The β1 and β2‐adrenoceptor affinity and β1‐blocking potency of S‐ and R‐metoprolol

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Abstract
1 The β-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: >99.2% and >99.9%, respectively. 3 The β1- and β2-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 β1) and soleus muscle (β2). The β1-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 β2-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 β1 (about 500) than on β2-adrenoceptors (about 50). The β1-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 β1-selective). 4 In the anaesthetized cat, the (–log) intravenous doses (μmol 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 β1-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 β1-adrenoceptors has a stricter steric requirement than that for the binding of this β-blocker to β2-adrenoceptors. Furthermore, the non-specific cardiodepressive effect of metoprolol was observed at equally high doses for the two enantiomers.