Tricyclic Compounds as Selective Antimuscarinics. 2. Structure-Activity Relationships of M1-Selective Antimuscarinics Related to Pirenzepine

Article abstract of DOI:10.1021/jm00401a016

In order to gain some insight into those structural features that control M₁ selectivity, a selected set of pirenzepine analogues has been studied in which both the tricyclic ring system and the basic side chain have varied.Binding studies were conducted in rat tissue homogenates from cerebral cortex (M₁) and gastric fundus (M₂).The ratio of IC₅₀ values of the test compounds in the two different tissues was taken as a measure of M₁ receptor selectivity.Several derivatives, especially those with flexible side chains, i.e. high degree of freedom of rotation around single bonds, proved to be nonselective.Among semirigid compounds only those containing 6-membered ring systems (11, 13, 14, and 15) showed significant M₁ selectivity.Principles of structure-activity and structure-selectivity are discussed.