Richman S J, Goodman M, Nguyen T M, Schiller P W
Int J Pept Protein Res. 1985 Jun;25(6):648-62. doi: 10.1111/j.1399-3011.1985.tb02222.x.
As part of our continuing effort to define structure-activity relationships for enkephalin and design enzymatically resistant analogs, we report the synthesis and biological activities of linear and cyclic enkephalin analogs modified at the Gly3-Phe4 amide bond. The partial retro-inverso enkephalin analog Tyr-D-Ala-gGly-(R,S)-mPhe-Leu-NH2 and its cyclic counterpart, Tyr-cyclo[D-A2 bu-gGly-(R,S)-mPhe-Leu-], were synthesized as diastereomeric mixtures using solution methodology. The racemic benzylmalonate allowed the linear analog to be synthesized by fragment coupling at the reversed bond. Cyclization of the second analog was carried out at high concentration, eliminating formation of polymer by the use of an insoluble base. All gem-diaminoalkyl residues were prepared by conversion of peptidyl amides with benzene iodonium bis(trifluoroacetate). Diastereomers of both compounds were separable by reverse phase HPLC but those of the linear compound racemized rapidly under conditions of testing and were therefore tested together. All analogs tested had activities ranging from 6 to 14% of the activity of Leu enkephalin, indicating that the Gly3-Phe4 amide bond is important, though not crucial, for receptor binding.
作为我们持续确定脑啡肽构效关系并设计酶抗性类似物工作的一部分，我们报告了在Gly3 - Phe4酰胺键处修饰的线性和环状脑啡肽类似物的合成及生物活性。部分反向内啡肽类似物Tyr - D - Ala - gGly - (R,S) - mPhe - Leu - NH2及其环状类似物Tyr - cyclo[D - A2bu - gGly - (R,S) - mPhe - Leu - ]，采用溶液法合成了非对映异构体混合物。外消旋苄基丙二酸酯使线性类似物能够通过在反向键处的片段偶联来合成。第二个类似物的环化在高浓度下进行，通过使用不溶性碱消除了聚合物的形成。所有偕二氨基烷基残基均通过用苯碘鎓双（三氟乙酸酯）转化肽酰胺来制备。两种化合物的非对映异构体可通过反相高效液相色谱分离，但线性化合物的非对映异构体在测试条件下迅速消旋，因此一起进行测试。所有测试的类似物活性范围为亮氨酸脑啡肽活性的6%至14%，表明Gly3 - Phe4酰胺键对于受体结合很重要，但并非关键因素。
