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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | VU6067416 (19d) |
| Topics | 5-MeO-DMT DMT Serotonin |
| Keywords | Drug development Serotonin receptors Medicinal chemistry Pharmacology |
| Citations | 6 |
| Key findings | 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.
Comparable studies
Other experimental studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Human cerebral organoids | 2017 | Experimental study | |
| Bufo alvarius: a potent hallucinogen of animal origin. Bufo alvarius toad venom | 1994 | Experimental study | |
| Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment Volunteers | 2019 | Within-subjects experimental study | n = 11 |
| Unmasking of a neonatal somatovesical reflex in adult cats by the serotonin autoreceptor agonist 5-methoxy-N,N-dimethyltryptamine. Adult cats | 1990 | Experimental study | n = 10 |
| Studies on the Mechanism of Action of Monoamine Oxidase: Metabolism of N,N-Dimethyltryptamine and N,N-Dimethyltryptamine-N-Oxide | 1962 | Experimental study |
Citations in the library
Cited by 2
- Psychedelic Drugs Rediscovered-In Silico Study of Potential Fetal Exposure to Analogues of Psychedelic Drugs During Pregnancy. Molecules January 8, 2026
- Structural Pharmacology of Bufotenine Derivatives in Activating the 5-HT 1A Receptor for Therapeutic Potential in Depression and Anxiety Research 2025
Cites 21
- The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology April 26, 2017
- Differences Between the Mechanism of Action of MDMA, MBDB, and the Classic Hallucinogens. Identification of a New Therapeutic Class: Entactogens Journal of Psychoactive Drugs October 1, 1986
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- The pharmacology of psilocybin Addiction Biology October 1, 2002
- MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nature Medicine October 1, 2023
and 16 more in the library