%0 Journal Article
%A Dichiara, Maria
%A Artacho-Cordón, Antonia
%A Turnaturi, Rita
%A Santos-Caballero, Miriam
%A González-Cano, Rafael
%A Pasquinucci, Lorella
%A Barbaraci, Carla
%A Rodríguez-Gómez, Isabel
%A Gómez-Guzmán, Manuel
%A Marrazzo, Agostino
%A Cobos, Enrique J
%A Amata, Emanuele
%T Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation.
%D 2022
%U http://hdl.handle.net/10668/22186
%X 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.
%K Analgesia
%K Antagonist
%K Dual ligands
%K Hydrogen sulfide donor
%K Sigma-1 receptor
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