Katsumata S, Ienaga Y, Minami M, Nakagawa T, Kanematsu K, Satoh M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Eur J Pharmacol. 1996 Oct 3;312(3):349-55. doi: 10.1016/0014-2999(96)00469-4.
We analyzed the pharmacological characteristics of (-)-3-acetyl-6 beta-acetylthio-N-cyclopropylmethyl-normorphine (KT-90) using Chinese hamster ovary (CHO) cells expressing cloned rat mu-, delta- and kappa-opioid receptors. KT-90 displaced the specific binding of the following radiolabeled ligands selective to the mu-, delta- and kappa-opioid receptors, [3H][D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO), [3H][D-Pen2,D-Pen5]enkephalin (DPDPE), [3H] (+)-(5 alpha, 7 alpha, 8 beta)-N-methyl-N-[7-(1-pyrrolidinyl) l-oxaspiro-(4,5)dec-8-yl]benzeneacetamide (U69,593), with Ki values of 3.3 +/- 0.7, 22.8 +/- 1.5 and 1.9 +/- 0.3 nM, respectively In CHO cells expressing the mu-, delta- and kappa-opioid receptors, KT-90 inhibited forskolin (10 microM)-induced cyclic AMP accumulation in a concentration-dependent manner with IC50 values of 2337 +/- 750, 17.3 +/- 4.6 and 2.0 +/- 0.1 nM, respectively. The maximal inhibitory effects of KT-90 in the cells expressing mu-, delta- and kappa-opioid receptors were significantly lower than those of the type-selective agonists DAMGO, DPDPE and U69,593, respectively. These results indicated that KT-90 acts as a partial agonist on mu-, delta- and kappa-opioid receptors. KT-90 (10 and 100 nM), when added with morphine, produced a rightward shift of the concentration-response curve of morphine to inhibit the cyclic AMP accumulation in CHO cells expressing mu-, but not delta- or kappa-, opioid receptors. This finding is consistent with the findings that lower doses of KT-90 antagonize morphine analgesia in vivo.
我们使用表达克隆大鼠μ-、δ-和κ-阿片受体的中国仓鼠卵巢（CHO）细胞，分析了（-）-3-乙酰基-6β-乙酰硫基-N-环丙基甲基去甲吗啡（KT-90）的药理学特性。KT-90取代了以下对μ-、δ-和κ-阿片受体具有选择性的放射性标记配体的特异性结合，即[3H][D-Ala2,MePhe4,Gly(ol)5]脑啡肽（DAMGO）、[3H][D-Pen2,D-Pen5]脑啡肽（DPDPE）、[3H]（+）-（5α，7α，8β）-N-甲基-N-[7-（1-吡咯烷基）-1-氧杂螺（4,5）癸-8-基]苯乙酰胺（U69,593），其Ki值分别为3.3±0.7、22.8±1.5和1.9±0.3 nM。在表达μ-、δ-和κ-阿片受体的CHO细胞中，KT-90以浓度依赖性方式抑制福斯可林（10μM）诱导的环磷酸腺苷（cAMP）积累，IC50值分别为2337±750、17.3±4.6和2.0±0.1 nM。KT-90在表达μ-、δ-和κ-阿片受体的细胞中的最大抑制作用分别显著低于类型选择性激动剂DAMGO、DPDPE和U69,593。这些结果表明KT-90在μ-、δ-和κ-阿片受体上作为部分激动剂起作用。当与吗啡一起添加时，KT-90（10和100 nM）使吗啡抑制表达μ-但不表达δ-或κ-阿片受体的CHO细胞中环磷酸腺苷积累的浓度-反应曲线向右移动。这一发现与低剂量KT-90在体内拮抗吗啡镇痛作用的发现一致。
