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Development of receptor antagonists to neuropeptide Y,galanin and pancreastatin

神经肽Y、甘丙肽、胰酶受体拮抗剂的研制

基本信息

批准号：
05557047
负责人：
TATEMOTO Kazuhiko
金额：
$ 10.11万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05557047/
关键词：
peptide hormone neuropeptide antagonist agonist neuropeptide Y pancreatatin galanin

项目摘要

The principal aim of this proposal is to develop receptor antagonists to neuropeptide Y (NPY), galanin and pancreastatin (PST) as drugs against diabetes, hypertension and endocrine abnormalities. Toward this goal, we first set up a new laboratory which is capable of carrying out cell culture experiments, peptide synthesis and structural determination, and then, we carried out synthetic studies for the development of the antagonists. In this study, we employed a novel strategy for the development of receptor antagonists based on the design and synthesis of analog mixtures and the subsequent isolation and characterization of receptor anragonists from these mixtures. Using this strategy, a series of NPY analog mixtures was designed and synthesized. Screening of these mixtures using an NYP antagonist assay identified the receptor antagonists containing from 4 to 10 amino acids. The receptor antagonists inhibited the release of intracellular calcium elicited by NPY or PYY in human erythroleukemia (HEL) cells. On the other hand, to develop receptor antagonists of pancreastatin (PST), we needed a simple bioassay method for screening of receptor antagonists to PST.We therefore first examined the effects of PST on the increase in[Ca2+]i induced by several insulin secretagogues by using the dissociated rat pancreatic B-cells. We found that PST (1-100nM) dose-dependently inhibited the glucose-induced rise in[Ca2+]i insingle pancreatic islet cells. This observation allows us to develop an assay method for screening of the PST antagonists and to synthesize a series of PST analogs possibly used as receptor antagonists to PST.This study demonstrates that the analog mixture screening strategy significantly reduces the time and resources previously required for the development of receptor antagonists or agonists, and promises to enhance our ability to design new pharmacological agents for therapeutic uses.

该提案的主要目的是开发神经肽 Y (NPY)、甘丙肽和胰酶 (PST) 的受体拮抗剂，作为治疗糖尿病、高血压和内分泌异常的药物。为了这个目标，我们首先建立了一个新的实验室，能够进行细胞培养实验、肽合成和结构测定，然后，我们进行拮抗剂开发的合成研究。在这项研究中，我们采用了一种基于类似物混合物的设计和合成以及随后从这些混合物中分离和表征受体拮抗剂的受体拮抗剂开发的新策略。利用该策略，设计并合成了一系列 NPY 类似物混合物。使用 NYP 拮抗剂测定筛选这些混合物，鉴定出含有 4 至 10 个氨基酸的受体拮抗剂。受体拮抗剂抑制人红白血病 (HEL) 细胞中 NPY 或 PYY 引起的细胞内钙的释放。另一方面，为了开发胰腺素（PST）受体拮抗剂，我们需要一种简单的生物测定方法来筛选PST受体拮抗剂。因此，我们首先使用离解的大鼠胰腺B细胞检查PST对几种胰岛素促分泌素诱导的[Ca2+]i增加的影响。我们发现 PST (1-100nM) 剂量依赖性地抑制葡萄糖诱导的单个胰岛细胞中 [Ca2+]i 的升高。这一观察结果使我们能够开发一种筛选PST拮抗剂的测定方法，并合成一系列可能用作PST受体拮抗剂的PST类似物。这项研究表明，类似物混合物筛选策略显着减少了以前开发受体拮抗剂或激动剂所需的时间和资源，并有望增强我们设计用于治疗用途的新药物的能力。