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Dernière mise à jour : Mai 2018

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Neuroendocrinologie Moleculaire de la Reproduction

Rational design of triazololipopeptides analogs of kisspeptin inducing a long-lasting increase of gonadotropins.

J Med Chem. 2015 Apr 23;58(8):3459-70. doi: 10.1021/jm5019675. Epub 2015 Apr 13.

Journal of medical Chemistry
© Journal of medical Chemistry
Beltramo M., Robert V., Galibert M., Madinier J.B., Marceau P., Dardente H., Decourt C., De Roux N., Lomet D., Delmas A.F., Caraty A., Aucagne V.

Abstract

New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-resistant amide mimic and a serum albumin-binding motif, respectively. These triazololipopeptides are highly potent full agonists of KISS1R and are >100 selective over the closely related NPFF1R. When injected in ewes with a quiescent reproductive system, the best compound of our series induced a much prolonged increase of luteinizing hormone release compared to KP10 and increased follicle-stimulating hormone plasma concentration. Hence, this KISS1R agonist is a new valuable pharmacological tool to explore the potential of KP system in reproduction control. Furthermore, it represents the first step to develop drugs treating reproductive system disorders due to a reduced activity of the hypothalamo-pituitary-gonadal axis such as delayed puberty, hypothalamic amenorrhea, and hypogonadotropic hypogonadism.

Link to PubMed