Development of novel NK3 receptor antagonists with reduced environmental impact.
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.
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Koki
K
Yamamoto
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Shiho
S
Okazaki
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Hiroaki
H
Ohno
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.
Fuko
F
Matsuda
Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
Satoshi
S
Ohkura
Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Kei-Ichiro
K
Maeda
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Nobutaka
N
Fujii
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: soishi@pharm.kyoto-u.ac.jp.
Shinya
S
Oishi
D000818:Animals; D004785:Environmental Pollutants; D006801:Humans; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*
D004785:Environmental Pollutants; D018042:Receptors, Neurokinin-3
Environmental toxicity; GnRH; NK3 receptor; Neurokinin B; Talnetant