Synthetic and metabolic studies on 1-methyl-4-(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine, a neurotoxic analog of the Parkinsonian inducing agent MPTP

1-Methyl-4-(1-methylpyrrol-2-yl)-1 ,2,3,6-tetrahydropyridine (TMMP) is a neurotoxic analog of the parkinsonian inducing agent MPTP. TMMP and its putative metabolites 1-methyl-4-(1-methylpyrrol-2-yl)-2,3-dihydropyridinium (MMDP+) and 1-methyl-4-(1-methylpyrrol-2-yl)pyridinium (MMP+) were synthesized and fully characterized. Substrate/inactivation properties of TMMP and its analog N-propargyl-4-(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine with MAO-B were investigated. Kinetic data was obtained, including Km and Vmax for TMMP as an MAO-B substrate, and KI and kinact values for N-propargyl-4-(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine. The metabolic studies of TMMP and MMDP+ were conducted with an HPLC diode array assay. Both in-vivo and in-vitro metabolic studies showed that TMMP is oxidized to its dihydropyridinium species (MMDP+) in a reaction catalyzed by MAO-B. MMDP+ undergoes autoxidation to form the pyridinium species (MMP+), the mechanism of this conversion is not clear. In-vitro studies show that MAO-B is not responsible for this conversion and the oxidation of MMDP+ to MMP+ is likely to be enzyme catalyzed. Toxicity investigations include dopamine depletion studies of TMMP and MMDP+, mitochondrial respiration and microdialysis studies of MMDP+ and MMP+. The above studies show that TMMP is an MPTP-type neurotoxin.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

1991

Author dc:creator

• Bai, Hong

Chair dc:contributor.committeechair

• Castagnoli, Neal Jr.

Committee members dc:contributor.committeemember

• Merola, Joseph S.
• Becker, David A.

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

etd-08042009-040225

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/44138