Multitarget μ-Opioid Receptor Agonists─Neuropeptide FF Receptor Antagonists Induce Potent Antinociception with Reduced Adverse Side Effects.
Fiche publication
Date publication
avril 2024
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr SIMONIN Frédéric, Dr KREMER Mélanie
Tous les auteurs :
De Neve J, Elhabazi K, Gonzalez S, Herby C, Schneider S, Utard V, Fellmann-Clauss R, Petit-Demouliere N, Lecat S, Kremer M, Ces A, Daubeuf F, Martin C, Ballet S, Bihel F, Simonin F
Lien Pubmed
Résumé
The design of bifunctional compounds is a promising approach toward the development of strong analgesics with reduced side effects. We here report the optimization of the previously published lead peptide , which contains opioid receptor agonist and neuropeptide FF receptor antagonist pharmacophores and is shown to induce potent antinociception and reduced side effects. We evaluated the novel hybrid peptides for their activity at MOP, NPFFR1, and NPFFR2 and selected four of them () for assessment of their acute antinociceptive activity in mice. We further selected and and observed that their antinociceptive activity is mostly peripherally mediated; they produced no respiratory depression, no hyperalgesia, significantly less tolerance, and strongly attenuated withdrawal syndrome, as compared to morphine and the recently FDA-approved TRV130. Overall, these data suggest that MOP agonist/NPFF receptor antagonist hybrids might represent an interesting strategy to develop novel analgesics with reduced side effects.
Référence
J Med Chem. 2024 04 30;: