Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation.

The development of σ receptor antagonists hybridized with a HS-donor is here reported. We aimed to obtain improved analgesic effects when compared to σ receptor antagonists or HS-donors alone. In an in vivo model of sensory hypersensitivity, thioamide 1a induced analgesia which was synergistically enhanced when associated with the σ receptor antagonist BD-1063. The selective σ receptor agonist PRE-084 completely reversed this effect. Four thioamide HS-σ receptor hybrids (5a-8a) and their amide derivatives (5b-8b) were synthesized. Compound 7a (AD164) robustly released HS and showed selectivity for σ receptor over σ and opioid receptors. This compound induced marked analgesia that was reversed by PRE-084. The amide analogue 7b (AD163) showed only minimal analgesia. Further studies showed that 7a exhibited negligible acute toxicity, together with a favorable pharmacokinetic profile. To the best of our knowledge, compound 7a is the first dual-acting ligand with simultaneous HS-release and σ antagonistic activities.