Structure-activity relationship in a new series of atropine analogs. 1. N,N'-Disubstituted 6,7-diazabicyclo[3.2.2]nonane derivatives

Abstract

The synthesis of a new series of N,N'-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. Kd 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 3alpha configuration is more potent than the 3beta configuration, and the quaternary analogues are more potent than the tertiary ones. The antimuscarinic activity of the drugs is dicussed in terms of their acetylcholine-like molecular arrangement that gives rise to a characteristic interaction pharmacophore.

Monomeric, Dimeric, and Trimeric Tropane Alkaloids from Pellacalyx saccardianus

“…Although significantly less potent than atropine (EC 50 0.98 ± 0.25 nM), compounds 4 and 9 were the most potent among all the alkaloids tested, with EC 50 values of 3.6 ± 0.74 and 7.83 ± 0.36 μM, respectively (Table ). These observations are consistent with the structure–activity relationships of atropine as a muscarinic receptor antagonist. , The absence of the basic tropanyl nitrogen atom in all the tested alkaloids probably precluded them from achieving optimal binding interaction with the muscarinic receptors.…”

“…These observations are consistent with the structure−activity relationships of atropine as a muscarinic receptor antagonist. 33,34 The absence of the basic tropanyl nitrogen atom in all the tested alkaloids probably precluded them from achieving optimal binding interaction with the muscarinic receptors.…”