Discovery of 3-indolealkylamines as novel dual-target σ1R/H3R ligands with potent analgesia

Abstract

Dual-acting ligands targeting the sigma-1 receptor (σ₁R) and histamine H₃ receptor (H₃R) are emerging as promising candidates for novel and safe analgesics. In this work, we designed, synthesized, and evaluated twenty-nine 3-indolealkylamines as dual σ₁R/H₃R ligands. In vitro radioligand receptor binding assay or surface plasmon resonance assay were performed to determine their affinities toward σ₁R or H₃R. Among them, compound 67 demonstrated high binding affinity for both σ₁R (Kᵢ = 8.8 nM) and H₃R (K_D = 31.2 nM). Further in vivo pharmacological evaluations confirmed its antagonistic activity at both receptors. Compound 67 exhibited significant antinociceptive effects in the acetic acid-induced constriction test (ED₅₀ = 0.18 mg/kg) and paclitaxel-induced neuropathic pain model (ED₅₀ = 0.06 mg/kg), which demonstrated potency superior to that of marketed drug gabapentin. Moreover, compound 67 showed no side effects in the open-field test and rotarod test, and acute toxicity studies revealed a high safety profile with an excellent therapeutic window (LD₅₀ > 250 mg/kg, TI > 1388.9). These findings demonstrated that compound 67 is a promising dual σ₁R/H₃R ligand to develop safe and effective analgesics.