Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists.
Navoda Jayakodiarachchi, Mallory A Maurer, Daniel C Schultz, Cayden J Dodd, Analisa Thompson Gray, Hyekyung P Cho, Olivier Boutaud, Carrie K Jones, Craig W Lindsley, Aaron M Bender
ACS medicinal chemistry letters February 8, 2024 DOI: 10.1021/acsmedchemlett.3c00566 via PubMed
Summary
AI-generated from the abstractA new set of indazole-based compounds was synthesized and tested as potent agonists of the serotonin 5-HT2 receptor subtypes. The direct indazole analogs of 5-MeO-DMT showed strong activity, but many, including the optimized compound VU6067416 (19d), also acted as potent 5-HT2B agonists, which prevented further development due to safety concerns. Computational docking studies suggest that the high potency of 19d may arise from a halogen-bonding interaction with Phe2345.38 in the 5-HT2A binding pocket. The work underscores the importance of rigorous subtype selectivity profiling for these serotonergic compounds.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | VU6067416 (19d) |
| Keywords | Drug development Neuroscience Serotonin receptors Medicinal chemistry Pharmacology |
| Citations | 6 |
| Key finding | The potent 5-HT2 agonist VU6067416 (19d) had suitable preclinical pharmacokinetic properties but was precluded from further characterization due to potent 5-HT2B agonist activity. |
Abstract
Herein, we report the synthesis and characterization of a novel set of substituted indazole-ethanamines and indazole-tetrahydropyridines as potent serotonin receptor subtype 2 (5-HT2) agonists. Specifically, we examine the 5-HT2 pharmacology of the direct indazole analogs of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and related serotonergic tryptamines, and highlight the need for rigorous characterization of 5-HT2 subtype selectivity for these analogs, particularly for the 5-HT2B receptor subtype. Within this series, the potent analog VU6067416 (19d) was optimized to have suitable preclinical pharmacokinetic properties for in vivo dosing, although potent 5-HT2B agonist activity precluded further characterization for this series. Additionally, in silico docking studies suggest that the high potency of 19d may be a consequence of a halogen-bonding interaction with Phe2345.38 in the 5-HT2A orthosteric pocket.