Structure-Activity Relationship in a New Series of Atropine Analogues. 1. N, Nʹ-Disubstituted 6, 7-Diazabicyclo[3.2.2]nonane Derivatives

The synthesis of a new series of N, Nʹ-disubstituted 6, 7-diazabicyclo[3.2.2]nonane derivatives is described. The antimuscarinic potency of these drugs was evaluated in the guinea pig ileum and compared to that of atropine sulfate. All the drugs tested competitively inhibited the acetylcholine-induced contractions. K_d values were calculated and, in several cases, compared to those obtained by direct binding to the muscarinic receptor from mouse brain. The order of potencies followed that which is known for various tropine and pseudotropine esters; that is, the 3a configuration is more potent than the 3β configuration, and the quaternary analogues are more potent than the tertiary ones. The antimuscarinic activity of the drugs is discussed in terms of their acetylcholine-like molecular arrangement that gives rise to a characteristic interaction pharmacophore.