The Beta 1- and Beta 2-adrenoceptor Affinity and Beta 1-blocking Potency of S- and R-metoprolol

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 1990 Mar 1

PMID 1970503

Citations 6

Authors

G Wahlund

V Nerme

T Abrahamsson

P O Sjoquist

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Development of a sensitive and rapid method for quantitation of ()-(-)- and ()-(+)-metoprolol in human plasma by chiral LC-ESI-MS/MS.

Sharma P, Contractor P, Guttikar S, Patel D, Shrivastav P J Pharm Anal. 2018; 4(1):63-79.

PMID: 29403869 PMC: 5761053. DOI: 10.1016/j.jpha.2013.02.008.

Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients.

Antunes N, Cavalli R, Marques M, Moises E, Lanchote V Br J Clin Pharmacol. 2014; 79(4):605-16.

PMID: 25291152 PMC: 4386945. DOI: 10.1111/bcp.12523.

The design, synthesis and pharmacological characterization of novel β₂-adrenoceptor antagonists.

Hothersall J, Black J, Caddick S, Vinter J, Tinker A, Baker J Br J Pharmacol. 2011; 164(2):317-31.

PMID: 21323900 PMC: 3174413. DOI: 10.1111/j.1476-5381.2011.01269.x.

Influence of metoprolol dosage release formulation on the pharmacokinetic drug interaction with paroxetine.

Stout S, Nielsen J, Welage L, Shea M, Brook R, Kerber K J Clin Pharmacol. 2010; 51(3):389-96.

PMID: 20400652 PMC: 3006004. DOI: 10.1177/0091270010365559.

Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties. A study of metoprolol.

Kaila T, Roivas L, Neuvonen P Eur J Clin Pharmacol. 1994; 46(3):237-42.

PMID: 8070504 DOI: 10.1007/BF00192555.

References

Danilewicz J, Kemp J . Absolute configuration by asymmetric synthesis of (+)-1-(4-acetamidophenoxy)-3-(isopropylamino)-propan-z-ol (practolol). J Med Chem. 1973; 16(2):168-9. DOI: 10.1021/jm00260a020. View

El Tayar N, Testa B, van de Waterbeemd H, Carrupt P, Kaumann A . Influence of lipophilicity and chirality on the selectivity of ligands for beta 1- and beta 2-adrenoceptors. J Pharm Pharmacol. 1988; 40(9):609-12. DOI: 10.1111/j.2042-7158.1988.tb05319.x. View

Ablad B, Carlsson B, Carlsson E, Dahlof C, Ek L, Hultberg E . Cardiac effects of beta-adrenergic receptor antagonists. Adv Cardiol. 1974; 12(0):290-302. DOI: 10.1159/000395473. View

Harry J, Linden R, Snow H . The effects of three beta-adrenoceptor blocking drugs on isolated preparations of skeletal and cardiac muscle. Br J Pharmacol. 1974; 52(2):275-81. PMC: 1776866. DOI: 10.1111/j.1476-5381.1974.tb09710.x. View

Patil P, Miller D, Trendelenburg U . Molecular geometry and adrenergic drug activity. Pharmacol Rev. 1974; 26(4):323-92. View

Toda N, Hayashi S, Hatano Y, Okunishi H, Miyazaki M . Selectivity and steric effects of metoprolol isomers on isolated rabbit atria, arteries and tracheal muscles. J Pharmacol Exp Ther. 1978; 207(2):311-9. View

Bryan L, Cole J, ODonnell S, Wanstall J . A study designed to explore the hypothesis that beta-1 adrenoceptors are "innervated" receptors and beta-2 adrenoceptors are "hormonal" receptors. J Pharmacol Exp Ther. 1981; 216(2):395-400. View

Harron D, Balnave K, Kinney C, Wilson R, Russell C, Shanks R . Effects on exercise tachycardia during forty-eight hours of a series of doses of atenolol, sotalol, and metoprolol. Clin Pharmacol Ther. 1981; 29(3):295-302. DOI: 10.1038/clpt.1981.39. View

Wachter W, Munch U, Lemoine H, Kaumann A . Evidence that (+)-bupranolol interacts directly with myocardial beta-adrenoceptors. Control of optical purity with differential thermal analysis. Naunyn Schmiedebergs Arch Pharmacol. 1980; 313(1):1-8. DOI: 10.1007/BF00505796. View

10.

Lemoine H, Kaumann A . A model for the interaction of competitive antagonists with two receptor-subtypes characterized by a Schild-plot with apparent slope unity. Agonist-dependent enantiomeric affinity ratios for bupranolol in tracheae but not in right atria of guinea.... Naunyn Schmiedebergs Arch Pharmacol. 1983; 322(2):111-20. DOI: 10.1007/BF00512383. View

11.

Quast U, VOLLMER K . Binding of beta-adrenoceptor antagonists to rat and rabbit lung: special reference to levobunolol. Arzneimittelforschung. 1984; 34(5):579-84. View

12.

Badia A, Bermejo P, Jane F . Beta-adrenergic blocking effects and cardiodepressant activity of penbutolol and its two optical isomers in the guinea-pig left atrium. Methods Find Exp Clin Pharmacol. 1984; 6(8):445-8. View

13.

Walter M, Lemoine H, Kaumann A . Stimulant and blocking effects of optical isomers of pindolol on the sinoatrial node and trachea of guinea pig. Role of beta-adrenoceptor subtypes in the dissociation between blockade and stimulation. Naunyn Schmiedebergs Arch Pharmacol. 1984; 327(2):159-75. DOI: 10.1007/BF00500912. View

14.

Morris T, Kaumann A . Different steric characteristics of beta 1- and beta 2-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1984; 327(2):176-9. DOI: 10.1007/BF00500913. View

15.

Hellenbrecht D, Enenkel J . Estimation of the nonspecific cardiovascular toxicity of beta-adrenoceptor blocking drugs with different hydrophobic properties in the cat. Arzneimittelforschung. 1984; 34(9):980-3. View

16.

Nerme V, Severne Y, Abrahamsson T, Vauquelin G . Endogenous noradrenaline masks beta-adrenergic receptors in rat heart membranes via tight agonist binding. Biochem Pharmacol. 1985; 34(16):2917-22. DOI: 10.1016/0006-2952(85)90016-4. View

17.

Lemoine H, Ehle B, Kaumann A . Direct labelling of beta 2-adrenoceptors. Comparison of binding potency of 3H-ICI 118,551 and blocking potency of ICI 118,551. Naunyn Schmiedebergs Arch Pharmacol. 1985; 331(1):40-51. DOI: 10.1007/BF00498850. View

18.

Neve K, McGonigle P, Molinoff P . Quantitative analysis of the selectivity of radioligands for subtypes of beta adrenergic receptors. J Pharmacol Exp Ther. 1986; 238(1):46-53. View

19.

McGonigle P, Neve K, Molinoff P . A quantitative method of analyzing the interaction of slightly selective radioligands with multiple receptor subtypes. Mol Pharmacol. 1986; 30(4):329-37. View

20.

ARIENS E . Stereochemistry: a source of problems in medicinal chemistry. Med Res Rev. 1986; 6(4):451-66. DOI: 10.1002/med.2610060404. View