NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

工作总结：结构-活性研究 高选择性Delta-阿片类二肽和三肽拮抗剂 对含有DMT-Tic的膜进行了改性以增强膜 渗透性。它们在N-端和C-端被修饰成不同的 通过以下方式提高生物稳定性的疏水成分 消除环化为二酮基哌嗪类化合物。结晶 N，N(二甲基)DMT-Tic-OH(George，个人 通信)表明其结构与 H-DMT-Tic-OH和环(DMT-Tic)； 类似物表现出独特的构象，其活性低于 线性分子。DMT-Tic的N-末端N-烷基化反应 甲基保留了较高的三角洲亲和力和选择性，而 乙基、哌啶、吡咯烷或吡咯降低与1-2的亲和力 NM范围和降低的选择性。H-DMT-Tic-OH的C-末端 用甲氧基、肼、甲胺、叔丁胺、 四唑-5基或1-金刚烷基酰胺通过以下方式降低三角洲选择性 增强Mu亲和力。事实上，叔丁胺和1-金刚烷 酰胺类多肽具有双重高亲和力(Delta和Mu)。 有趣的是，1-金刚烷酰胺衍生物含有激动剂 生物活性，而叔丁胺是一种强有力的拮抗剂。 二肽和五肽在MU中由Tic向D-Phe的转变 对抗者。加成芳香族的新二肽和三肽 目前正在对这些中心进行调查。总而言之，这些 疏水增强的Delta阿片肽将有更大的 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。这些都是- 和三肽于14日获得美国专利5780589号 1997年7月。

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.