The kisspeptin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the kisspeptin receptor [3]), like neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) responds to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. Kisspeptin-54 (KISS1, Q15726) (KP54, originally named metastin), kisspeptin-13 (KISS1, Q15726) (KP13) and kisspeptin-10 (KISS1) (KP10) are biologically-active peptides cleaved from the KISS1 (Q15726) gene product. Kisspeptins have roles in, for example, cancer metastasis, fertility/puberty regulation and glucose homeostasis.

2-acylamino-4,6-diphenylpyridine derivatives have been described and are the first small molecule kisspeptin receptor antagonists reported with potential for treatment of sex-hormone dependent diseases such as prostate cancer and endometriosis [2,4].

* Key recommended reading is highlighted with an asterisk

* Harter CJL, Kavanagh GS, Smith JT. (2018) The role of kisspeptin neurons in reproduction and metabolism. J Endocrinol, 238 (3): R173-R183. [PMID:30042117]

* Kanda S, Oka Y. (2013) Structure, synthesis, and phylogeny of kisspeptin and its receptor. Adv Exp Med Biol, 784: 9-26. [PMID:23550000]

* Kirby HR, Maguire JJ, Colledge WH, Davenport AP. (2010) International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin receptor nomenclature, distribution, and function. Pharmacol Rev, 62 (4): 565-78. [PMID:21079036]

Millar RP, Roseweir AK, Tello JA, Anderson RA, George JT, Morgan K, Pawson AJ. (2010) Kisspeptin antagonists: unraveling the role of kisspeptin in reproductive physiology. Brain Res, 1364: 81-9. [PMID:20858467]

* Oakley AE, Clifton DK, Steiner RA. (2009) Kisspeptin signaling in the brain. Endocr Rev, 30 (6): 713-43. [PMID:19770291]

* Pasquier J, Kamech N, Lafont AG, Vaudry H, Rousseau K, Dufour S. (2014) Molecular evolution of GPCRs: Kisspeptin/kisspeptin receptors. J Mol Endocrinol, 52 (3): T101-17. [PMID:24577719]

Roseweir AK, Millar RP. (2013) Kisspeptin antagonists. Adv Exp Med Biol, 784: 159-86. [PMID:23550006]

Tena-Sempere M. (2010) Kisspeptin signaling in the brain: recent developments and future challenges. Mol Cell Endocrinol, 314 (2): 164-9. [PMID:19464345]

1. Curtis AE, Cooke JH, Baxter JE, Parkinson JR, Bataveljic A, Ghatei MA, Bloom SR, Murphy KG. (2010) A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10. Am J Physiol Endocrinol Metab, 298 (2): E296-303. [PMID:19934405]

2. Davidson JS, Assefa D, Pawson A, Davies P, Hapgood J, Becker I, Flanagan C, Roeske R, Millar R. (1997) Irreversible activation of the gonadotropin-releasing hormone receptor by photoaffinity cross-linking: localization of attachment site to Cys residue in N-terminal segment. Biochemistry, 36 (42): 12881-9. [PMID:9335546]

3. Kirby HR, Maguire JJ, Colledge WH, Davenport AP. (2010) International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin receptor nomenclature, distribution, and function. Pharmacol Rev, 62 (4): 565-78. [PMID:21079036]

4. Kobayashi T, Sasaki S, Tomita N, Fukui S, Nakayama M, Kiba A, Kusaka M, Matsumoto S, Yamaguchi M, Itoh F et al.. (2010) 2-acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats. Bioorg Med Chem, 18 (14): 5157-71. [PMID:20580563]

5. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F et al.. (2001) The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem, 276 (37): 34631-6. [PMID:11457843]

6. Mead EJ, Maguire JJ, Kuc RE, Davenport AP. (2007) Kisspeptins are novel potent vasoconstrictors in humans, with a discrete localization of their receptor, G protein-coupled receptor 54, to atherosclerosis-prone vessels. Endocrinology, 148 (1): 140-7. [PMID:17023533]

7. Moriya Y, Kogame A, Tagawa Y, Morohashi A, Kondo T, Asahi S. (2019) Investigation of disposition for TAK-448, a synthetic peptide of kisspeptin analog, in rats and dogs using the radiolabeled TAK-448 suitable for pharmacokinetic study. Xenobiotica, 49 (7): 833-839. [PMID:30044673]

8. Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P et al.. (2001) AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem, 276 (31): 28969-75. [PMID:11387329]

9. Nishizawa N, Takatsu Y, Kumano S, Kiba A, Ban J, Tsutsumi S, Matsui H, Matsumoto SI, Yamaguchi M, Ikeda Y et al.. (2016) Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH₂ (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility. J Med Chem, 59 (19): 8804-8811. [PMID:27589480]

10. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y et al.. (2001) Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature, 411 (6837): 613-7. [PMID:11385580]

11. Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, Pineda R, Gottsch ML, Tena-Sempere M, Moenter SM et al.. (2009) Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci, 29 (12): 3920-9. [PMID:19321788]

12. Tomita K, Oishi S, Ohno H, Fujii N. (2008) Structure-activity relationship study and NMR analysis of fluorobenzoyl pentapeptide GPR54 agonists. Biopolymers, 90 (4): 503-11. [PMID:18302161]

Subcommittee members: Anthony P. Davenport (Chairperson) Experimental Medicine and Immunotherapeutics University of Cambridge Addenbrooke’s Hospital Cambridge UK Janet J. Maguire Experimental Medicine and Immunotherapeutics University of Cambridge Addenbrooke’s Hospital Cambridge UK Edward J. Mead Clinical Pharmacology Unit University of Cambridge Level 6 Centre for Clinical Investigation Box 110 Addenbrooke's Hospital Cambridge CB2 2QQ UK

Other contributors: Adam J Pawson (Past Senior Database Curator) Centre for Discovery Brain Sciences Edinburgh Medical School: Biomedical Sciences Room 338, Hugh Robson Building George Square Edinburgh, EH8 9XD