Chemical and biological studies of 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine.
Peyton Jacob, T Kline, N Castagnoli
Journal of Medicinal Chemistry June 1979 DOI: 10.1021/jm00192a011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical biochemical study Peer reviewed |
|---|---|
| Population | Rabbit liver homogenate fractions, rabbit microsomes, bovine serum albumin, and rats |
| Interventions | 1-(2 5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) bis(O-demethyl)-p-hydroquinone metabolite bicyclic imino quinone |
| Key points | The hydroquinone metabolite of DOM autoxidizes to a lipophilic bicyclic imino quinone that alkylates thiols and binds irreversibly to macromolecules, including in brain tissue after intravenous administration to rats. The authors propose that DOM's psychotomimetic properties may be mediated through 6-hydroxydopamine-type interactions of this metabolite with macromolecules in the brain. |
Abstract
Autoxidation of the bis(O-demethyl)-p-hydroquinone metabolite of the psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) at pH 7.4 leads exclusively to a bicyclic imino quinone. This imino quinone is a good alkylating agent, forming covalent adducts via 1,4 addition to thiols. The autoxidation appears to be dependent on trace metal catalysis and is dramatically inhibited by components of the 10000g supernatant fraction of rabbit liver homogenates. Incubation of tritium-labeled hydroquinone with bovine serum albumin under oxidizing conditions leads to significant amounts of nonextractable radioactivity which presumably is dependent on imino quinone alkylation of nucleophilic functionalities present on macromolecules. Incubation of tritium-labeled DOM with rabbit microsomes in the presence of NADPH leads to irreversible binding of the label to macromolecular components of the microsomes. Since this binding is NADPH dependent, it is likely that metabolic conversion of DOM to the hydroquinone is involved. The imino quinone oxidation product is highly lypophilic and is capable of crossing the blood-brain barrier. Intravenous administration of tritium-labeled imino quinone to rats resulted in significant nonextractable radioactivity in brain tissue. These properties of the hydroquinone metabolite parallel those reported for the structurally related sympatholytic compound 6-hydroxydopamine and have led to the hypothesis that the psychotomimetic properties of DOM may be mediated through 6-hydroxydopamine-type interactions of the hydroquinone with important macromolecules in the brain.