Cardioselectivity as a Function of Molecular Structure in β-Adrenoceptor Blocking Agents of the 1-(Para-substituted aryloxy)-3-(isopropylamino)propan-2-ol Type

The relationship between molecular structure and cardioselectivity is described in the l-(para-substituted aryloxy)-3-(isopropylamino)propan-2-ol type of β-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 Å. 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 β-adrenoceptor subtype which does not occur in the β1 subtype. Evidence in favor of this suggestion was obtained by the finding that the trans isomer of l-[4-(l-propenyl)-2-methoxyphenoxy]-3-(isopropylamino)propan-2-ol is cardioselective (β1/β2 = 25), whereas the cis isomer is β2 selective (β1/β2 = 0.1).