ANTAGONISM BY (R)-TRIHEXYPHENIDYL AND (S)-TRIHEXYPHENIDYL OF MUSCARINIC STIMULATION OF ADENYLYL-CYCLASE IN RAT OLFACTORY-BULB AND INHIBITION IN STRIATUM AND HEART

1 Activation of muscarinic receptors in rat olfactory bulb stimulates adenylyl cyclase activity. This response was competitively antagonized by the (R)- and (S)-enantiomers of trihexyphenidyl with pA(2) values of 8.84 and 6.09, respectively. 2 Similarly, in rat striatal homogenat es, muscarinic inhibition of adenylyl cyclase activity was antagonized by the (R)- and (S)-enantiomers with pA(2) values of 8.75 and 6.12, r espectively. 3 In contrast, in rat myocardium the muscarinic inhibitio n of the adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation w as more weakly antagonized by trihexyphenidyl, with a particularly mar ked loss (15 fold) in activity of the (R)-enantiomer. The (R)- and (S) -enantiomers had pA(2) values of 7.64 and 5.72, respectively. 4 Each m uscarinic response was completely antagonized by increasing concentrat ions of (R)-trihexyphenidyl with a Hill coefficient not significantly different from unity. 5 The present study shows that the muscarinic re ceptors coupled to stimulation of adenylyl cyclase in the olfactory bu lb display high stereoselectivity for the enantiomers of trihexyphenid yl. The affinities of these receptors for the antagonists are similar to those shown by the striatal receptors. This finding supports the hy pothesis that both the muscarinic stimulation of adenylyl cyclase in t he olfactory bulb and the muscarinic inhibition of the enzyme in stria tum are mediated by activation of a receptor subtype pharmacologically equivalent to the m4 gene product. On the other hand, the weaker affi nities and the lower stereoselectivity for the trihexyphenidyl enantio mers exhibited by the muscarinic inhibition of adenylyl cyclase in the heart are consistent with the involvement of M(2) receptors in this r esponse.