Discovering a painkiller devoid of side effects is the grail sought by many academic teams and the pharmaceutical industry. Indeed, opiates such as morphine, whose analgesic action is mainly linked to its ability to activate the mu opioid receptor, are still the most widely used molecules in clinical practice, despite numerous short- and long-term side effects such as respiratory depression, constipation, tolerance (decrease in analgesic effect over time) and dependence.
A previous study involving Frédéric Simonin's team, Frédéric Bihel’s team of the Laboratoire d'Innovation Thérapeutique (Illkirch) and Steven Ballet’s team (Vreii University of Brussels) identified a new compound with a dual action: mu-biased agonist - antagonist of FF neuropeptide receptors (NPFF1 and NPFF2). This compound (KGFF09) displayed a powerful analgesic effect with attenuated side effects, however it still showed impaired motor coordination upon acute administration, and a significant withdrawal syndrome.
In a work recently published in the Journal of Medicinal Chemistry, the teams sought to further improve these ligands through an in-depth study of structure-activity relationships. This study revealed important structural features for maintaining G-protein signaling and reducing beta-arrestin recruitment at the mu-opioid receptor (thought to be responsible for certain side effects), as well as antagonistic activity at the FF1 and FF2 neuropeptide receptors, whose blockade limits some opioid adverse side effects. The researchers characterized the most promising compounds in vivo and showed that they produce no impairment of motor coordination, no respiratory depression, no hyperalgesia, significantly less analgesic tolerance and a strong attenuation of the withdrawal syndrome compared with morphine and the biased mu-opioid agonist TRV130 (or oliceridine) recently approved by the FDA.
These properties make these new compounds promising candidates for the development of new analgesics that are safer, more effective and with limited short- and long-term side effects.
Article :
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* (2024). Multitarget μ-Opioid Receptor Agonists - Neuropeptide FF Receptor Antagonists Induce Potent Antinociception with Reduced Adverse Side Effects. J Med Chem 67(9):7603-7619. doi: 10.1021/acs.jmedchem.4c00442.
