The beta 1- and beta 2-adrenoceptor affinity and beta 1-blocking potency of S- and R-metoprolol.

1. The beta-adrenoceptor affinity and blocking potency of the two enantiomers and the racemate of metoprolol were investigated in vitro, by use of a receptor-binding technique, and in vivo in the anaesthetized cat. 2. The enantiomeric purity of the S- and R-form was: greater than 99.2% and greater than 99.9%, respectively. 3. The beta 1- and beta 2-adrenoceptor affinity (-log equilibrium dissociation constant) of the enantiomers was determined from competition binding experiments (radioligand: [125I]-(S)-pindolol) performed in membranes prepared from the guinea-pig left ventricular free wall (predominantly beta 1) and soleus muscle (beta 2). The beta 1-adrenoceptor affinity was (means +/- s.d.): 7.73 +/- 0.10 and 5.00 +/- 0.06 for the S- and R-form of metoprolol, respectively. The corresponding values for beta 2-adrenoceptors were 6.28 +/- 0.06 (S) and 4.52 +/- 0.09 (R). Thus, the difference in affinity for the two enantiomers was greater on beta 1- (about 500) than on beta 2-adrenoceptors (about 50). The beta 1-adrenoceptor selectivity of the S-form (about 30) was similar to that of the racemic metoprolol, while the R-form was almost non-selective (3 fold beta 1-selective). 4. In the anaesthetized cat, the (-log) intravenous doses (mumol kg-1) of S- and R-metoprolol causing a 50% reduction (ED50) in the heart rate response to sympathetic nerve stimulation were determined. The doses inducing a 25% depression (DD25) of the basal myocardial contractility were also estimated. For the two enantiomers, the beta 1-blocking potency (-log ED50) was 7.04 +/- 0.16 (S) and 4.65 +/- 0.16 (R). A significant cardiodepressive effect was observed at high doses (-log DD25): 4.18 + 0.20 (S) and 4.08 + 0.10 (R). 5. It is concluded that the binding of metoprolol to beta 1-adrenoceptors has a stricter steric requirement than that for the binding of this beta l-blocker to beta 2-adrenoceptors. Furthermore, the non-specific cardiodepressive effect of metoprolol was observed at equally high doses for the two enantiomers.