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 atoms of differing size (here primarily thioxanth-9-ones and phenoxathiins) monosubstituted meta to the sulfur by C(O)NHMe include potent and selective 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 sulfone 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 tyramine to controls. This is in contrast to a large blood pressure rise in rats pretreated with phenelzine followed by tyramine, and in accord with 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 tyramine).
Harfenist
M
M
Department of Organic Chemistry, Wellcome Research Laboratories, Research Triangle Park, North Carolind 27709, USA.
Joseph
D M
DM
Spence
S C
SC
Mcgee
D P
DP
Reeves
M D
MD
White
H L
HL
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000929:Antidepressive Agents, Tricyclic; D002264:Carboxylic Acids; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors