Monoamine Oxidase Inhibitory Properties of Some Methoxylated and Alkylthio Amphetamine Derivatives: Structure–Activity Relationships

• Published in: Biochemical pharmacology 1997-12, Vol.54 (12), p.1361-1369
• Main Authors: Scorza, Ma.Cecilia, Carrau, Cecilia, Silveira, Rodolfo, Zapata-Torres, Gerald, Cassels, Bruce K, Reyes-Parada, Miguel
• Format: Article
• Language: English
• Subjects: amphetamine derivatives; Amphetamines - pharmacology; Animals; antidepressants; Biological and medical sciences; Brain Chemistry - drug effects; General pharmacology; Hydroxyindoleacetic Acid - analysis; Male; MAO inhibitors; Medical sciences; monoamine oxidase; Monoamine Oxidase Inhibitors - pharmacology; Pharmacology. Drug treatments; phenylisopropylamine derivatives; Physicochemical properties. Structure-activity relationships; Rats; Serotonin - analysis; Structure-Activity Relationship; structure–activity relationships
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(97)00405-X

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 ( ic 50 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.