Structure-activity relationships for the anticholinoceptor action of tricyclic antidepressants

1 The anticholinoceptor action of 15 tricyclic antidepressants and derivatives has been studied on the guinea-pig ileum. At the muscarinic receptors the compounds were found to exert antagonism which was reversible and apparently competitive up to dose-ratios of around 100 but non-competitive above this level. 2 Log affinity constants were derived from log dose-response curves at dose-ratios less than 100, where parallel curves were obtained. Amitriptyline, the most potent compound, had 214 X the potency of the weakest, hydroxyimipramine, but was itself 20 X weaker than atropine. 3 Structure-activity studies showed that dibenzocycloheptane derivatives were more potent than dibenzazepines and that S or O substitution for C-11 or other major changes in the central ring of the tricyclic nucleus greatly reduced activity. Side-chain N-methylation increased potency markedly. This and other findings indicate that both tricyclic nucleus and side-chain receptor attachments are largely non-polar in type.