Development of Dipeptidic hGPR54 Agonists

Abstract

A series of dipeptides were designed as potential agonists of the human KiSS1-derived peptide receptor (hGPR54). While the sequence Arg-Trp-NH was the most efficient in terms of affinity, we established a convergent synthetic strategy to optimize the N terminus. Using two successive Sonogashira cross-coupling reactions on a solid-supported peptide, we were able to introduce various alkynes at the N terminus to afford compounds with sub-micromolar affinities for hGPR54. However, functional assays indicated the benzoylated dipeptide Bz-Arg-Trp-NH as the most promising compound in terms of agonistic properties. Interestingly, this compound appeared much more stable than the endogenous neuropeptide kisspeptin, both in serum and in liver microsomes of rats. This compound was also found to be able to induce a significant in vivo increase in testosterone levels in male rats.

GnRHand the photoperiodic control of seasonal reproduction: Delegating the task to kisspeptin andRFRP‐3

“…In recent years, several KISS1R agonists with a longer half‐life than the natural Kp10 peptide have been designed: TAK‐448 219 ; C6, 220 Bz‐Arg‐Trp‐NH 2. 221 Among those, C6 delivered i.m. triggered fertile ovulations in anoestrus ewes and goats 220,222 .…”

Transition Metal‐Catalyzed Reactions and Solid‐Phase Synthesis: A Convenient Blend

“…Bihel et al [27] . reported the application of Sonogashira coupling to solid‐phase peptide synthesis.…”

“…Moderate to good yields were achieved, being the best results when electron-withdrawing containing aryl iodides were used. For example, N-[3-(4-cyanophenyl)prop-2-yn-1yl]acetamide (29) was obtained from 4-iodobenzonitrile (27) in 60 % yield (overall yield, from initial Wang resin loading to final release from the support, 4 steps) (Scheme 6).…”

“…Bihel et al [27] reported the application of Sonogashira coupling to solid-phase peptide synthesis. They designed two consecutive Sonogashira couplings to prevent racemization of the supported peptide.…”

Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction

“…Another small molecule, benzoylated dipeptide Bz-Arg-Trp-NH2, shows promising KISS1R agonistic activity and better stability than the endogenous kisspeptins in rats. However, its selectivity towards other RFamide receptors such as NPFF1R and NPFF2R needs to be resolved [ 96 ]. Because the cost of synthesis and the stability of small molecules are more favorable than those of kisspeptin, it is worth investigating whether these small molecules can facilitate oral administration in the future and provide a therapeutic advantage in clinical trials.…”