Development of 2,8-diazaspiro[4.5]decan-3-ones as novel sigma-1 receptor antagonists and evaluation of...

Hyperalgesia is a common clinical condition that can be alleviated by blocking the sigma-1 receptor (σ1R). This study focuses on designing a series of 2,8-diazaspiro[4.5]decan-3-one scaffold compounds derived from 4-IBP, with the aim of developing novel σ1R-selective analgesic antagonists. Using radioligand binding assays, we evaluated the affinity (K_i values) of the designed compounds. Compound 52 emerged as a high-affinity, with a K_i of 8.6 nM for σ1R. Pharmacokinetic evaluation showed that compound 52 has a half-life of 2.79 h, and at the 1 h-point, the brain-to-plasma total drug ratio was 4.04. Analgesic efficacy, assessed through Von Frey and Hargreaves tests, demonstrated significant pain relief against both mechanical and thermal stimuli at a dose of 30 mg/kg, with effects comparable to those of E-52862. Our study indicates that compound 52 is a promising candidate for the treatment of hyperalgesia, exhibiting strong selectivity and efficacy as a σ1R antagonist.