Dichiara, MariaArtacho-Cordón, AntoniaTurnaturi, RitaSantos-Caballero, MiriamGonzález-Cano, RafaelPasquinucci, LorellaBarbaraci, CarlaRodríguez-Gómez, IsabelGómez-Guzmán, ManuelMarrazzo, AgostinoCobos, Enrique JAmata, Emanuele2023-05-032023-05-032022-01-01http://hdl.handle.net/10668/22186The 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.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/AnalgesiaAntagonistDual ligandsHydrogen sulfide donorSigma-1 receptorAnimalsGuinea PigsHydrogenHydrogen SulfideLigandsMaleMorpholinesPainPiperazinesRats, Sprague-DawleyReceptors, sigmaresearch article35016113open access10.1016/j.ejmech.2021.1140911768-3254https://digibug.ugr.es/bitstream/10481/75477/1/Dichiara%20et%20al%20EJMed%20Chem%202022-Preprint.pdf