Development of non-peptide bulimin (NPY) antagonist for the treatment of obesity, diabetes mellitus, and bulimia nervosa

本研究旨在确定神经肽Y（NPY）受体介导的强大的摄食刺激特性的白蛋白。我们合成了NPY羧基端八肽的构象限制性类似物，发现Ac-[D-Cys^<29>，Cys^<34>]-NPY 29 -36对SK-N-MC细胞的Y_1受体具有高亲和力（IC_<50>= 10 nM），而对主动脉平滑肌膜的Y_1受体亲和力较低，对Y_2受体无亲和力。类似物作为一个有效的喂养刺激剂后，到小鼠的第三脑室，但没有在脊髓大鼠和小鼠模型的血管收缩效力。这些结果表明，Y_1受体可能具有异质性，它们可能同时介导NPY的摄食刺激和血管收缩特性，我们还发现了非肽类NPY拮抗剂，它们可调节摄食而不影响血压调节。近年来的研究表明，NPY至少存在六种受体亚型，其中Y_5受体被认为是介导NPY的摄食刺激作用的受体，但仍有研究者认为是Y_1受体而不是Y_5受体介导了NPY的摄食刺激作用。因此，迫切需要进一步表征这些受体亚型与喂养和受体亚型特异性类似物的鉴定。

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.