Discovery and In Vitro Characterization of SPL028: Deuterated N, N-Dimethyltryptamine

Marie Layzell; Peter Rands; Meghan Good; Zelah Joel; Rick Cousins; Tiffanie Benway; Ellen James; Carol Routledge

doi:10.1021/acsmedchemlett.3c00143

Discovery and In Vitro Characterization of SPL028: Deuterated N, N-Dimethyltryptamine

ACS Med Chem Lett. 2023 Aug 31;14(9):1216-1223. doi: 10.1021/acsmedchemlett.3c00143. eCollection 2023 Sep 14.

Authors

Marie Layzell¹, Peter Rands¹, Meghan Good¹, Zelah Joel¹, Rick Cousins², Tiffanie Benway¹, Ellen James¹, Carol Routledge¹

Affiliations

¹ Small Pharma., 50 Featherstone Street, London EC1Y 8RT, U.K.
² Cinnabar Consulting Ltd., 43 Pedley Lane, Clifton, Beds SG17 5QT, U.K.

Abstract

The psychedelic N,N- dimethyltryptamine (DMT) is in clinical development for the treatment of major depressive disorder. However, when administered via intravenous infusion, its effects are short-lived due to rapid clearance. Here we describe the synthesis of deuterated analogues of DMT with the aim of prolonging the half-life and decreasing the clearance rate while maintaining similar pharmacological effects. The molecule with the greatest degree of deuteration at the α-carbon (N,N-D₂-dimethyltryptamine, D₂-DMT) demonstrated the longest half-life and intrinsic clearance in hepatocyte mitochondrial fractions when compared with DMT. The in vitro receptor binding profile of D₂-DMT was comparable to that of DMT, with the highest affinity at the 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors. D₂-DMT was therefore the preferred candidate to consider for further evaluation.