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

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 Ki of 2.6 X 10(-7) M which was about 1/20 the potency of propranolol. At 100 microM, 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 Ki values of 1.4 X 10(-7) to 8.3 X 10(-6) M. A 35-fold beta 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 microM celiprolol did not stimulate basal lipolysis in the presence or absence of 10 microM 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: in vitro beta adrenergic receptor antagonist activity can be demonstrated for celiprolol, cardioselectivity is due to a combination of many factors including stereochemistry of the molecule and in vivo distribution and metabolism, celiprolol does not possess "non-specific" membrane activity, the "intrinsic-sympathomimetic activity" of celiprolol is selectively observed in some but not all in vitro test models, celiprolol has about a 10-fold selectivity for alpha 2-vs. alpha 1-receptors which is relatively unique to beta-antagonists and needs further investigations as to the potential physiological significance.