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Chemical and biological studies of 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine
- Source :
- Journal of medicinal chemistry. 22(6)
- Publication Year :
- 1979
-
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.
- Subjects :
- Male
Chemical Phenomena
Stereochemistry
Macromolecular Substances
Metabolite
Dopamine
In Vitro Techniques
chemistry.chemical_compound
Hydroxydopamines
Drug Discovery
Animals
Bovine serum albumin
Serum Albumin
Hydroxydopamine
Hydroquinone
biology
Autoxidation
2,5-Dimethoxy-4-Methylamphetamine
Amphetamines
Quinones
Brain
Quinone
Hydroquinones
Rats
Chemistry
chemistry
biology.protein
Microsome
Microsomes, Liver
Molecular Medicine
Amine gas treating
Rabbits
Oxidation-Reduction
Protein Binding
Subjects
Details
- ISSN :
- 00222623
- Volume :
- 22
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....50fe9fafb98b7ae8bfbeab6728636185