M3/M1-Selective antimuscarinic tropinyl and piperidinyl esters.

ABSTRACT

The binding affinities of some tropinyl and piperidinyl esters for the submandibulary glands (M3/M1) and heart ventricle (M2) were determined from displacement experiments using 3H-labelled N-methylscopolamine as radioligand. The antimuscarinic activities of these esters were also evaluated on guinea pig bronchi. The esters inhibited the M3-mediated carbachol-induced contraction of the bronchial smooth muscle and a reasonable correlation was obtained between the binding affinities of the esters for the submandibulary glands (pKM3,M1) and their inhibitory activities (pIC50) on guinea pig bronchi. A promising compound, N-methylpiperidinyl cyclohexylphenylpropionate (NCPP) which combined good antimuscarinic activity (pA2=9.34) with a 20-fold selectivity at the M3/M1 receptors, was identified. Quantitative structure-activity relationships (QSAR) showed that the size of the ester was the main structural feature determining both binding affinity for the M3/M1 receptors and inhibitory activity on guinea pig bronchi. Esters with substituted acyl side chains (fewer hyperconjugable H atoms at the alpha-carbon) are generally associated with better activity and affinity.