RT Journal Article
T1 Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation.
A1 Dichiara, Maria
A1 Artacho-Cordón, Antonia
A1 Turnaturi, Rita
A1 Santos-Caballero, Miriam
A1 González-Cano, Rafael
A1 Pasquinucci, Lorella
A1 Barbaraci, Carla
A1 Rodríguez-Gómez, Isabel
A1 Gómez-Guzmán, Manuel
A1 Marrazzo, Agostino
A1 Cobos, Enrique J
A1 Amata, Emanuele
K1 Analgesia
K1 Antagonist
K1 Dual ligands
K1 Hydrogen sulfide donor
K1 Sigma-1 receptor
AB 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.
YR 2022
FD 2022-01-01
LK http://hdl.handle.net/10668/22186
UL http://hdl.handle.net/10668/22186
LA en
DS RISalud
RD Apr 14, 2025