Relationship of the crystal structure of γ-N,N-dimethylaminopropyl 2,2-diphenylpropionate hydrochloride to antimuscarinic activity

Abstract

The title compound was synthesized, characterized by¹H nmr, and crystallized for x-ray crystallography. The antimuscarinic potency of the title compound was about equipotent to aprophen or atropine in inhibiting acetylcholine-induced contraction of guinea pig ileum (K _B =4.5 nM) and in inhibiting carbachol-stimulated release ofα-amylase from rat pancreatic acinar cells (K _i =1.4nM), and in inhibiting the binding of [N-methyl-³H]scopolamine to cerebral cortex (K _i =6.6nM). In the crystal, the O-C-C-C-N⁺ segment adopted a gauche-gauche configuration resulting in an N⁺⋯O (carbonyl) distance of 5.001(9)Å, a distance comparable to that in aprophen. The ether oxygen atom is buried rendering it inaccessible for interaction with the muscarinic receptor. The carbonyl oxygen atom is exposed to the surface of the molecule and is readily accessible for intermolecular interactions. The similarity in biological activities of the title compound and aprophen is congruous with their similar N⁺⋯O (carbonyl) distances.