Effects of celiprolol (REV 5320), a new cardioselective beta-adrenoceptor antagonist, on in vitro adenylate cyclase, alpha- and beta-adrenergic receptor binding and lipolysis

Abstract

Celiprolol has been previously shown in vivo to be an effective beta-adrenergic antagonist with cardio-selectivity and weak intrinsic sympathomimetic activity but no membrane stabilizing or 'quinidine-like' effects. With in vitro systems reported here, the following was observed. Against the stimulation of adenylate cyclase from dog ventricular muscle by isoproterenol, celiprolol had a K(i) of 2.6 x 10-7 M which was about 1/20 the potency of propranolol. At 100 μM, celiprolol did not affect histamine or dopamine concentration-response curves for the stimulation of adenylate cyclase from guinea-pig cerebral cortex. By itself, up to 1 mM, celiprolol did not affect basal adenylate cyclase activity from either preparation. With in vitro radioligand binding assays to directly measure beta-adrenergic receptor interactions, celiprolol had K(i) values of 1.4 x 10-7 to 8.3 x 10-6 M. A 35-fold beta1 selectivity was noted with membranes from rat heart vs. rat reticulocytes, which supports previously reported in vivo data on cardioselectivity. No difference in affinity to beta-receptors was noted with frog vs. turkey erythrocyte membranes which supports the contention that these two non-mammalian systems are not predictive of beta1/beta2 specificity with mammalian systems. Celiprolol also showed some selective alpha2-adrenoceptor antagonism against (3H)-yohimbine binding vs. (3H)-prazosin binding to membranes from rat cerebral cortex. With rat adipocytes, up to 300 μM celiprolol did not stimulate basal lipolysis in the presence or absence of 10 μM 1-methyl-3-isobutyl-xanthine. Celiprolol inhibited isoproterenol-induced lipolysis with a potency about 2 times greater than practolol. Unlike propranolol, celiprolol at very high concentrations did not show non-specific inhibition of lipolysis induced with cyclic nucleotides. These and other published data would suggest the following: 1) in vitro beta adrenergic receptor antagonist activity can be demonstrated for celiprolol, 2) cardioselectivity is due to a combination of many factors including stereochemistry of the molecule and in vivo distribution and metabolism, 3) celiprolol does not possess 'non-specific' membrane activity, 4) the 'intrinsic-sympathomimetic activity' of celiprolol is selectively observed in some but not all in vitro test models, 5) celiprolol has about a 10-fold selectivity for alpha2-vs. alpha1-receptors which is relatively unique to beta-antagonists and needs further investigations as to the potential physiological significance.