DIFFERENTIAL ANALGESIC ACTIVITY OF THE ENANTIOMERS OF ATROPINE DERIVATIVES DOES NOT CORRELATE WITH THEIR MUSCARINIC SUBTYPE SELECTIVITY

The enantiomers of several tropic and p-substituted tropic acid esters related to atropine obtained by esterification under non-racemizing c onditions after resolution of the corresponding racemic acids [(+)- an d (-)-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 b eing the R-(+) or R-(+)-p-substituted tropic acid derivatives. However , this property, which is a consequence of increased central release o f ACh, seems unrelated to muscarinic subtype selectivity insofar as th e 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 in verse agonism.