Comparison of the effects of two 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine analogs, 1-methyl-4-(2-thienyl)-1,2,3,6- tetrahydropyridine and 1-methyl-4-(3-thienyl)-1,2,3,6- tetrahydropyridine, on monoamine oxidase in vitro and on dopamine in mouse brain

RW Fuller, DW Robertson and SK Hemrick-Luecke

1-Methyl-4-(2-thienyl)-1,2,3,6-tetrahydropyridine (2-MTTP) and 1-methyl- 4-(3-thienyl)-1,2,3,6-tetrahydropyridine were compared with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) with respect to their interactions with MAO (monoamine oxidase) in vitro and their ability to produce persistent depletion of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in mice. Both 2- MTTP and 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine were like MPTP in being potent, competitive inhibitors of MAO-A (MAO type A) and weak, noncompetitive inhibitors of MAO-B (MAO type B) in vitro. 2-MTTP resulted in persistent depletion of striatal dopamine, 3,4- dihydroxyphenylacetic acid and homovanillic acid 1 week after the last of four daily injections to mice although 2-MTTP was less than one- fourth as potent as MPTP. The other isomer, 1-methyl-4-(3-thienyl)- 1,2,3,6-tetrahydropyridine, failed to deplete dopamine or its metabolites in mouse striatum. Dopamine and its metabolites were also depleted in mouse nucleus accumbens by 2-MTTP and by MPTP; however, norepinephrine in frontal cortex was depleted by MPTP but not by 2- MTTP. The depletion of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid by 2-MTTP was prevented by pretreatment with deprenyl, a selective inhibitor of MAO-B, or with EXP 561, a dopamine uptake inhibitor, just as the depletion by MPTP was prevented. Mouse brain MAO oxidized 2-MTTP in vitro less rapidly than it oxidized MPTP; deprenyl was a potent inhibitor of the oxidation of both substrates, suggesting that MAO-B oxidizes both 2-MTTP and MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 240, Issue 2, pp. 415-420, 02/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics