FIG. 3.

MPTP (IV) is a byproduct sometimes formed in the illicit synthesis of MPPP (III), a narcotic that differs by a single methyl group from alphaprodine (1,3-dimethyl-4-phenyl-4-propionoxypiperidine; Nisentil). Compound I (3,6-dimethyl-6-phenyltetrahydro-1,3-oxazine), which can be produced from easily available ingredients, is treated with sulfuric or hydrochloric acid to produce II (1-methyl-4-phenyl-4- propionoxypiperidine; also called HPMP in Davis et al.²¹). Compound II, when treated with propionic anhydride and sulfuric acid is converted to III (1-methyl-4-phenyl-4-propionoxypiperidine; MPPP; PPMP in Davis et al.²¹). Under excess acidity,²⁰ in the presence of “wet” propionic anhydride,²² or in the presence of dehydrating reagents,¹⁹ II can be converted to IV, (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine; MPTP; HPMP in Davis et al.²¹). Compound I can also be directly converted to MPTP in excess acid.²⁰ Following entry into cells, monoamine oxidase (particularly MAO B, which is more highly expressed in astrocytes than DA neurons) in mitochondria converts MPTP (via conversion to 1-methyl-4-phenyl-2,3, dihydropyridinium; MPFP+, not shown) to V, MPP+ (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridinium),¹⁵⁶ which is accumulated by catecholamine uptake transporters selectively into DA and other catecholamine neurons.¹⁵⁷