Effects of enantiomers of M3 antagonists on muscarinic receptors in rabbit trachea.

The effects of the enantiomers of structurally related chiral M3 antagonists (trihexyphenidyl, p-fluorohexahydrodifenidol, hexahydrodifenidol and p-fluorohexbutinol) were studied at the presynaptic M2 and postsynaptic M3 receptor level in the rabbit trachea. All isomers were M3- over M2-selective as they did not increase the release of acetylcholine (an M2 effect) at concentrations that significantly inhibited smooth muscle contraction (an M3 effect). At the smooth muscle receptor, the R-enantiomers were consistently more potent than the S-enantiomers. The potency ratios (IC50(S)/IC50(R)) varied from 6 for p-fluorohexbutinol to 288 for trihexyphenidyl, and increased with higher eutomer potencies, in accordance to Pfeiffer's rule. Furthermore, we found that the potency of the racemic mixture of hexahydrodifenidol was significantly lower than that of the eutomer R-hexahydrodifenidol. To exclude that this difference was due to the lower concentration of the more active isomer, present in a racemic mixture, we calculated the potencies (-log IC50 values) of mixtures of the isomers of hexahydrodifenidol with varying amounts of S-hexahydrodifenidol and a constant amount of R-hexahydrodifenidol. We found that the presence of the distomer altered the potency of the eutomer in a dose-related manner. In conclusion, we have shown that the muscarinic smooth muscle receptor can be blocked differentially by the isomers of muscarinic antagonists and that the presence of the less active compound alters the potency of the most active isomer. We, therefore, suggest that, in bronchodilating therapy, the use of the pure eutomer might have advantages.