Almquist R G, Olsen C M, Uyeno E T, Toll L
J Med Chem. 1984 Feb;27(2):115-20. doi: 10.1021/jm00368a003.
A peptide analogue of Leu-enkephalin was synthesized in which the amide linkages between Tyr-Gly and Gly-Gly were replaced by ketomethylene groups. The resulting analogue, 12, had 1/4000th and 1/2400th the opiate receptor binding activity of Leu-enkephalin when (3H) [D-Ala2,D-Leu5]enkephalin and (3H)naloxone, respectively, were used as tritiated ligands. When tested for analgesia in mice by the tail-flick assay, 12 produced analgesia in 50% of the mice tested at a dose of 24.3 micrograms/mouse (icv), while the ED50 of Leu-enkephalin is 240 micrograms/mouse (icv). At a dose of 40 micrograms/mouse (icv) or higher, 12 caused convulsions in a dose-dependent manner. No analgesia was observed after intravenous (iv) administration of 240 micrograms/mouse of 12.
合成了亮氨酸脑啡肽的一种肽类似物，其中Tyr-Gly和Gly-Gly之间的酰胺键被酮亚甲基取代。所得类似物12，当分别使用(3H)[D-Ala2,D-Leu5]脑啡肽和(3H)纳洛酮作为氚化配体时，其阿片受体结合活性分别为亮氨酸脑啡肽的1/4000和1/2400。通过甩尾试验在小鼠中测试镇痛作用时，12以24.3微克/小鼠（脑室内注射）的剂量使50%的受试小鼠产生镇痛作用，而亮氨酸脑啡肽的半数有效剂量为240微克/小鼠（脑室内注射）。在40微克/小鼠（脑室内注射）或更高剂量时，12以剂量依赖性方式引起惊厥。静脉注射240微克/小鼠的12后未观察到镇痛作用。
