Conformational structure of some beta 1-blockers, their partitioning in lipid and the role of parasubstituents.

ABSTRACT

The conformational structure of beta1-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 substituent para to the aminoalkanol moiety. The graphical representation of the B1-antagonists for the final conformation reveals that only in the S-form, three interacting sites, namely, aromatic moiety, the beta-hydroxyl group and the -NH2(+) groups of aminoalkanol moiety are available 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 partitioning of the beta-blocker in DMPC and also in octanol/water) and the potencies of these beta1-antagonists. Possibly, the role of para substituent is to act as an anchor by partitioning in the lipid bilayer so that the beta1-antagonist adopts the proper orientation for binding to the receptor.