M-3/M-1-selective antimuscarinic tropinyl and piperidinyl esters

The binding affinities of some tropinyl and piperidinyl esters for the subm andibulary glands (M-3/M-1) and heart ventricle (M-2) were determined from displacement experiments using H-3-labelled N-methylscopolamine as radiolig and. The antimuscarinic activities of these esters were also evaluated on g uinea pig bronchi. The esters inhibited the M-3-mediated carbachol-induced contraction of the bronchial smooth muscle and a reasonable correlation was obtained between the binding affinities of the eaters for the submandibula ry glands (pK(M3,M1)) and their inhibitory activities (pIC(50)) on guinea p ig bronchi. A promising compound, N-methylpiperidinyl cyclohexylphenylpropi onate (NCPP) which combined good antimuscarinic activity (pA(2)=9.34) with a 20-fold selectivity at the M-3/M-1 receptors, was identified. Quantitativ e structure-activity relationships (QSAR) showed that the size of the ester was the main structural feature determining both binding affinity for the M-3/M-1 receptors and inhibitory activity on guinea pig bronchi. Esters wit h substituted acyl side chains (fewer hyperconjugable H atoms at the alpha- carbon) are generally associated with better activity and affinity. (C) 199 9 Elsevier Science B.V. All rights reserved.