Discovery\nand <i>In Vitro</i> Characterization\nof SPL028: Deuterated <i>N</i>,<i>N</i>‑Dimethyltryptamine

Abstract

The\npsychedelic <i>N</i>,<i>N</i>- dimethyltryptamine\n(DMT) is in clinical development for the treatment of major depressive\ndisorder. However, when administered via intravenous infusion, its\neffects are short-lived due to rapid clearance. Here we describe the\nsynthesis of deuterated analogues of DMT with the aim of prolonging\nthe half-life and decreasing the clearance rate while maintaining\nsimilar pharmacological effects. The molecule with the greatest degree\nof deuteration at the α-carbon (<i>N</i>,<i>N</i>-D₂-dimethyltryptamine, D₂-DMT) demonstrated\nthe longest half-life and intrinsic clearance in hepatocyte mitochondrial\nfractions when compared with DMT. The <i>in vitro</i> receptor\nbinding profile of D₂-DMT was comparable to that of DMT,\nwith the highest affinity at the 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors. D₂-DMT was therefore\nthe preferred candidate to consider for further evaluation.