Development of a Peptidomimetic Antagonist of Neuropeptide FF Receptors for the Prevention of Opioid-Induced Hyperalgesia

Abstract

Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

Effects of systematic N-terminus deletions and benzoylations of endogenous RF-amide peptides on NPFF1R, NPFF2R, GPR10, GPR54 and GPR103

“…Indeed, most of the RFamide peptides do not show any cationic amino acids in their sequence, so N-terminus were acylated. The choice of the benzoyl moiety instead of the acetoyl group came from the fact that short N-benzoylated RFamide peptides were already reported to display good affinities for NPFF receptors or GPR54 [15][16][17][18][19]. Binding experiments were performed with endogenous radiolabeled ligands as tracers except with NPFF1R and NPFF2R for which we used [ 3 H]FFRF-NH 2 .…”

Rapid and scalable synthesis of innovative unnatural α,β or γ-amino acids functionalized with tertiary amines on their side-chains

“…A first application for these novel non-natural basic amino acids was demonstrated in a liquidphase synthesis of compounds 9a and 9b (Scheme 2), which were recently reported as the first orally active antagonists of NPFF receptors to prevent opioid-induced hyperalgesia in rodents. 9 Starting from compounds 2a and 2j, compounds 9a and 9b were easily synthesized using standard peptide synthesis. This new strategy appears to be much more efficient and less time-consuming than the previously reported method.…”

“…This new strategy appears to be much more efficient and less time-consuming than the previously reported method. 9 More importantly, the availability of the building block 2 allows a fast optimization of the N-and C-terminus in a convergent manner, which is not possible with the reported synthesis. 9 Compounds 9 were initially developed as a peptidomimetic of the corresponding arginine residue.…”

“…9 More importantly, the availability of the building block 2 allows a fast optimization of the N-and C-terminus in a convergent manner, which is not possible with the reported synthesis. 9 Compounds 9 were initially developed as a peptidomimetic of the corresponding arginine residue. 9 Using standard solid-phase synthesis, we pushed the concept further by replacing the arginine moiety of the neuropeptide FF by the residue 2j in order to generate a peptidomimetic analog of the peptide NPFF (Fig.…”

“…9 Compounds 9 were initially developed as a peptidomimetic of the corresponding arginine residue. 9 Using standard solid-phase synthesis, we pushed the concept further by replacing the arginine moiety of the neuropeptide FF by the residue 2j in order to generate a peptidomimetic analog of the peptide NPFF (Fig. 1).…”