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

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-HT_2B 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-HT_2B 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 Phe234^5.38 in the 5-HT_2A orthosteric pocket.