Abstract

Nebivolol [the (S,R,R,R)- + (R,S,S,S)-racemic mixture], the 10 stereoisomers, and known beta-adrenergic blockers were investigated in vitro for binding to beta 1- and beta 2-adrenergic receptor sites and various neurotransmitter, peptide, and ion channel binding sites and for inhibition of neurotransmitter uptake. Selective labeling of beta 1- and beta 2-adrenergic receptor sites in rabbit and rat lung, respectively, was obtained with [3H]CGP-12177 and [3H] dihydroalprenololin the presence of an appropriate concentration of the selective beta 2-adrenergic blocker ICI 118-551 or the selective beta 1-adrenergic blocker CGP 20712-A. Nebivolol revealed high affinity and selectivity for beta 1-adrenergic receptor sites in the rabbit lung membrane preparation (Ki value = 0.9 nM and beta 2/beta 1 ratio = 50). The drug dissociated slowly from these receptor sites. The activity resided in the (S,R,R,R)-enantiomer (R 67 138); the (R,S,S,S)-enantiomer (R 67 145) revealed 175 times lower beta 1-adrenergic binding affinity. Within the series of stereoisomers, nebivolol and R 67 138 showed the best combination of high affinity and selectivity. Among the reference compounds, only CGP 20712-A shared these properties. Nebivolol bound to S1A binding sites with a Ki value of 20 nM. The stereospecific requirements for interaction with these sites were different from those for the beta 1-adrenergic receptor site. S1A binding site affinity was also observed with the potent but nonselective beta-adrenergic blockers carvedilol, pindolol, and propranolol. In the various other investigated radioligand binding and neurotransmitter uptake assays, nebivolol and its stereoisomers showed activity only at micromolar concentrations or were inactive. Clinical studies have shown an interesting hemodynamic profile of nebivolol, offsetting the negative effects on left ventricular performance generally observed with classical beta-adrenergic blockers. Several hypotheses regarding the mechanism of action of nebivolol are summarized.