Discovery of a structurally novel opioid kappa-agonist derived from 4,5-epoxymorphinan.
Discovery of a structurally novel opioid kappa-agonist derived from 4,5-epoxymorphinan.
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发现一种结构新颖的阿片类 kappa 激动剂，源自 4,5-环氧吗啡喃。
DOI：
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发表时间：
1998
影响因子：
1.7
通讯作者：
T. Endo
中科院分区：
文献类型：
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作者：
H. Nagase;J. Hayakawa;K. Kawamura;Kouji Kawai;Yuko Takezawa;H. Matsuura;C. Tajima;T. Endo
通过一个新的工作假说，发现了一种新型的kappa激动剂--17-环丙基甲基-3，14-二羟基-4，5α-环氧基-6-β-[N-甲基-反式-3-(3-呋喃)丙烯酰胺]吗啡盐酸盐(1，TRK-820)。TRK-820的设计采用了阿片类拮抗剂的“消息-地址概念”和普通拮抗剂的“辅助站点”。与其他典型的kappa-阿片受体激动剂不同，TRK-820的一个独特的结构特征是存在内源性阿片肽(如强啡肽)的4，5-环氧吗啡结构和酪氨酸-甘氨酸部分。Trk-820在豚鼠回肠(GPI)和小鼠输精管(MVD)标本上表现出高效价和高kappa选择性。在小鼠醋酸扭体模型和甩尾模型中，TRK-820的作用分别是吗啡的85-140倍和U-50488H的85-350倍。这种结构新颖的kappa激动剂在条件性位置偏爱测试中既没有表现出厌恶，也没有表现出偏好，尽管kappa激动剂的原型(U-50488H衍生物)表现出厌恶的事实。
A new type of kappa-agonist, 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4,5 alpha-epoxy-6 beta-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride (1, TRK-820), was discovered by a new working hypothesis. The "message-address concept" for opioid antagonists and the "accessory site" for general antagonists were applied to design TRK-820. A unique structural feature of TRK-820, which is different from other prototypical kappa-opioid receptor agonists, is the existence of the 4,5-epoxymorphinan structure with a tyrosine-glysine moiety for endogenous opioid peptides such as dynorphins. TRK-820 exhibited high potency and high kappa-selectivity in guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. In the mouse acetic-acid-induced writhing model and mouse tail flick model of antinociception, TRK-820 was 85-140 times more potent than morphine and 85-350 times more potent than U-50488H. This structurally novel kappa-agonist showed neither aversion nor preference in the Conditioned Place Preference test, in spite of the fact that prototypes of kappa-agonists (U-50488H derivatives) demonstrated aversion.