Modeling, design, chiral aspects and role of para-substituents in aryloxypropranolamine based beta-blockers

The conformation of the beta-blockers viz. metoprolol, atenolol, bisoprolol, betaxolol and celiprolol has been investigated using Perturbative Configuration Interaction of Localized Orbitals (PCILO) method. The conformational energy maps have been constructed for both the enantiomers (R and S) by rotating the molecule from the para-substituent end. The aryloxypropranolamine moiety adopts the same conformation for all antagonists. The graphical view of R- and S- form of these antagonists in the lowest energy conformation reveals that it is only in the S- form of beta-blockers, all the three functionalities--aromatic moiety, amino and beta-hydroxyl groups are available for interaction with beta-adrenoceptors. The para-substituents of the beta-blockers adopt a conformation which is perpendicular to the aryloxy moiety resulting in an L-shaped structure. The beta-antagonists possibly partition into the lipid bilayer through the para-substituents and the aryloxypropranolamine moiety containing the functionalities, thus, lies parallel to the plane of lipid bilayer for interaction with beta-adrenoceptors. Superimposition of S-bisoprolol in lowest energy conformation with the 3rd putative transmembranous segment of the beta-adrenoceptors reveals that the aromatic moiety, amino and beta-hydroxyl groups of antagonists are involved in interaction with the side chains of Trp-109, Asp-113 and Thr-110 respectively. This has been further substantiated by the interaction studies on the model systems.