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Antagonism by (R)‐ and (S)‐trihexyphenidyl of muscarinic stimulation of adenylyl cyclase in rat olfactory bulb and inhibition in striatum and heart
Author(s) -
Onali Pierluigi,
Aasen Arne J.,
Olianas Maria C.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17060.x
Subject(s) - muscarinic acetylcholine receptor , trihexyphenidyl , adenylyl cyclase , chemistry , muscarinic acetylcholine receptor m1 , muscarinic acetylcholine receptor m4 , medicine , muscarinic acetylcholine receptor m2 , endocrinology , muscarinic acetylcholine receptor m3 , pharmacology , stimulation , biology , receptor , biochemistry
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 homogenates, muscarinic inhibition of adenylyl cyclase activity was antagonized by the ( R )‐ and ( S )‐enantiomers with pA 2 values of 8.75 and 6.12, respectively. 3 In contrast, in rat myocardium the muscarinic inhibition of the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) formation was more weakly antagonized by trihexyphenidyl, with a particularly marked 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 muscarinic response was completely antagonized by increasing concentrations of ( R )‐trihexyphenidyl with a Hill coefficient not significantly different from unity. 5 The present study shows that the muscarinic receptors coupled to stimulation of adenylyl cyclase in the olfactory bulb display high stereoselectivity for the enantiomers of trihexyphenidyl. The affinities of these receptors for the antagonists are similar to those shown by the striatal receptors. This finding supports the hypothesis that both the muscarinic stimulation of adenylyl cyclase in the olfactory bulb and the muscarinic inhibition of the enzyme in striatum are mediated by activation of a receptor subtype pharmacologically equivalent to the m4 gene product. On the other hand, the weaker affinities and the lower stereoselectivity for the trihexyphenidyl enantiomers exhibited by the muscarinic inhibition of adenylyl cyclase in the heart are consistent with the involvement of M 2 receptors in this response.