP 20712A was measured by a saturation experiment using [125I]-ICYP in the presence and absence of 300 nM CGP 20712A. In ventricular membranes, the proportions of high-affinity and low-affinity binding sites for CGP 20712A were 73% and 27%, respectively, whereas in myocyte membranes, the corresponding figures were 90% and 10%, respectively. The density of low-affinity binding sites for CGP 20712A in ventricular membranes, defined as [125I]-ICYP-specific binding in the presence of 300 nM CGP 20712A, was decreased by addition of 50 nM ICI 118,551, whereas that in myocyte membranes was not affected. 4. In myocytes, specific binding of [125I]-ICYP and [3H]-CGP 12177 was not detected by saturation experiments performed in the presence of 300 nM CGP 20712A. 5 In myocytes, the activation of adenylate cyclase caused by beta2-adrenoceptors was not detected in the presence of 10 nM, 100 nM or 1000 nM CGP 20712A, which selectively antagonized beta1-adrenoceptors.Furthermore, the concentration-response curve for isoprenaline-stimulated cyclic AMP accumulation was not shifted by 10 nm or 100 nM ICI 118,551, which selectively antagonized beta2-adrenoceptors, but was shifted to the right by 1000 nM ICI 118,551.6 These results indicate that beta2-adrenoceptors are not present on rat ventricular myocytes and that beta2-adrenoceptor stimulation does not cause any detectable production of cyclic AMP. We conclude that only beta1-adrenoceptors exist on rat ventricular myocytes.

CGP 20712 A: a useful tool for quantitating beta 1- and beta 2-adrenoceptors.[Pubmed:2877892]

Eur J Pharmacol. 1986 Oct 14;130(1-2):137-9.

CGP 20712 A (1-[2-((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]-3- [4-(1-methyl-4-trifluoromethyl-2-imidazolyl) phenoxy]-2-propanol methanesulfonate), a specific beta 1-adrenoceptor antagonist, was tested for resolution of beta 1- and beta 2-adrenoceptors in an in vitro [3H]dihydroalprenolol ([3H]DHA) binding assay. Competition experiments, using rat neocortical and cerebellar membranes, yielded two dissimilar concentration-effect curves. A distinct biphasic curve was evident for neocortex, with a plateau at 100 nM CGP 20712 A (60% [3H]DHA displacement). This plateau indicated a differentiation between beta 1- and beta 2-adrenoceptors; the ratio of IC50-beta 2 to IC50-beta 1 was approximately 10,000. In contrast, only a monophasic curve was obtained for cerebellum. CGP 20712 A is a useful tool for estimating percentages of beta 1- and beta 2-adrenoceptors in a given tissue.