E-Mail karger@karger.com At the Cutting Edge Neuroendocrinology 2014;99:49–60 DOI: 10.1159/000357809 Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis Hisanori Matsui a Taiji Asami b a Extra Value Generation and General Medicine Drug Discovery Unit and b Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan lished. In this review, we present a brief overview on kiss- peptin/KISS1R physiology in reproductive functions and summarize the available knowledge of both agonists and antagonists. We also focus on the kisspeptin agonist analogs by summarizing key pharmacological findings from both clinical and preclinical studies, and discuss their potential therapeutic utility. © 2014 S. Karger AG, Basel Introduction Kisspeptin (Kp) is encoded by the KISS1 gene and is a peptide ligand of the G protein-coupled receptor KISS1R (GPR54) [1–3]. The physiological roles of the Kp/KISS1R system in mammalian reproductive functions were first demonstrated in 2003–2004. Defective onset of puberty was observed to be associated with mutation of KISS1R in humans or deletion of Kiss1r in mice [4–6]. Moreover, central or peripheral Kp administration to several mam- malian species, including humans, induced robust release of GnRH and gonadotropin [7–12]. Subsequent studies have revealed that GnRH neurons express Kiss1r mRNA and are depolarized by Kp exposure in vitro [13–15], sug- Key Words Kisspeptin · KISS1R · Kisspeptin analog · Testosterone · Desensitization Abstract The hypothalamic peptide kisspeptin (metastin), the endog- enous ligand of the G protein-coupled receptor KISS1R, plays a critical role in controlling GnRH release from hypothalamic GnRH neurons and thereby regulates hypothalamic-pitu- itary-gonadal functions. Although the therapeutic potential of kisspeptin is attractive, its susceptibility to proteolytic degradation limits its utility. To overcome this, KISS1R ago- nists or antagonists as peptide analogs or small molecules have been investigated. Kisspeptin analogs have been most extensively studied by reducing the length of the peptide from the original 54 amino acids to 10 amino acids or less and by substituting key amino acid residues. Also, 2 investi- gational kisspeptin agonist analogs have been evaluated in clinical studies in men; in agreement with animal studies, abrupt elevations in gonadotropin and testosterone levels were observed as an acute effect, followed by rapid reduc- tions in these hormones as a chronic effect. Some studies of small-molecule KISS1R antagonists have also been pub- Received: August 28, 2013 Accepted after revision: December 7, 2013 Published online: March 8, 2014 Hisanori Matsui Pharmaceutical Research Division Takeda Pharmaceutical Company Limited 2-26-1 Muraoka-Higashi, Fujisawa, Kanagawa 251-8555 (Japan) E-Mail hisanori.matsui  @  takeda.com © 2014 S. Karger AG, Basel 0028–3835/14/0991–0049$39.50/0 www.karger.com/nen