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. 2022 Feb 15:230:114091.
doi: 10.1016/j.ejmech.2021.114091. Epub 2022 Jan 1.

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

Maria Dichiara  1 , Antonia Artacho-Cordón  2 , Rita Turnaturi  1 , Miriam Santos-Caballero  2 , Rafael González-Cano  2 , Lorella Pasquinucci  1 , Carla Barbaraci  1 , Isabel Rodríguez-Gómez  3 , Manuel Gómez-Guzmán  4 , Agostino Marrazzo  1 , Enrique J Cobos  5 , Emanuele Amata  6
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Free article

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

Maria Dichiara et al. Eur J Med Chem. .
Free article

Abstract

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.

Keywords: Analgesia; Antagonist; Dual ligands; Hydrogen sulfide donor; Sigma-1 receptor.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.