NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

基于Dmt-Tic药效团的强效受体选择性δ -阿片样物质在分子的两个部分经历了许多修饰：要么直接改变Tic残基或其芳香核，要么改变二肽的c端。质子化的氮仍然是仲胺或叔胺。除了Tic的完整性被严重破坏外，所有c端取代基对δ亲和的影响基本不大。然而，在Tic芳香环上含有取代基的类似物中，与mu受体相互作用的显著增加产生了缺乏选择性的肽。在含Dmt二肽的[des-COOH]Tic的芳香环上加入亲核试剂可产生多种多肽，其生物活性谱显示出混合拮抗作用/拮抗作用或拮抗作用/拮抗作用。数据进一步验证了δ亲和不需要带负电荷；其他因素，包括受体内Dmt的强相互作用似乎占主导地位。h - dmt - tic - nh -1金刚烷的晶体结构表明，该肽与N，N(Me)2-Dmt-Tic-OH具有明显的差异，这可能是它们生物活性差异的原因。高活性三角洲拮抗剂所需的关键残基是Dmt和Tic；然而，目前正在研究新的具有额外芳香中心的Dmt二肽和伪三肽。最近与日本合作开发的一系列缺乏Tic的Dmt类似物可能会导致新型的mu激动剂，从而可能减轻癌症引起的疼痛。

Summary of Work: The potent receptor selective delta-opioid based on the Dmt-Tic pharmacophore underwent numerous modifications at two portions of the molecule: either direct alterations to the Tic residue or its aromatic nucleus, or changes at the C-terminus of the dipeptide. The protonated nitrogen remained either a secondary or teriary amine. All C-terminal substituents basically exhibited little effects on delta affinity except those in which the integrity of Tic was substantially disrupted. In analogues containing substituents on the Tic aromatic ring, however, the remarkable and dramatic increase in interaction toward the mu receptor yielded peptides lacking selectivity. The addition of nucleophiles to the aromatic ring of [des-COOH]Tic containing Dmt dipeptides produced a variety of peptides whose bioactivity spectrum indicated mixied delta antagonism/mu agonism or delta antagonism/mu antagonism. The data further verified that delta affinity does not require a negative charge; other factors, including the strong interaction of Dmt within the receptor appears to dominate. The crystalline structure of H-Dmt-Tic-NH-1-adamantane revealed that this peptide, which lacks delta antagonism, differed considerably from N,N(Me)2-Dmt-Tic-OH and may account for the differences in their bioactivity. The key residues required for highly active delta antagonist are Dmt and Tic; however, new Dmt di- and pseudo-tripeptides with additional aromatic centers are currently being investigated. A series of Dmt analogues lacking Tic and recently developed in collaboration with Japan may lead to new type of mu agonists to permit a possible alleviation of cancer-induced pain.