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Binding and functional profiles of the selective M 1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine
Author(s) -
Giachetti A.,
Giraldo E.,
Ladinsky H.,
Montagna E.
Publication year - 1986
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.1476-5381.1986.tb11123.x
Subject(s) - trihexyphenidyl , muscarinic acetylcholine receptor , pharmacology , medicine , muscarinic acetylcholine receptor m1 , neuroscience , chemistry , receptor , psychology
1 The selectivity profiles of the muscarinic receptor antagonists dicyclomine and trihexyphenidyl have been examined in binding and functional studies and compared with those of pirenzepine and atropine. 2 Dicyclomine, trihexyphenidyl and pirenzepine demonstrated the highest affinity for the M 1 muscarinic receptor subtype as revealed in competition experiments against [ 3 H]‐pirenzepine labelling of cortical membranes. Their affinity values lay in a narrow range (3.7–14 nM) approaching that of atropine (1.6 nM). 3 Competition experiments against [ 3 H]‐N‐methylscopolamine in cardiac and glandular (salivary) membranes revealed differences between the drugs examined. Dicyclomine, trihexyphenidyl and pirenzepine displayed low affinity for the cardiac and intermediate affinity for the glandular receptors. Thus, the drugs appeared to discriminate between the M 1 (cortical) and the peripheral muscarinic subtypes (cardiac and glandular). However, atropine displayed similar affinities for either subtype with IC 50 s varying only slightly (1.6‐4.6 nM). The rank order of selectivity was: pirenzepine > dicyclomine > trihexyphenidyl > atropine. 4 Mirroring the binding data, pirenzepine, dicyclomine and trihexyphenidyl showed a tenfold greater ability at inhibiting M 1 ‐preceptor mediated ganglionic responses (McN A‐343 pressor effect in pithed rats and nictitating membrane contraction in cats) than at inhibiting peripheral muscarinic responses in the heart and cardiovascular smooth muscle (vagal bradycardia in rats and cats and vagally‐induced vasodilatation in cats). 5 The muscarinic antagonists so far examined can be categorized into two groups. Trihexyphenidyl, dicyclomine and pirenzepine, included in one group, are characterized by a higher affinity for the neuronal (M 1 ) muscarinic receptor, hence they antagonize functional responses mediated by the M 1 subtype. Atropine, a member of the other group, shows essentially no selectivity. 6 Differentiation of M 1 and peripheral muscarinic receptor subtypes appears to be a property not confined to tricyclics such as pirenzepine but shared by diverse chemical structures. Both trihexyphenidyl and dicyclomine appear to be useful pharmacological tools in the classification of muscarinic receptor subtypes.