Design and synthesis of μ-selective opioidomimetic peptides

μ选择性阿片样肽的设计与合成

• 批准号: 11694326
• 负责人: OKADA Yoshio
• 金额: $ 1.28万
• 依托单位: Kobe Gakuin University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11694326/
• 关键词: opioid mimetics; pyrazinone derivatives; endomorphine derivatives; diamine derivartives; dimethyltyrosine; μ-opioid receptor agoniat; 鎮痛薬; 皮下投与; オピオイドミナティクス; エンドモルーフィン誘導体; δ-オピオイドレセプターアンタゴニスト; 二機能性リガンド

This project started as International Scientific Research by The Ministry of Education, Culture, Sports, Science and Technology in 1999 and then as Grant-in-Aid for Scientific Research (C) in 2000 and 2001. Therefore, Dr. Lawrence H. Lazarus and Ms. Sharon D. Bryant of National Institute of Environmental Health Sciences, USA were investigators in this project. Dr. Yoshio Okada has been engaged in synthesis of peptides based on the peptide synthesis we made a plan of this project with objective to develop novel type of anti-pain medicine, and obtained following results. 1) We could develop synthetic methodologies ofpeptides. 2) We designed and synthesized endomorphin derivatives and obtained compounds which exhibited potent μ-opioid receptor agonistic activity and δ-opioid receptor antagonistic activity. We designated them as bifunctional opioid mimetics. 3) Employing new method to synthesize pyrazinones from dipeptidyl chloromethyl ketones, novel type opioid memetics containing pyrazinone ring were prepared. 4) Instead of pyrazinone ring, NH_2(CH_2)nNH_2 (n=2-8)were employed to prepare novel types of anti-pain drugs. 5) Compounds obtained above exhibited more potent in vitro and in vivo activity than morphine.6) International conference Annual ' Conference on Opioid Mimetic Analgesics 2002" was successfully held from 17 to 19 of March, 2002 at Awaji Yumebutai International Conference Center and we exchanged our mutual interest concerning the developme t of anti-pain medicines."

该项目始于1999年教育，文化，体育，科学和技术部的国际科学研究，然后在2000年和2001年作为科学研究授予授予。因此，美国国家环境健康科学研究所的劳伦斯·H·拉扎鲁斯（Lawrence H.冈田洋子博士一直根据肽的合成参与肽的合成，我们制定了该项目的计划，其目标是开发新型的抗Pain药物，并获得了以下结果。 1）我们可以开发肽的合成方法。 2）我们设计和合成了内啡肽衍生物，并获得了暴露有效的μ-阿片受体激动剂活性和δ-阿片受体拮抗活性的化合物。我们将它们设计为双功能阿片类模拟物。 3）制备了采用新方法从二肽基氯聚甲基酮合成吡嗪酮的新型含有吡唑酮环的新型阿片类药物。 4）使用NH_2（CH_2）NNH_2（n = 2-8）代替吡嗪酮环，用于制备新型的抗皮革药物。 5）上面获得的化合物在2002年3月17日至19日在Awaji Yumebutai国际会议中心成功举行了国际大会的阿片类模拟镇痛学会议，在阿片类模拟镇痛2002年的国际年度会议上，在体外和体内活动中的潜力更大。

项目成果

Yoshio Okada: "Synthesis of Peptides by Solution Methods"Current Organic Chemistry. 5. 1-43 (2001)

Yoshio Okada：“溶液法合成肽”当前有机化学。

Yoshio Okada et al.: "Synthesis of Stereoisomeric Analogues of Endomorphin-2, H-Tyr-Pro-Phe Phe-NH_2, and Examination of Their Opioid Receptor Binding Acitivities"Biocheim.Biophys.Res.Commun.. 276. 7-11 (2000)

Yoshio Okada 等：“Endomorphin-2、H-Tyr-Pro-Phe Phe-NH_2 立体异构类似物的合成及其阿片受体结合活性的检查”Biochem.Biophys.Res.Commun. 276. 7-11

Y.Okada et al.: "Computational chemistry and opioidmimetics : Receptor-ligand interactions of three classes of biologically potent peptides"Peptides 2000. 407-408 (2001)

Y.Okada 等人：“计算化学和阿片模拟物：三类生物活性肽的受体-配体相互作用”肽 2000. 407-408 (2001)

Y.Okada: "Synthesis of Peptides by Solution Method"Current Oganic Chemistry. 5. 1-43 (2001)

Y.Okada：“溶液法合成肽”当前有机化学。

Yoshio Okada et al.: "Amino Acids and Peptides. LVI. Synthesis of pyrazinone ring-containing opioid mimetics and examination of their opioid receptor binding activity"Tetrahedron. 55. 14391-14406 (1999)

Yoshio Okada 等人：“氨基酸和肽。LVI。含吡嗪酮环阿片模拟物的合成及其阿片受体结合活性的检查”四面体。