Doi T, Kuzuna S, Fujino M
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Jpn J Pharmacol. 1988 Aug;47(4):409-15. doi: 10.1254/jjp.47.409.
The analgesic action of the enkephalin analog EK-399 (Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH) and the subtypes of the opiate receptors mediating the action were studied. The analgesic effect of subcutaneously injected EK-399 was ten times as potent as that of morphine in the rat tail flick test. EK-399 had a longer latency time and duration time than morphine. The analgesic action of EK-399 injected into the rat spinal subarachnoid space was about 800 (1800 in molar ratio) times as potent as that of morphine in the hot plate test. EK-399 had high affinities for both mu and delta opiate receptors in the rat brain receptor binding assay. The apparent pA2 values with naloxone were 7.65 for morphine and 5.98 for EK-399 in the rat tail flick test; the difference was significant. A cross tolerance between EK-399 and morphine was examined in the rat tail flick test. Although morphine tolerant rats showed no tolerance to EK-399, EK-399 tolerant rats showed a clear tolerance to morphine. These results indicate that EK-399 has a potent and long lasting analgesic effect via opiate receptors in rats. In addition to mu-receptors, delta-receptors may be involved in its analgesic mechanism.
研究了脑啡肽类似物EK - 399（酪氨酸 - D - 蛋氨酸（O） - 甘氨酸 - 乙基苯丙氨酸 - 肼基甲酸甲酯·醋酸）的镇痛作用及其介导该作用的阿片受体亚型。在大鼠甩尾试验中，皮下注射EK - 399的镇痛效果比吗啡强10倍。与吗啡相比，EK - 399的潜伏期和持续时间更长。在热板试验中，注入大鼠脊髓蛛网膜下腔的EK - 399的镇痛作用比吗啡强约800倍（摩尔比为1800倍）。在大鼠脑受体结合试验中，EK - 399对μ和δ阿片受体均具有高亲和力。在大鼠甩尾试验中，纳洛酮的表观pA2值，吗啡为7.65，EK - 399为5.98；差异显著。在大鼠甩尾试验中检测了EK - 399与吗啡之间的交叉耐受性。虽然吗啡耐受的大鼠对EK - 399无耐受性，但EK - 399耐受的大鼠对吗啡表现出明显的耐受性。这些结果表明，EK - 399通过大鼠体内的阿片受体具有强效且持久的镇痛作用。除了μ受体外，δ受体可能也参与其镇痛机制。
