Michio Ishikawa

Yasushi Shigeri; Michio Ishikawa; Yasunobu Ishihara; Masafumi Fujimoto

We describe here a nonpeptide neuropeptide Y Y1 receptor antagonist, 2,4-dioxo-1,5-bis(2-oxo-2-orthotolyl-ethyl)-3-[3-[3-([3-[3-(3-p iperidin-1-ylmethyl-phenoxy)-propylcarbamoyl]-propyl]-car bamoyloxymethyl)-phenyl]-ureido]-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaz epine (Compound 1), which was previously synthesized as a linked type of dual cholecystokinin (CCK)-B and histamine H2 receptor antagonist. Compound 1 competitively inhibited [125I]peptide YY (PYY) binding to Y1 receptors in human neuroblastoma SK-N-MC cells with Ki of 6.4 +/- 1.0 nM, while it had no effect on [125I]PYY binding to Y2 or Y5 receptors even at 1 microM. Functionally, Compound 1 inhibited the Y1 receptor-mediated increase in cytosolic free Ca2+ concentration and Y1 receptor-mediated attenuation of cAMP accumulation in a dose-dependent manner with IC50 values of 95 +/- 5 and 320 +/- 10 nM in SK-N-MC cells, respectively. Neither its CCK-B receptor antagonistic moiety of Compound 1 (Compound 2) nor its histamine H2 receptor antagonistic moiety of Compound 1 (Compound 3) had any effect on [125I]PYY binding, suggesting that the entire structure of Compound 1 is essential for Y1 receptor blocking activity. It showed no significant activity (IC50 > 1 microM) in 30 receptor binding assays and 5 enzyme assays, with the exception of CCK-B and histamine H2 receptors. We conclude that Compound 1 is a useful molecule not only for studying the physiological role of neuropeptide Y but also for exploring more specific Y1 receptor antagonists.

Yasuyuki Kawanishi; Shoichi Ishihara; Kimio Takahashi; Tadahiko Tsushima; Sanji Hagishita; Michio Ishikawa; Yasunobu Ishihara

Akira Shiozawa; Yuhichiro Ichikawa; Chikara Komuro; Genichi Idzu; Michio Ishikawa; Shuji Kurashige; Hiroshi Miyazaki; Hiroshi Yamanaka; Takao Sakamoto

Akira Shiozawa; Michio Ishikawa; Giichi Izumi; Katsuhiko Sakitama; Kazuhisa Narita; Shuji Kurashige; Takeji Sakasai; Kazuo Ohtsuki; Hideo Sugimura; Hirotaka Yamamoto

Akira Shiozawa; Michio Ishikawa; Giichi Izumi; Katsuhiko Sakitama; Kazuhisa Narita; Shuji Kurashige

Akira Shiozawa; Yuh-Ichiro Ichikawa; Michio Ishikawa; Yoshiya Kogo; Shuji Kurashige; Hiroshi Miyazaki; Hiroshi Yamanaka; Takao Sakamoto

Akira Shiozawa; Michio Ishikawa; Hideo Sugimura; Kazuhisa Narita; Hirotaka Yamamoto; Takeji Sakasai; Kazuo Ohtsuki; Shuji Kurashige

Akira Shiozawa; Yuhichiro Ichikawa; Chikara Komuro; Michio Ishikawa; Yasuhiko Furuta; Shuji Kurashige; Hiroshi Miyazaki; Hiroshi Yamanaka; Takao Sakamoto

Akira Shiozawa; Yoshiya Kogo; Yuhichiro Ichikawa; Chikara Komuro; Michio Ishikawa; Shuji Kurashige; Hiroshi Miyazaki; Hiroshi Yamanaka; Takao Sakamoto

Akira Shiozawa; Michio Ishikawa; Hideo Sugimura; Kazuhisa Narita; Hirotaka Yamamoto; Takeji Sakasai; Kazuo Ohtsuki; Shuji Kurashige