Cardioselectivity as a function of molecular structure in beta-adrenoceptor blocking agents of the...

The relationship between molecular structure and cardioselectivity is described in the 1-(para-substituted aryl-oxy)-3-(isoprophylamino)propan-2-ol type of beta-adrenoceptor blocking agents. Cardioselectivity in the aforementioned series requires that the aromatic substitution in the position para to the amino alcohol side chain will have a minimal linear length of 5.0 A. Highest cardioselectivity is obtained when this para substituent is a rigid group coplanar with the aromatic ring. This may result from steric hindrance for binding at the beta2-adrenoceptor subtype which does not occur in the beta1 subtype. Evidence in favor of this suggestion was obtained by the finding that the trans isomer of 1-[4-(1-propenyl)-2-methoxyphenoxy]-3-(isopropylamino)propan-2-ol is cardioselective (beta1/beta2 = 25), whereas the cis isomer is beta2 selective (beta1/beta2 = 0.1).