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

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-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.

Figure 1

Chemical structures of DMT, 5-MeO-DMT, and 1H-indazole 3.

Scheme 1. Synthesis of Indazoles 6a–6c

(a) LiOH, THF, H₂O, rt; (b) dimethylamine hydrochloride or diethylamine, HATU, DIPEA, DMF, rt; (c) LiAlH₄, or LiAlD_4, THF, rt.

Scheme 2. Synthesis of indazole 11

(a) MeI, Cs₂CO₃, DMF, rt, 27%; (b) DIBAL, DCM, −78 °C to rt, 67%; (c) Dess–Martin periodinane, DCM, rt, 91%; (d) dimethylamine hydrochloride, NaBH(OAc)₃, DCM, rt, 33%.

Scheme 3. Synthesis of Indazoles 14 and 16

(a) LiOH, THF, H₂O, rt.; (b) dimethylamine hydrochloride, HATU, DIPEA, DMF, rt, 26% over 2 steps; (c) LiAlH₄, THF, rt, 14%; (d) dimethylamine hydrochloride, HATU, DIPEA, THF, DMF, rt; (e) LiAlH₄, THF, rt, 11% over 2 steps.

Scheme 4. Synthesis of Indazoles 19a-f, 20, and 21

(a) tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate, K₂CO₃, PdCl₂(dppf)·DCM, 1,4-dioxane, H₂O, 110 °C; (b) HCl, DCM, rt; (c) 10% Pd/C, ammonium formate, MeOH, 60 °C; (d) phenylboronic acid, K₂CO₃, PdCl₂(dppf)·DCM, 1,4-dioxane, H₂O, 110 °C.

Figure 2

(A) Compound 19d docked to 5-HT_2AR, with predicted halogen bonding interaction (yellow dashes) with Phe234^5.38. (B) Compound 19d docking pose overlaid with (R)-69 (pink) cryo-EM pose. (C) Compound 19d docked to 5-HT_2BR. (D) Compound 19d 5-HT_2BR docking pose overlaid with the LSD (yellow) cryo-EM pose. Blue dashes depict salt bridges and hydrogen bonds.