CONFORMATIONAL STRUCTURE OF SOME BETA(1)-BLOCKERS, THEIR PARTITIONINGIN LIPID AND THE ROLE OF PARASUBSTITUENTS

The conformational structure of beta(1)-blockers metoprolol, atenolol and practolol has been investigated by PCILO method. The aminoalkanol moiety adopts the same conformation in all these compounds. These beta -antagonists differ only in the conformation adopted by the substituen t para to the aminoalkanol moiety. The graphical representation of the beta(1)-antagonists for the final conformation reveals that only in t he S-form, three interacting sites, namely, aromatic moiety, the beta- hydroxyl group and the -NH2+ groups of aminoalkanol moiety are availab le for interactions with the receptor. The interaction of the aryloxy oxygen of the beta-antagonists with water molecule has also been taken into account. A linear relationship was obtained between log K (the p artitioning of the beta-blocker in DMPC and also in octanol/water) and the potencies of these beta(1)-antagonists. Possibly, the role of par a substituent is to act as an anchor by partitioning in the lipid bila yer so that the beta(1)-antagonist adopts the proper orientation for b inding to the receptor.