Conversion of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (mptp) and its 5‐methyl analog into pyridinium salts

Abstract

SummaryMonoamine oxidase B metabolizes I-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 1) first to l-methyl-4-phenyl-2,3-dihydropyridinium salt (MPDP+; 5), and then to 1-methyl-4-phenylpyridinium salt (MPP+; 7). Chemical synthesis of MPDP+ and its 5-methyl analog 6 was accomplished from the N-oxides 3 and 4 of MPTP and its 5-methyl analog, respectively, by a Polonovski reaction. Oxidation of MPDP' to MPP+ was accomplished with air, and greatly accelerated by Pt catalyst. Reduction of MPDP' and MPP' with NaBH, afforded MPTP.The compound l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP; 1) [I] was found to be highly neurotoxic in man and certain animal species, depleting the substantia nigra of dopamine and causing effects similar to those observed in Parkinson's disease [2-51. The pyridinium salt 7 (MPP'), isolated from brain tissue of monkey and characterized by HPLC/MS, is considered to be the major metabolite of MPTP in human and primates [&8].The 5-methyl derivative 2 was included in this investigation since it is closly related to analgetics of the prodine family of drugs [9].Chemistry. -In this communication we report the facile chemical conversion of MPTP (1) and its 5-methyl derivative 2 [9] to their pyridinium analoges 7 and 8, respectively, via dihydropyridinium salts 5 and 6. Although oxidation of tetrahydropyridines to pyridines can be accomplished directly using mercury acetate [lo], we considered the approach via dihydropyridinium derivatives to be more 'physiological' since the 1 -methyl-4-phenyl-2,3-dihydropyridinium salt (5, MPDP+) is a likely intermediate metabolite of MPTP [7] [8]. The methodology applied for conversion of tetrahydropyridines to dihydropyridinium salts was based on the Polonovski reaction utilized successfully ') ' ) Dedicated to Prof. Dr. H . C. Beyerrnun of the Laboratory of Organic Chemistry at the Technical Highschool in Delft, the Netherlands, on the occasion of his 65th birthday. Visiting scientist from A.

Liquid chromatographic–electrospray mass spectrometric determination of 1-methyl-4-phenylpyridine (MPP+) in discrete regions of murine brain

“…The facility of this generation led to the conclusion that the dihydropyridine structure MPDP + is a necessary intermediate, as shown in Scheme 2. This was a fortunate speculation even in the absence of support from an m/z 172 peak in Figure 6b, since it agreed with the well known reactivity of the MPDP + intermediate (Gessner et al 1984; 1985), particularly under oxidizing conditions, and since it helped explain the more complex m/z 174 product ion mass spectrum of MPTP in Figure 6a. Specifically, the observation of many ions differing by 2 amu values encouraged assignment of MPTP fragments as belonging to either MPTP+H + , MPDP + , or even MPP + itself.…”

Molecular determinants in the bioactivation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

“…The primary product of this oxidation is the resonance-stabilized cation MPDP + which is rapidly oxidized to the stable MPP + [39,40]. In contrast to MPTP, 1-methyl-4-phenylpiperidine, the product of the partial hydrogenation of MPTP, is a poor substrate of MAO [41].…”

Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP+by Transporter-Independent Export of the Intermediate MPDP+

“… Synthesis of MPTP-HCI ( 4) and MPDP + bromide ( 6 ) . (a) THF, −78°C→ rt, overnight; ( 18 ) (b) aq HCl, reflux, 5 h, quantitative; ( 18 ) (c) (i) NaEtO, EtOH, 0°C (ii) aq H 2 O 2 , EtOH, 50°C, quantitative; ( 20 ) (d) DCM, TFAA, aq HBr, 0°C, 53%. ( 20 ).…”