Differential analgesic activity of the enantiomers of atropine derivatives does not correlate with their muscarinic subtype selectivity

Abstract

Summary The enantiomers of several tropic and p -substituted tropic acid esters related to atropine obtained by esterification under non-racemizing conditions after resolution of the corresponding racemic acids [(+)- and (-)− 18 , (+)- and (-)− 19 ] are reported. They were tested in vitro on muscarinic subtype receptors and in vivo for their analgesic activity on mice. As in the case of the lead compound, R -(+)-hyoscyamine, these substances show enantioselectivity in analgesic tests, the eutomers being the R -(+) or R -(+)- p -substituted tropic acid derivatives. However, this property, which is a consequence of increased central release of ACh, seems unrelated to muscarinic subtype selectivity insofar as the compounds are unable to discriminate muscarinic subtype receptors. A possible explanation of these results which does not involve subtype selectivity is proposed, based on the recently developed concept of inverse agonism.