Steric aspects of agonism and antagonism at beta-adrenoceptors: synthesis of and pharmacological experiments with the enantiomers of formoterol and their diastereomers

Chirality
J TrofastBertil Waldeck

Abstract

The enantiomers of formoterol (R;R and S;S) and their diastereomers (R;S and S;R) were synthesized and purified using a new procedure which required the preparation of the (R;R)- and (S;S)-forms of N-(1-phenylethyl)-N-(1-(p-methoxyphenyl)-2-propyl)-amine as important intermediates. The enantiomeric purity obtained was greater than 99.3%, usually greater than 99.7%. The four stereoisomers were examined with respect to their ability to interact in vitro with beta-adrenoceptors in tissues isolated from guinea pig. The effects measured were (1) relaxation of the tracheal smooth muscle (mostly beta 2), (2) depression of subtetanic contractions of the soleus muscle (beta 2), and (3) increase in the force of the papillary muscle of the left ventricle of the heart (beta 1). All enantiomers caused a concentration-dependent and complete relaxation of the tracheal smooth muscle which was inhibited by propranolol. The order of potency was (R;R) much greater than (R;S) = (S;R) greater than (S;S). There was a 1,000-fold difference in potency between the most and the least potent isomer. The presence of the (S;S)-isomer did not affect the activity of the (R;R)-isomer on the tracheal smooth muscle. Also on the skeletal and cardiac muscles (R;R...Continue Reading

References

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Citations

Oct 24, 1995·European Journal of Pharmacology·S LindbergT Runer
Jun 1, 1996·General Pharmacology·Bertil Waldeck
Jun 18, 2002·European Journal of Pharmacology·Bertil Waldeck
Oct 1, 2003·Clinical Positron Imaging : Official Journal of the Institute for Clinical P.E.T·Philip H. ElsingaWillem Vaalburg
Sep 19, 2002·British Journal of Clinical Pharmacology·Mei ZhangJohn P Shaw
Sep 26, 2013·Pediatric Allergy, Immunology, and Pulmonology·Kathryn Blake, Hengameh Raissy
Oct 1, 1992·Pharmacology & Toxicology·A B JeppssonBertil Waldeck
Jan 1, 1995·Pharmacology & Toxicology·Bertil Waldeck
Jun 9, 2009·American Journal of Respiratory Cell and Molecular Biology·Philippe Delmotte, Michael J Sanderson
Oct 1, 1992·Journal of Clinical Pharmacology·J Caldwell
Sep 28, 2007·Bioorganic & Medicinal Chemistry Letters·Alan D BrownRob Webster
Jan 25, 2006·British Journal of Pharmacology·Peter MolenaarWilliam A Parsonage
Oct 31, 2008·Angewandte Chemie·Dominik KoszelewskiWolfgang Kroutil
Jan 15, 2005·Pulmonary Pharmacology & Therapeutics·Jan LötvallBertil Waldeck
May 18, 1999·The Journal of Allergy and Clinical Immunology·Bertil Waldeck
Jul 2, 2002·Pulmonary Pharmacology & Therapeutics·Dean A HandleyJohn Morley
Nov 25, 2003·Pharmacology & Toxicology·Bertil Waldeck
Feb 15, 2000·British Journal of Clinical Pharmacology·M ZhangJ P Shaw
Jan 15, 2004·American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions·David W Boulton, J Paul Fawcett

Related Concepts

BD 40A
Adrenergic beta-Agonists
Broncholytic Effect
Ethanolamines
Cavia porcellus
Inotropism
Beta-adrenergic receptor
Molecular Stereochemistry
Trachea

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