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

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 (KD = 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.