Nipradilol displays a unique pharmacological profile of affinities for the different alpha 1-adrenoceptor subtypes

The selectivity of antagonistic effects of nipradilol, its four isomers and denitronipradilol, a major metabolite of nipradilol, on alpha 1-adrenoceptor subtypes in rat heart, brain and spleen were examined by radioligand binding assay with [3H]-prazosin. Pharmacological characteristics of these compounds were determined in isolated aortae from rats and guinea pigs. The order of the pKi values for alpha 1High-affinity sites in the heart, spleen and brain was SR > nipradiolol > or = RR > or = SS-RS >> denitronipradilol, but the order of the pKi values for the alpha 1Low-affinity sites was different in the heart and brain. There were good correlations between the pKi values of these compounds for the alpha 1High-affinity sites and the pA2 values for the contractile inhibition of the phenylephrine-induced response in rat aorta. There was no correlation between the pKi values of these compounds for the alpha 1Low-affinity sites and the pA2 values. These results indicate that: 1) alpha 1High-Affinity sites are related to vasoconstriction mediated by alpha 1-adrenoceptors; 2) Nipradilol and its isomers possess low affinity to alpha 1-adrenoceptors; and 3) The nitroxy group in nipradilol is important for its alpha 1-blocking activity.