Molecular Pharmacology, Vol 14, 930-939, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Dimethyltryptamine Biosynthesis by N,N'-Bis-(3-methyl-2-thiazolidinylidene)Succinamide (I) and 2-Imino-3-Methylthiazolidine (II)

¹ Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065, West Point, Pennsylvania 19486, and Dorval, Quebec, Canada H9R4P8

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.

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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.