title: Monoamine oxidase inhibitory properties of some methoxylated and alkylthio amphetamine derivatives: structure-activity relationships.
abstract: The monoamine oxidase (MAO) inhibitory properties of a series of amphetamine derivatives with different substituents at or around the para position of the aromatic ring were evaluated. In in vitro studies in which a crude rat brain mitochondrial suspension was used as the source of MAO, several compounds showed a strong (IC50 in the submicromolar range), selective, reversible, time-independent, and concentration-related inhibition of MAO-A. After i.p. injection, the compounds induced an increase of serotonin and a decrease of 5-hydroxyindoleacetic acid in the raphe nuclei and hippocampus, confirming the in vitro results. The analysis of structure-activity relationships indicates that: molecules with amphetamine-like structure and different substitutions on the aromatic ring are potentially MAO-A inhibitors; substituents at different 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 increase in the activity; the para-substituent must be an electron donor; bulky groups next to the para substituent lead to a decrease in the activity; substituents located at positions more distant on the aromatic ring have less influence and, even when the substituent is a halogen (Cl, Br), an increase in the activity of the compound is obtained. Finally, 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 effects.
authors.affiliation: División Biología Celular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
authors.forename: M C
authors.initials: MC
authors.lastname: Scorza
authors.forename: C
authors.initials: C
authors.lastname: Carrau
authors.forename: R
authors.initials: R
authors.lastname: Silveira
authors.forename: G
authors.initials: G
authors.lastname: Zapata-Torres
authors.forename: B K
authors.initials: BK
authors.lastname: Cassels
authors.forename: M
authors.initials: M
authors.lastname: Reyes-Parada
mesh_terms: D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D051381:Rats; D012701:Serotonin / Q000032:analysis; D013329:Structure-Activity Relationship
chemical_list: D000662:Amphetamines; D008996:Monoamine Oxidase Inhibitors; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid