Inhibition of dimethyltryptamine biosynthesis by N,N'-bis- (3-methyl-2-thiazolidinylidene) succinamide (I) and 2-imino-3-methylthiazolidine (II)
Mandel, L.R.; Rokach, J.; Rooney, C.S.; Cragoe, E.J.
Molecular Pharmacology 14(5): 930-939
1978
ISSN/ISBN: 0026-895X PMID: 280749 Document Number: 138208
N,N'-bis-(3-methyl-2-thiazolidinylidene)succinamide (1) and 2-imino-3-methylthiazolidine (2) are inhibitors of indoleamine-N-methyltransferase, the enzyme which biosynthesizes N,N-dimethyltryptamine [DMT]. Compound 1 was designed as a neutral compound which will form the active basic metabolite 2 in rabbits. In vitro, 1 is not an effective inhibitor, while 2 is a potent inhibitor of the rabbit and human lung enzyme (IC50 [concentration producing 50% inhibition] .ltoreq. 3 .mu.M). When administered to rabbits at 4-5 mg/kg i.v., both compounds produced a 60% reduction in the specific activity of the lung methyltransferase. A single oral dose of 1 produced 50% inhibition of enzyme activity in animals sacrificed 2 h after dosage (8 mg/kg) or at 7 h (68 mg/kg). Administration of 2 in the drinking H2O for 12 days at a daily dose equivalent to about 7 mg/kg resulted in a 36% inhibition in the activity of the lung enzyme. When enzyme preparations from drug-treated rabbits were dialyzed, the specific activity returned to control values, suggesting a reversible type inhibition. Compound 1 was also evaluated orally for its effect on DMT biosynthesis in rabbits; at single doses of 100 mg/kg or at 25 mg/kg twice daily for 4 days, there was a 65% reduction in the conversion of [14C]N-methyltryptamine [NMT] (administered i.v.) to [14C]DMT in lung. The level of carotid arterial DMT appearing over 1 min after the i.v. injection of NMT (10 mg/kg) was reduced 75%. Inhibition of indoleamine-N-methyltransferase results in a block in the in vivo biosynthesis of DMT (an endogenous psychogenic compound thought to have a role in schizophrenia and to have behavioral effects in animals).