Abstract

Methylenedioxymethamphetamine (MDMA) and methylenedioxyamphetamine (MDA) are both schedule 1 controlled substances with abuse potential as hallucinogens. The ready demethylation of most xenobiotics would suggest that MDMA is a prodrug and rapidly converted to its active form, MDA, by metabolism. However, some differences in pharmacological effects have been noted that suggest the two compounds are pharmacologically distinct. This project evaluates this notion and investigates the mechanism for the neurotoxicity of MDA by a study of the metabolism, neurochemistry and neurotoxicity of MDA and MDMA. The methylenedioxyphenyl function is the focus of the research since it could be responsible for inhibition of monooxygenase catalyzed metabolism, affinity for the 5HT neuron and formation of potentially toxic intermediates. The interaction of MDA and MDMA with cytochrome P450 will be determined from metabolic reactions and spectroscopic analysis. The affinities of the two compounds for catecholaminergic and serotonergic nerve terminals will be determined in vitro using synaptosome preparations and in vivo with voltammetry. The mechanism of neurotoxicity of the compounds will be determined by biochemical and histological procedures.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004206-02
Application #
3209537
Study Section
(DABB)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Chu, T; Kumagai, Y; DiStefano, E W et al. (1996) Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion. Biochem Pharmacol 51:789-96
Lin, L Y; Kumagai, Y; Hiratsuka, A et al. (1995) Cytochrome P4502D isozymes catalyze the 4-hydroxylation of methamphetamine enantiomers. Drug Metab Dispos 23:610-4
Hiratsuka, A; Chu, T Y; Distefano, E W et al. (1995) Inactivation of constitutive hepatic cytochromes P450 by phencyclidine in the rat. Drug Metab Dispos 23:201-6
Kumagai, Y; Lin, L Y; Hiratsuka, A et al. (1994) Participation of cytochrome P450-2B and -2D isozymes in the demethylenation of methylenedioxymethamphetamine enantiomers by rats. Mol Pharmacol 45:359-65
Cho, A K; Hiramatsu, M; Kumagai, Y et al. (1993) Pharmacokinetic approaches to the study of drug action and toxicity. NIDA Res Monogr 136:213-25
Cho, A K; Hiramatsu, M; Schmitz, D A et al. (1993) A behavioral and pharmacokinetic study of the actions of phenylcyclohexyldiethylamine and its active metabolite, phenylcyclohexylethylamine. J Pharmacol Exp Ther 264:1401-5
Kumagai, Y; Lin, L Y; Philpot, R M et al. (1992) Regiochemical differences in cytochrome P450 isozymes responsible for the oxidation of methylenedioxyphenyl groups by rabbit liver. Mol Pharmacol 42:695-702
Lin, L Y; Kumagai, Y; Cho, A K (1992) Enzymatic and chemical demethylenation of (methylenedioxy)amphetamine and (methylenedioxy)methamphetamine by rat brain microsomes. Chem Res Toxicol 5:401-6
Kumagai, Y; Schmitz, D A; Cho, A K (1992) Aromatic hydroxylation of methylenedioxybenzene (MDB) and methylenedioxymethamphetamine (MDMA) by rabbit liver microsomes. Xenobiotica 22:395-403
Kumagai, Y; Wickham, K A; Schmitz, D A et al. (1991) Metabolism of methylenedioxyphenyl compounds by rabbit liver preparations. Participation of different cytochrome P450 isozymes in the demethylenation reaction. Biochem Pharmacol 42:1061-7

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