Development of novel NK3 receptor antagonists with reduced environmental impact

  • Bioorg Med Chem. 2016 Aug 15;24(16):3494-500. doi: 10.1016/j.bmc.2016.05.054.
Koki Yamamoto  1 ,  Shiho Okazaki  1 ,  Hiroaki Ohno  1 ,  Fuko Matsuda  2 ,  Satoshi Ohkura  3 ,  Kei-Ichiro Maeda  4 ,  Nobutaka Fujii  1 ,  Shinya Oishi  5
Affiliations
  • 1. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • 2. Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan; Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
  • 3. Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
  • 4. Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
  • 5. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: [email protected].
PMID: 27298001 DOI: 10.1016/j.bmc.2016.05.054
Abstract

The neurokinin B (NKB)-neurokinin-3 receptor (NK3R) signaling positively regulates the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. The NK3R-selective antagonists may suppress the reproductive functions of mammals. For development of novel NK3R antagonists with reduced environmental toxicity, a structure-activity relationship study of an NK3R Antagonist, talnetant, was carried out. Among several talnetant derivatives with labile functional groups in the natural environment, 3-mercaptoquinoline 2f exhibited a comparable biological activity to that of the parent talnetant. Additionally, compound 2f was converted into the disulfide 3f or isothiazolone 8 by air-oxidation, both of which showed no binding affinity to NK3R.

Keywords
Environmental toxicity; GnRH; NK3 receptor; Neurokinin B; Talnetant.