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

Abstract

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.

Interactions of Nitrogen-Containing Xenobiotics with Monoamine Oxidase (MAO) Isozymes A and B: SAR Studies on MAO Substrates and Inhibitors

“…Previous studies have shown that tricyclic compounds such as xanthone ( 106 ) possess MAO-A-selective inhibitory properties (Figure ) ( , ). Further structural modifications afforded a series of phenoxathiin dioxides that retained MAO-A potency and selectivity observed with xanthones ( , ). BW 137OU87 ( 107 ) is one of the most potent and selective MAO-A inhibitors known with an in vitro K i = 10 nM and an in vivo ED 50 = 8 mg/kg ().…”

Regiocontrolled Formation of a Novel Dioxadithiapentacene

“…In the course of a drug discovery effort targeting phenoxathiin 10,10-dioxides as potential antidepressant agents, , we observed regiocontrolled formation of the 3,10-diisopropoxy derivative of 3 . Herein are described the details of this polycyclization and the X-ray crystal structure of the new ring system, which may be of interest to researchers in the field of organic charge-transfer complexes.…”

Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

“…8). The dataset of 65 compounds previously published [121,147,148] was divided in training set (52 compounds were used to generate the pharmacophoric model) and test set (13 compounds). Pharmacophore modeling was developed with the help of Maestro software [149] through Phase module [150] that combines conformational sampling with different scoring methods to identify pharmacophoric hypothesis.…”