Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine.

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. Dicyclomine, trihexyphenidyl and pirenzepine demonstrated the highest affinity for the M1 muscarinic receptor subtype as revealed in competition experiments against [3H]-pirenzepine labelling of cortical membranes. Their affinity values lay in a narrow range (3.7-14 nM) approaching that of atropine (1.6 nM). Competition experiments against [3H]-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 M1 (cortical) and the peripheral muscarinic subtypes (cardiac and glandular). However, atropine displayed similar affinities for either subtype with IC50s varying only slightly (1.6-4.6 nM). The rank order of selectivity was: pirenzepine greater than dicyclomine greater than trihexyphenidyl greater than atropine. Mirroring the binding data, pirenzepine, dicyclomine and trihexyphenidyl showed a tenfold greater ability at inhibiting M1-receptor 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). 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 (M1) muscarinic receptor, hence they antagonize functional responses mediated by the M1 subtype. Atropine, a member of the other group, shows essentially no selectivity. 6 Differentiation of M1 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.