title: 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-NH2was 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-NH2as 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.
authors: Faculté de pharmacie, UMR7200, CNRS, University of Strasbourg, 74 route du Rhin, 67400, Illkirch, France.
authors: Christelle
authors: C
authors: Doebelin
authors: UMR7242, CNRS, University of Strasbourg, ESBS, 67412, Illkirch, France.
authors: Isabelle
authors: I
authors: Bertin
authors: Faculté de pharmacie, UMR7200, CNRS, University of Strasbourg, 74 route du Rhin, 67400, Illkirch, France.
authors: Séverine
authors: S
authors: Schneider
authors: Faculté de pharmacie, UMR7200, CNRS, University of Strasbourg, 74 route du Rhin, 67400, Illkirch, France.
authors: Martine
authors: M
authors: Schmitt
authors: Faculté de pharmacie, UMR7200, CNRS, University of Strasbourg, 74 route du Rhin, 67400, Illkirch, France.
authors: Jean-Jacques
authors: JJ
authors: Bourguignon
authors: UPR3212, CNRS, University of Strasbourg, ICIN, 67000, Strasbourg, France.
authors: Caroline
authors: C
authors: Ancel
authors: UPR3212, CNRS, University of Strasbourg, ICIN, 67000, Strasbourg, France.
authors: Valerie
authors: V
authors: Simonneaux
authors: UMR7242, CNRS, University of Strasbourg, ESBS, 67412, Illkirch, France. simonin@unistra.fr.
authors: Frédéric
authors: F
authors: Simonin
authors: Faculté de pharmacie, UMR7200, CNRS, University of Strasbourg, 74 route du Rhin, 67400, Illkirch, France. fbihel@unistra.fr.
authors: Frédéric
authors: 0000-0002-4122-0929
authors: F
authors: Bihel
mesh_terms: D000818:Animals; D004151:Dipeptides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000074502:Receptors, Kisspeptin-1; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000096:biosynthesis
chemical_list: D004151:Dipeptides; C118688:KISS1R protein, human; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D013739:Testosterone
keywords: GPR54; Sonogashira cross-coupling; agonists; solid-phase peptide synthesis; testosterone