STEREOSELECTIVE INHIBITION OF MUSCARINIC RECEPTOR SUBTYPES BY THE 8 STEREOISOMERS RELATED TO ROCIVERINE

The chemical structure corresponding to 1-hydroxy[1,1'-bicyclohexyl]-2 -carboxylic acid 2-(diethylamino)-1-methylethyl ester has the classica l profile of ester-type antimuscarinic drugs. The presence of three ch iral carbons leads to eight stereoisomers and the substitutions on the cyclohexyl ring generate cis-isomers (1, named rociverine) and trans- isomers (2). The aim of this study was to determine the binding patter n of the eight stereoisomers and two derived compounds, (1S,2S)-1-hydr oxy[1,1'-bicyclohexyl]-2-carboxylic acid 2-(dimethylamino)-1-ethyl est er (3) and (1S,2S)-1-hydroxy[1,1'-bicyclohexyl]-2-carboxylic acid (S)- 2-(diethylamino)-1-methylethyl ester methyl iodide (4), at the five cl oned muscarinic receptors stably expressed in chinese hamster ovary ce lls, in order to define how stereochemical modifications could affect the affinity. Our data showed that cis-stereoisomers exhibited higher variations in affinity than trans-stereoisomers. Among the cis-stereoi somers, those with the (1R,2R) configuration showed considerably highe r affinities (up to 240-fold) than those with the (1S,2S) configuratio n. The (1S,2S) configuration was important for binding selectivity; th is was confirmed also by the use of the two additional compounds.