1995 Fiscal Year Final Research Report Summary
Development of non-peptide bulimin (NPY) antagonist for the treatment of obesity, diabetes mellitus, and bulimia nervosa
| Project/Area Number |
06557060
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
内分泌・代謝学
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| Research Institution | Kobe University |
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Principal Investigator |
INUI Akio Kobe University, Second Department of Internal Medicine, Assistant Professor, 医学部, 助手 (80168418)
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| Co-Investigator(Kenkyū-buntansha) |
UEMOTO Masaharu Kobe University, Department of Psychiatry, Associate Professor, 医学部・附属病院, 講師 (90176644)
SANO Kimihiko Kobe University, Department of Pediatrics, Associate Professor, 医学部・附属病院, 講師 (40205993)
KOSHIYA Kazuo Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., LTD,Resear, 第一創薬研究所, 主任研究員
YAMAGUCHI Tokio Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., LTD,Resear, 第一創薬研究所, 主管研究員
MASE Toshiyasu Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., LTD,Direct, 第一創薬研究所, 所長
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| Project Period (FY) |
1994 – 1995
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| Keywords | Neuropeptide Y / Antagonist / Bulimin / Obesity / Diabetes mellitus / Bulimia nervosa |
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| Research Abstract |
The present study was designed to pharmacologically characterize neuropeptide Y (NPY) receptors which mediate powerful feeding-stimulatory properties of NPY as those of bulimin. We developed conformationally restricted analogues of COOH-terminal octapeptide of NPY.We found that Ac-[D-Cys^<29>, Cys^<34>]-NPY29-36 had a high affinity for Y_1 receptors in the SK-N-MC cells (IC_<50>=10nM) but had a low affinity for Y_1 receptors in aortic smooth muscle membranes and no affinity for Y_2 receptors. The analog acted as a potent feeding stimulator after administration into the third cerebral ventricle of mice, but was devoid of vasoconstrictor potency in pithed rat and mouse models. These results suggests heterogeneity of the Y_1 receptors which are supposed to mediate both the feeding-stimulatory and the vasoconstrictive proterties of NPY.
We have also found non-peptide NPY antagonists which modulate feeding without affecting blood pressure regulation. However, we still do not succeed to find non-peptide compounds which do not possess sedative property.
Recent studies demonstrated the existence of at least six receptor subtype for NPY,among which Y_5 receptor is assumed to mediate the feeding stimulatory effects of NPY.However, some researchers still hold the opinion that Y_1 receptor variant, but not Y_5 receptor, is responsible for this effect. Therefore, further characterization of these receptor subtype in connection with feeding and identification of receptor subtype-specific analogs are urgently needed.
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[Publications] M.Miura, A.Inui, K.Sano, N.Ueno, A.Teranishi, Y.Hirosue, M.Nakajima, M.Okita, J.Togami, K.Koshiya, S.Baba, M.Kasuga.: "Dynorphin binds to neuropeptide Y and peptide YY neceptors in human neuroblotoma cell lines." Diabetes, 1994 S.Baba & T.Kaneko (eds.), Elsevier Science. 560-563 (1995)
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