Schiller P W, Weltrowska G, Berezowska I, Nguyen T M, Wilkes B C, Lemieux C, Chung N N
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Biopolymers. 1999;51(6):411-25. doi: 10.1002/(SICI)1097-0282(1999)51:6<411::AID-BIP4>3.0.CO;2-Z.
The discovery of the prototype delta opioid antagonists TIPP (H-Tyr-Tic-Phe-Phe-OH) and TIP (H-Tyr-Tic-Phe-OH) in 1992 was followed by extensive structure-activity relationship studies, leading to the development of analogues that are of interest as pharmacological tools or as potential therapeutic agents. Stable TIPP-derived delta opioid antagonists with subnanomolar delta receptor binding affinity and extraordinary delta receptor selectivity include TIPP[Psi] (H-Tyr-TicPsi[CH(2)NH]Phe-Phe-OH] and TICP[Psi] (H-Tyr-TicPsi[CH(2)NH]Cha-Phe-OH); Cha: cyclohexylalanine), which are widely used in opioid research. Theoretical conformational analyses in conjunction with the pharmacological characterization of conformationally constrained TIPP analogues led to a definitive model of the receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-OH-related delta opioid antagonists, which is characterized by all-trans peptide bonds. Further structure-activity studies revealed that the delta antagonist vs delta agonist behavior of TIP(P)-derived compounds depended on very subtle structural differences in diverse locations of the molecule and suggested a delta receptor model involving a number of different inactive receptor conformations. A further outcome of these studies was the identification of a new class of potent and very selective dipeptide delta agonists of the general formula H-Tyr-Tic-NH-X (X = arylalkyl), which are of interest for drug development because of their low molecular weight and lipophilic character. Most interestingly, TIPP analogues containing a C-terminal carboxamide group displayed a mixed mu agonist/delta antagonist profile, and thus were expected to be analgesics with a low propensity to produce tolerance and physical dependence. This turned out to be the case with the TIPP-derived mu agonist/delta antagonist DIPP-NH(2)[Psi] (H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2)); Dmt: 2',6'- dimethyltyrosine).
1992年发现原型δ阿片样物质拮抗剂TIPP（H-Tyr-Tic-Phe-Phe-OH）和TIP（H-Tyr-Tic-Phe-OH）之后，开展了广泛的构效关系研究，从而开发出作为药理学工具或潜在治疗药物备受关注的类似物。具有亚纳摩尔级δ受体结合亲和力和非凡δ受体选择性的稳定的源自TIPP的δ阿片样物质拮抗剂包括TIPP[Psi]（H-Tyr-TicPsi[CH(2)NH]Phe-Phe-OH]）和TICP[Psi]（H-Tyr-TicPsi[CH(2)NH]Cha-Phe-OH；Cha：环己基丙氨酸），它们在阿片样物质研究中被广泛应用。结合对构象受限的TIPP类似物的药理学特性进行的理论构象分析，得出了与H-Tyr-Tic-(Phe-Phe)-OH相关的δ阿片样物质拮抗剂的受体结合构象的确定模型，其特征为全反式肽键。进一步的构效研究表明，源自TIP(P)的化合物的δ拮抗剂与δ激动剂行为取决于分子不同位置非常细微的结构差异，并提示了一个涉及多种不同无活性受体构象的δ受体模型。这些研究的另一个成果是鉴定出一类通式为H-Tyr-Tic-NH-X（X = 芳基烷基）的新型强效且高度选择性的二肽δ激动剂，因其低分子量和亲脂性特征而在药物开发方面备受关注。最有趣的是，含有C末端羧酰胺基团的TIPP类似物表现出μ激动剂/δ拮抗剂的混合特征，因此有望成为产生耐受性和身体依赖性倾向较低的镇痛药。TIPP衍生的μ激动剂/δ拮抗剂DIPP-NH(2)[Psi]（H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2)；Dmt：2',6'-二甲基酪氨酸）就是这样。
