Studies on the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP+, the monoamine oxidase catalyzed oxidation product of the nitrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Abstract

The nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is biotransformed by brain monoamine oxidase (MAO) to an unstable dihydropyridinium intermediate that reacts with cyanide ion to form an alpha-cyano-tetrahydropyridine adduct and, in the absence of cyanide ion, undergoes disproportionation to the 1-methyl-4-phenylpyridinium species MPP+ and MPTP. Comparison of the HPLC retention times, diode array UV, and chemical ion mass spectral characteristics of these products with those of synthetic standards led us to propose the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP+ and 6-cyano-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as tentative structure assignments for the dihydropyridinium metabolite and the cyano adduct, respectively. Results presented in this paper confirm the first assignment and establish that, although the proposed 6-cyano adduct is initially formed, the product that was isolated from the mitochondrial incubation mixtures of MPTP and sodium cyanide actually is the isomeric 2-cyano-1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine. On the basis of the selective incorporation of deuterium into these products, we provide rational mechanistic interpretations of the disproportionation reaction and the rearrangement of the cyano adducts. These results establish that the MAO-catalyzed bioactivation of MPTP leads to the formation of a variety of reactive molecules that are potentially cytotoxic to nigrostriatal cells.

Therapeutic Effects of Hydrogen in Animal Models of Parkinson's Disease

“…First, MPTP is converted to the intermediate 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP + ), catalyzed by MAO-B [8]. Then, unstable MPDP + dissociates to MPP + and MPTP [9, 10]. Conversion of MPTP to MPDP + occurs in glial cells and serotonergic cells, not in dopaminergic cells.…”

Characterization of Novel Dihydrothienopyridinium and Thienopyridinium Metabolites of Ticlopidine in Vitro: Role of Peroxidases, Cytochromes P450, and Monoamine Oxidases

“…Studies with other dihydropyridinium compounds have shown that these molecules undergo spontaneous (concentration-dependent) disproportionation to stoichiometric amounts of the pyridinium and tetrahydropyridine species at pH 7.4 (Peterson et al, 1985). Ticlopidine can undergo a similar process, presumably via a mechanism that appears to involve the conversion of M5 to a free base (21), followed by a hydride transfer to another molecule of M5, resulting in equimolar amounts of ticlopidine and M6 (Fig.…”

“…Alternatively, nucleophiles could add only reversibly to M5. Attempts to trap M5 with cyanide or other nucleophiles such as glutathione or N-acetylcysteine proved unsuccessful, even though cyanide additions to MPDP ϩ or 3,3-MPDP ϩ to form the respective cyanide adducts have been reported (Gessner et al, 1985;Peterson et al, 1985;Sayre et al, 1986). Furthermore, stability studies with M5 (generated in large amounts by incubating ticlopidine with the HRP/H 2 O 2 system) at a pH of 7.4 showed that the metabolite was stable to auto-oxidation or disproportionation at this pH (data not shown).…”

Therapeutic and Diagnostic Agents for Parkinson's Disease

“…This intermediate undergoes a two-electron oxidation to the stable 1-methyl-4-phenylpyridinium species (8) (Fig. 1) via auto-oxidation, disproportionation, and MAO-B catalysis [97][98][99] (Fig. 1).…”