Molecular Pharmacology, Vol 11, 690-693, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Inversion of Stereospecificity by Methylation of Compounds Acting at Acetylcholine Receptors

¹ Department of Pharmacology, University of Edinburgh, Edinburgh EH8 9JZ, and School of Pharmacy, Liverpool Polytechnic, Liverpool L3 3AF, United Kingdom

On guinea pig ileum R-(-)-3-acetoxyquinuclidine is less than one-tenth as active as the S-(+) enantiomer, but the methiodide of the R compound is about 40 times as active as its S enantiomer. Inversion of stereospecificity occurs because methylation reduces the activity of the stronger (S) base about 1000-fold whereas it reduces the activity of the weaker (R) base only about 2-fold. The affinity of the S base is reduced about 100-fold, and this marked effect of methylation may be associated with the rigidity of the quinuclidine ring and indicate a particularly close fit between S-(+)-3-acetoxyquinuclidine and the "muscarinic" receptor. On the frog rectus there is no detectable stereospecificity and activity is not reduced by methylation, but the compounds are not very active.