Synthesis and β-adrenergic properties of (Z)-N-[3-(alkylamino)-2-hydroxypropylidene](aryl-methyloxy)amines:: Effects of the configuration around the methyloxyiminomethyl (MOIM) double bond on the biopharmacological properties of MOIM-type β-blocking agents

The N-isopropyl- (3a-g) and N-tert-butyl-substituted (4a-g) (Z)-N-(3-(amino)-2-hydroxypropylidene)(arylmethyloxy)amines were synthesized in order to compare their beta(1)- and beta(2)-adrenergic properties with those of their previously studied corresponding analogues with the E configuration (la-g and 2a-g). Compounds 3 and 4 were tested for their affinity for beta(1)- and beta(2)-adrenoceptors by radioligand binding experiments, and the compounds with the highest affinity were also assayed for their activity towards the same types of beta-adrenoceptors by functional tests on isolated preparations. The Z-methyloxyiminomethyl (Z-MOIM) compounds 3 and 4 proved to possess, on the whole, affinity (K-i) and activity (pIC(50)) indices similar to those of the E isomers 1 and 2, thus indicating that for the MOIM-type beta-adrenergic antagonists 1-4, the type of configuration around the MOIM double bond does not have any appreciable effect either on the affinity or on the activity towards beta-adrenoceptors. These results are rationalized on the basis of the steric and electronic analogies existing between the MOIM groups of 1-4 in the two types of configurations (E and Z). (C) 1998 Elsevier Science Ltd. All rights reserved.