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
ACS Medicinal Chemistry Letters September 14, 2023 DOI: 10.1021/acsmedchemlett.3c00143 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Intervention | D2-DMT |
| Topics | 5-MeO-DMT DMT |
| Keywords | Psychedelics Drug development Mental health treatment Pharmaceutical research |
| Citations | 6 |
| Key points | Deuteration at the α-carbon of DMT yields D2-DMT, which has a longer half-life and comparable receptor binding affinity to DMT. |
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-HT1A, 5-HT2A, and 5-HT2C receptors. D2-DMT was therefore the preferred candidate to consider for further evaluation.