TY - JOUR T1 - Inhibition of Dimethyltryptamine Biosynthesis by N,N'-Bis-(3-methyl-2-thiazolidinylidene)Succinamide (I) and 2-Imino-3-Methylthiazolidine (II) JF - Molecular Pharmacology JO - Mol Pharmacol SP - 930 LP - 939 VL - 14 IS - 5 AU - LEWIS R. MANDEL AU - JOSHUA ROKACH AU - C. STANLEY ROONEY AU - EDWARD J. CRAGOE, JR. Y1 - 1978/09/01 UR - http://molpharm.aspetjournals.org/content/14/5/930.abstract N2 - N,N'-bis-(3-methyl-2-thiazolidinylidene)succinamide (I) and 2-imino-3-methylthiazolidine (II) are inhibitors of indoleamine-N-methyltransferase, the enzyme which biosynthesizes N,N-dimethyltryptamine. I was designed as a neutral compound which will form the active basic metabolite II in rabbits. In Vitro, I is not an effective inhibitor, while II is a potent inhibitor of the rabbit and human lung enzyme (IC50 ≤ 3 µM). When administered to rabbits at 4-5 mg/kg i.v., both compounds produce a 60% reduction in the specific activity of the lung methyltransferase. A single oral dose of I produces 50% inhibition of enzyme activity when the animals are sacrificed 2 hr after dosage (8 mg/kg) or at 7 hr (68 mg/kg). Administration of II in the drinking water for 12 days at a daily dose equivalent to about 7 mg/kg results 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. I was also evaluated orally for its effect on dimethyltryptamine biosynthesis in rabbits; at single doses of 100 mg/kg or at 25 mg/kg twice daily for four days, there was a 65% reduction in the conversion of [14C]N-methyltryptamine (administered i.v.) to [14C]dimethyltryptamine in lung. The level of carotid arterial DMT appearing over 1 minute after the intravenous injection of NMT (10 mg/kg) was also reduced 75%. Thus, inhibition of indoleamine-N-methyltransferase results in a block in the in vivo biosynthesis of dimethyltryptamine. ACKNOWLEDGMENTS The authors are grateful to Dr. R. A. Prasad, Dr. T. Farver, Dr. A. G. Zacchei, Mr. M. Schnall, Mr. R. W. Walker and Mr. B. Lopez-Ramos for valuable assistance on various aspects of this work. We also thank Dr. A. Rosegay and Dr. H. Mertel for the synthesis of the [14C]NMT, and Dr. Duggan for advice on preparing the manuscript. ER -