Monoamine Oxidase Inhibitory Properties of Some Methoxylated and Alkylthio Amphetamine Derivatives STRUCTURE-ACTIVITY RELA TIONSHIPS

Abstract

The monoamine oxidase (MAO) inhibitory propenies of a series of amphetamine derivatives with difTerent substituents at or around rhe para position of the aromaric ring were evaluateJ. i¡, in viero stuJies in which a crude rar brain mirochllndrial suspension was used as rhe source of MAO, several compounds showed a srrong (ICS0 in rhe submicromolar range), selecrive, reversible, time-independenr, and concenrrarion-related inhibition of MAO-A. After i.p. injection, the compounds induced an inerease of serotonin and a decrease of j-hydroxyindoleacetic acid in the raphe nuclei and hippocampus, confinning rhe in virro results. The analysis of structure-activity relationships indicates rhat: molecules with amphetamine-Iike structure and different substitutions nn the aromaric ring are potentially MAO-A inhibitors; substituents at different positions of the aromatic ring moditY the porency but have litde inf1uence "n the selectiviry; substituents at rhe para position sllch as ,lmino, alkoxyl. halogens. or alkylthio produce a significant increase in rhe acrivity; the para-substituent musr be an e1ectron Jonor; hulky ~roups next to rhe para subsriruent Icad ro a Jecrease in the actÍ\'ityi ,ubstiruents loearcd ar posirions more Jistant ,m rhe aromaric ring havc less intluence anJ, even when the subsriruent is '1 halogen (CI, Br), an increase in rhe acrivity "f rhe cllmpound is llbtained. Final!y, rhe MAO-A inhibirory properties of some of rhe compounJs evaluareJ are Jiscussed in relation to: (a) potential antidepressant acri\"Íry, and (b) their reponed hallllcinogenic, neurotoxic, nr anxiolyric effecrs.