WCRB2014 POSTER PRESENTATIONS (1) (335 abstracts)
Development of novel neurokinin-3 receptor agonists that potently stimulate the GnRH pulse generator
Takashi Yamamura 1 , Ryosuke Misu 2 , Yoshihiro Wakabayashi 1 , Satoshi Ohkura 3 , Shinya Oishi 2 , Nobutaka Fujii 2 & Hiroaki Okamura 1
1National Institute of Agrobiological Sciences, Tsukuba, Japan; 2Kyoto University, Kyoto, Japan; 3Nagoya University, Nagoya, Japan.
Introduction: Pulsatile GnRH secretion is a key determinant for normal gonadal activities. Recent emerging evidence suggests that neurokinin B (NKB) plays a pivotal role in generating GnRH pulse. Here, we aimed to develop novel compounds with potent NKB receptor (NK3R) agonistic activity for future therapeutic applications to improve gonadal functions.
Materials and methods: On the basis of the structure-activity relationship study of NKB and tachykinin peptides, we designed and synthesized 72 compounds. Their binding affinity and agonistic activity for Gq-coupled NK3 receptor were evaluated by an in vitro-binding inhibition assay and an intracellular Ca2+ flux assay respectively. Actions of the peptides on the GnRH pulse generator were evaluated by the multiple-unit activity (MUA) recording method in ovariectomized goats, in which the electrophysiological manifestations of the GnRH pulse generator activity can be represented as characteristic increases in MUA (MUA volleys). Thirty nanomoles of each peptide was i.v. administered at the mid-point of two successive endogenous MUA volleys occurring with a constant interval of ~25 min. The given peptide was assessed to stimulate the GnRH pulse generator when the next MUA volley occurred within 240 s after administration.
Results and discussion: Eight compounds were found to exhibit superior in vitro activity than senktide, a classical NK3R agonist, and induce an MUA volley after administration. Because those compounds were capable of stimulating the GnRH pulse generator by peripheral administration, they might be potential candidates for novel agents to improve reproduction acting centrally.
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ISSN 2052-1472 (online)
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