AD164

The development of σ₁ receptor antagonists hybridized with a H₂S-donor is here reported. We aimed to obtain improved analgesic effects when compared to σ₁ receptor antagonists or H₂S-donors alone. In an in vivo model of sensory hypersensitivity, thioamide 1a induced analgesia which was synergistically enhanced when associated with the σ₁ receptor antagonist BD-1063. The selective σ₁ receptor agonist PRE-084 completely reversed this effect. Four thioamide H₂S-σ₁ receptor hybrids (5a-8a) and their amide derivatives (5b-8b) were synthesized. Compound 7a (AD164) robustly released H₂S and showed selectivity for σ₁ receptor over σ₂ 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 H₂S-release and σ₁ antagonistic activities.