Four novel fluorinated cyclic analogues of biphalin with excellent to modest binding affinity for μ-, δ-, and κ-receptors were synthesized. The cyclic peptides have a combination of piperazine or hydrazine linker with or without a xylene bridge. Among the ligands, MACE3 demonstrated a better activity than biphalin after intravenous administration, and its corresponding analogue incorporating the hydrazine linker (MACE2) was able to induce longer lasting analgesia following subcutaneous administration. An analogue of MACE2 containing 2,6-dimethyl-l-tyrosine (MACE4) showed the best potency and in vivo antinociceptive activity of this series.

中文翻译：

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外围给药后具有持久抗伤害作用的强效，有效和稳定的环状阿片肽。

合成了四种新型的联苯环的氟化环类似物，它们对μ-，δ-和κ受体具有优异至中等的结合亲和力。环状肽具有带有或不带有二甲苯桥的哌嗪或肼连接基的组合​​。在配体中，MACE3在静脉内给药后表现出比联苯醚更好的活性，皮下给药后，其相应的掺入肼接头（MACE2）的类似物能够诱导更长的镇痛作用。含有2,6-二甲基-1-酪氨酸（MACE4）的MACE2类似物显示了该系列药物的最佳效能和体内抗伤害感受活性。