NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

神经肽--分子作用机制

• 批准号: 6106783
• 负责人: LAWRENCE H LAZARUS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6106783
• 关键词: chemical models; endogenous opioid; molecular dynamics; neuropeptides; opioid receptor; protein structure function; receptor binding

Summary of Work: Structure-activity studies on highly selective delta-opioid di- and tripeptide antagonists containing Dmt-Tic were modified to enhance membrane permeability. They were modified at N- and C-termini with various hydrophobic constituents that increased biological stability by eliminating cyclization to a diketopiperazines. Crystallization of N,N(dimethyl)Dmt-Tic-OH (George, personal communication)indicated that its structure compared favorably with both H-Dmt-Tic-OH and cyclo(Dmt-Tic); although the cyclic analogue exhibited a unique conformation, its activity was less than linear molecules. N-Alkylation of the N-terminus of Dmt-Tic with methyl groups retained high delta affinity and selectivity, whereas ethyl, piperidine, pyrrolidine, or pyyrole reduced affinity to the 1-2 nM range and decreased selectivity. C-Terminal of H-Dmt-Tic-OH modified with methoxy, hydrazide, methyl amide, tert-butyl amide, tetrazole-5yl or 1-adamantanyl amide reduced delta-selectivity by enhancing mu-affinity. In fact, tert-butyl amide and 1-adamantanyl amide resulted in peptides with dual high affinities (delta and mu). Interestingly, the 1-adamantanyl amide derivative had agonist bioactivities, while the tert-butyl amide was a potent antagonist. Change from Tic to D-Phe in di and pentapeptides produced mu antagonists. New di- and tripeptides with additional aromatic centers are currently being investigated. All in all, these hydrophobic-enhanced delta opioid peptides will have greater application in clinical and therapeutic studies in immunosuppression, combatting drug and alcohol abuse. These di- and tripeptides were issued a U.S. Patent, number 5,780,589 on 14 July 1997.

工作总结：结构-活性研究 高选择性 δ-阿片类二肽和三肽拮抗剂 含有 Dmt-Tic 的修饰增强膜 渗透性。它们的 N 端和 C 端经过各种修饰 疏水性成分可提高生物稳定性 消除环化成二酮哌嗪。结晶 N,N(二甲基)Dmt-Tic-OH（乔治个人 通信）表明其结构与 H-Dmt-Tic-OH和环(Dmt-Tic)；虽然循环 类似物表现出独特的构象，其活性小于 线性分子。 Dmt-Tic N 末端的 N 烷基化 甲基保留了高δ亲和力和选择性，而 乙基、哌啶、吡咯烷或吡咯降低了与 1-2 的亲和力 nM 范围和选择性降低。 H-Dmt-Tic-OH 的 C 端 用甲氧基、酰肼、甲基酰胺、叔丁基酰胺改性， 四唑-5基或1-金刚烷基酰胺降低了δ选择性 增强mu亲和力。事实上，叔丁基酰胺和1-金刚烷基 酰胺导致肽具有双重高亲和力（δ和mu）。 有趣的是，1-金刚烷基酰胺衍生物具有激动剂 生物活性，而叔丁基酰胺是一种有效的拮抗剂。 产生的二肽和五肽中从 Tic 变为 D-Phe 对手。具有额外芳香族的新二肽和三肽 目前正在对中心进行调查。总而言之，这些 疏水性增强的 δ 阿片肽将具有更大的 在临床和治疗研究中的应用 免疫抑制、打击药物和酒精滥用。这些二 和三肽于14日获得美国专利，专利号为5,780,589 1997 年 7 月。