ANTAGONISM BY (R)-TRIHEXYPHENIDYL AND (S)-TRIHEXYPHENIDYL OF MUSCARINIC STIMULATION OF ADENYLYL-CYCLASE IN RAT OLFACTORY-BULB AND INHIBITION IN STRIATUM AND HEART
P. Onali et al., ANTAGONISM BY (R)-TRIHEXYPHENIDYL AND (S)-TRIHEXYPHENIDYL OF MUSCARINIC STIMULATION OF ADENYLYL-CYCLASE IN RAT OLFACTORY-BULB AND INHIBITION IN STRIATUM AND HEART, British Journal of Pharmacology, 113(3), 1994, pp. 775-780
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.