Development of Dipeptidic hGPR54 Agonists |
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| Authors: | Dr Christelle Doebelin Isabelle Bertin Séverine Schneider Dr Martine Schmitt Dr Jean‐Jacques Bourguignon Dr Caroline Ancel Dr Valerie Simonneaux Dr Frédéric Simonin Dr Frédéric Bihel |
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| Affiliation: | 1. Faculté de pharmacie, UMR7200, CNRS, University of Strasbourg, Illkirch, France;2. UMR7242, CNRS, University of Strasbourg, ESBS, Illkirch, France;3. UPR3212, CNRS, University of Strasbourg, ICIN, Strasbourg, France |
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| Abstract: | A series of dipeptides were designed as potential agonists of the human KiSS1‐derived peptide receptor (hGPR54). While the sequence Arg‐Trp‐NH2 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‐NH2 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. |
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| Keywords: | agonists GPR54 Sonogashira cross-coupling solid-phase peptide synthesis testosterone |
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