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The β 1 and β 2 ‐adrenoceptor affinity and β 1 ‐blocking potency of S‐ and R‐metoprolol
Author(s) -
Wahlund Göran,
Nerme Viveca,
Abrahamsson Tommy,
Sjöquist PerOve
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb12974.x
Subject(s) - potency , pindolol , metoprolol , enantiomer , chemistry , propranolol , dissociation constant , radioligand , receptor , in vivo , stereochemistry , pharmacology , medicine , endocrinology , in vitro , biology , biochemistry , microbiology and biotechnology
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 β 1 ‐ and β 2 ‐adrenoceptor affinity (–log equilibrium dissociation constant) of the enantiomers was determined from competition binding experiments (radioligand: [ 125 I ]‐( S )‐pindolol) performed in membranes prepared from the guinea‐pig left ventricular free wall (predominantly β 1 ) and soleus muscle (β 2 ). The β 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 β 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 β 1 (about 500) than on β 2 ‐adrenoceptors (about 50). The β 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 β 1 ‐selective). 4 In the anaesthetized cat, the (–log) intravenous doses (μmol kg −1 ) of S ‐ and R ‐metoprolol causing a 50% reduction (ED 50 ) in the heart rate response to sympathetic nerve stimulation were determined. The doses inducing a 25% depression (DD 25 ) of the basal myocardial contractility were also estimated. For the two enantiomers, the β 1 ‐blocking potency (‐log ED 50 ) was 7.04 ± 0.16 (S) and 4.65 ± 0.16 ( R ). A significant cardiodepressive effect was observed at high doses (‐log DD 25 ): 4.18 ± 0.20 ( S ) and 4.08 ± 0.10 ( R ). 5 It is concluded that the binding of metoprolol to β 1 ‐adrenoceptors has a stricter steric requirement than that for the binding of this β‐blocker to β 2 ‐adrenoceptors. Furthermore, the non‐specific cardiodepressive effect of metoprolol was observed at equally high doses for the two enantiomers.