Selective inhibitors of monoamine oxidase (MAO). 5. 1-Substituted phenoxathiin inhibitors containing no nitrogen that inhibit MAO A by binding it to a hydrophobic site.
It is believed that a monoamine oxidase (MAO) inhibitor specific for MAO A, which is reversibly bound to this enzyme and displaceable by tyramine, will be an antidepressant which will not cause a rise in blood pressure when tyramine-containing foods are ingested. Some linear tricyclic compounds with a larger and a smaller group forming the central ring and with a lipophilic group ortho to the larger group (here mostly the SO2 function of phenoxathiin 10,10-dioxide) are reported to have the sought properties. Potency appears to require short length and relatively small cross section for the substituent. The 1-ethyl (13), 1-vinyl (22), 1-trifluoromethyl (27), and 1-iodo (76) phenoxathiin dioxides had the best profiles. Structure-activity relationships, syntheses, and a possible rationale for the selectivity of these compounds and related tricyclics are given. Compound 13 was selected for further development. A summary of pharmacological data for 13 is given.
Harfenist
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M
Divisions of Organic Chemistry and Pharmacology, The Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709, USA.
McGee
D P
DP
Reeves
M D
MD
White
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HL
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D006571:Heterocyclic Compounds; D008996:Monoamine Oxidase Inhibitors; C076100:1-ethylphenoxathiin 10,10-dioxide