SELECTIVE INHIBITORS OF MONOAMINE-OXIDASE .4. SAR OF TRICYCLIC N-METHYLCARBOXAMIDES AND CONGENERS BINDING AT THE TRICYCLICS HYDROPHILIC BINDING-SITE

Linear [6.6.6] tricyclic moieties whose center ring is made of two ato ms of differing size (here primarily thioxanth-9-ones and phenoxathiin s) monosubstituted meta to the sulfur by C(O)NHMe include potent and s elective inhibitors of monoamine oxidase A. Similarities with effects on SAR of acylamide and of diazapentacyclic substitution on such rings , including positional variables, the requirement for monomethylation (primary and dialkylated amides are inactive and higher monoalkylated amides show little or no potency), and that sulfur is optimally in sul fone form, suggest that binding to the enzyme occurs similarly in each series. No significantly greater rise in blood pressure was found in rats given sufficient 8 to inhibit most brain and liver MAO A and then followed by oral tyramine than was found on administration of tyramin e to controls. This is in contrast to a large blood pressure rise in r ats pretreated with phenelzine followed by tyramine, and in accord wit h the belief that an inhibitor selective for MAO A which is reversibly bound to the enzyme and therefore displaced by any ingested tyramine will not lead to the ''cheese effect'' (hypertension during treatment with MAO inhibitors usually caused by ingestion of foods containing ty ramine).