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Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists

Summary

Researchers synthesized new drug candidates based on psychedelic molecules like 5-MeO-DMT, replacing the indole core with indazole scaffolds to potentially improve drug properties. While the lead compound VU6067416 showed excellent potency for serotonin receptors and favorable pharmacokinetics, it also activated 5-HT2B receptors strongly, raising safety concerns about heart problems. The study highlights the challenge of developing selective serotonin drugs and emphasizes the need for rigorous safety testing of psychedelic-based therapeutics.

Background

5-MeO-DMT and related tryptamines are potent serotonin 5-HT2A receptor agonists with potential therapeutic applications. Indazole scaffolds have shown superior pharmacokinetic properties as bioisosteres for indoles. Few studies have examined direct indazole analogs of serotonergic tryptamines.

Objective

To synthesize and characterize indazole-ethanamines and indazole-tetrahydropyridines as 5-HT2 agonists, evaluate their 5-HT2 subtype selectivity, and identify compounds suitable for in vivo characterization.

Results

The direct 1H-indazole analog of 5-MeO-DMT (6a) showed low micromolar 5-HT2A activity but displayed higher potency at 5-HT2B and 5-HT2C. The tetrahydropyridine series yielded VU6067416 (19d), a potent 5-HT2A agonist (EC50=189 nM) with favorable pharmacokinetic properties including low hepatic clearance and high brain penetration potential in rats.

Conclusion

While indazole tryptamine analogs demonstrate potent 5-HT2A agonism, achieving selectivity over 5-HT2B remains challenging due to the conserved orthosteric pocket. VU6067416 showed promising preclinical properties but potent 5-HT2B agonist activity limits clinical development due to cardiotoxicity concerns. A possible halogen-bonding interaction may contribute to VU6067416’s potency.
  • Published in:ACS Medicinal Chemistry Letters,
  • Study Type:Medicinal Chemistry Study,
  • Source: 10.1021/acsmedchemlett.3c00566, PMID: 38352850
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