MONOAMINE-OXIDASE INHIBITORY PROPERTIES OF SOME METHOXYLATED AND ALKYLTHIO AMPHETAMINE DERIVATIVES - STRUCTURE-ACTIVITY-RELATIONSHIPS

The monoamine oxidase (MAO) inhibitory properties of a series of amphe tamine derivatives with different substituents at or around the para p osition of the aromatic ring were evaluated. In in vitro studies in wh ich a crude rat brain mitochondrial suspension was used as the source of MAO, several compounds showed a strong (IC50 in the submicromolar r ange), selective, reversible, time-independent, and concentration-rela ted inhibition of MAO-A. After itp. injection, the compounds induced a n increase of serotonin and a decrease of 5-hydroxyindoleacetic acid i n the raphe nuclei and hippocampus, confirming the in vitro results. T he analysis of structure-activity relationships indicates that: molecu les with amphetamine-like structure and different substitutions on the aromatic ring are potentially MAO-A inhibitors; substituents at diffe rent positions of the aromatic ring modify the potency but have little influence on the selectivity; substituents at the para position such as amino, alkoxyl, halogens, or alkylthio produce a significant increa se in the activity; the para substituent must be an electron donor; bu lky groups next to the para substituent lead to a decrease in the acti vity; substituents located at positions more distant on the aromatic r ing have less influence and, even when the substituent is a halogen (C l, Br), an increase in the activity of the compound is obtained. Final ly, the MAO-A inhibitory properties of some of the compounds evaluated are discussed in relation to: (a) potential antidepressant activity, and (b) their reported hallucinogenic, neurotoxic, or anxiolytic effec ts. (C) 1997 Elsevier Science Inc.