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.
D000109:Acetylcholine / Q000037:antagonists & inhibitors; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002217:Carbachol / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008745:Methylation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011950:Receptors, Cholinergic / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000929:Antidepressive Agents, Tricyclic; D011950:Receptors, Cholinergic; D002217:Carbachol; D000109:Acetylcholine