In vitro O-demethylation of the psychotomimetic amine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane

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Abstract
The possible relationship between metabolism and psychotomimetic activity among the methoxylated 1-phenyl-2-aminopropanes led to the investigation of the in vitro O-demethylation of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (1). Employing a sensitive and highly selective stable isotope dilution assay, rabbit liver homogenates were observed to biotransform the amine 1 to its 2-O-demethyl, 5-O-demethyl and bis(O-demethyl) metabolites. Both monophenolic metabolites were enriched in their S enantiomers. The bis(O-demethyl) metabolite had structural, chemical and electrochemical similarities to the sympatholytic agent 6-hydroxydopamine. The significance of metabolic O-demethylation in terms of the psychotomimetic properties of amine was discussed.