Dipartimento di Farmacia, Università degli Studi "G. d'Annunzio" di Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
Eur J Med Chem. 2013 Oct;68:167-77. doi: 10.1016/j.ejmech.2013.07.044. Epub 2013 Aug 11.
Endomorphin-2 [Tyr-Pro-Phe-Phe-NH2] and DAMGO [Tyr-D-Ala-Gly-(N-Me)Phe-Gly-ol] are natural (EM2) and synthetic (DAMGO) opioid peptides both selective for μ opioid receptor with high analgesic activity. In this work we report synthesis, in vitro and in vivo biological evaluation of five new hybrid EM2/DAMGO analogues, with the aim to obtain compounds with high affinity at μ-opioid receptor, high activity in animal nociception tests (hot plate and tail flick) and improved enzymatic stability. Double N-methylation on both Phe residues and C-terminal ethanolamide led to analogue 6e, which possesses a good in vitro μ affinity (Kiμ=34 nM), combined with a remarkable in vivo antinociceptive activity.
内吗啡肽-2 [Tyr-Pro-Phe-Phe-NH2] 和 DAMGO [Tyr-D-Ala-Gly-(N-Me)Phe-Gly-ol] 是天然（EM2）和合成（DAMGO）阿片肽，两者均对 μ 阿片受体具有选择性，具有高镇痛活性。在这项工作中，我们报告了 5 种新的 EM2/DAMGO 混合类似物的合成、体外和体内生物学评价，目的是获得对 μ 阿片受体具有高亲和力、在动物疼痛测试（热板和尾巴闪烁）中具有高活性和改善酶稳定性的化合物。在两个 Phe 残基和 C 末端乙醇酰胺上进行双重 N-甲基化得到类似物 6e，其具有良好的体外 μ 亲和力（Kiμ=34 nM），并具有显著的体内抗伤害感受活性。
