Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation
Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation
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DOI：
10.1124/mol.111.074195
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发表时间：
2011-11-01
影响因子：
3.6
通讯作者：
Chavkin, Charles
中科院分区：
文献类型：
--
作者：
Melief, Erica J.;Miyatake, Mayumi;Chavkin, Charles
kappa-阿片受体是一种广泛表达的 G 蛋白偶联受体，与疼痛、压力、焦虑和抑郁的生物反应有关，其作为这些综合征的治疗靶点的潜力正变得越来越明显。然而，典型的选择性 kappa-阿片拮抗剂具有很长的作用持续时间，这归因于体内 c-Jun N 末端激酶 (JNK) 1 的激活。为了测试这种非竞争性机制的普遍性，我们使用 C57BL/6 野生型小鼠来确定新型 kappa-阿片受体配体的拮抗剂作用持续时间，并与传统的竞争性拮抗剂相比检查它们对 JNK1 激活的功效。在测试的 12 种化合物中，有 5 种具有较长的作用持续时间，与 JNK 激活呈正相关：RTI-5989-97 [(3S)-7-羟基-N-[(1S)-1-[(3R, 4R)-4-(3-羟基苯基)-3,4-二甲基-1-哌啶基]甲基}-(2-甲基丙基]-2-甲基-1,2, 3,4-四氢-3-异喹啉甲酰胺]、RTI-5989-194[(3R)-7羟基-N-[(1S)-1-[(3R,4R)-4-(3-羟基苯基)-3,4-二甲基-1-哌啶基]甲基}-(2-甲基丁基]-1,2,3,4-四氢-3-异喹啉甲酰胺], RTI-5989-241 [(3R)-7-羟基-N-[(1S)-1-{[(3R，4R)-4-(3-甲氧基苯基)-3,4-二甲基-1-哌啶基]甲基}-2甲基丙基]-1,2,3,4-四氢异喹啉-3-甲酰胺)]，去甲-联托菲胺(nor-BNI)；和(3R)-7-羟基-N-((1S)1-{[(3R, 4R)-4-(3-羟基苯基)-3,4-二甲基-1-哌啶基]甲基}2-甲基丙基)-1,2,3,4-四氢-3-异喹啉甲酰胺 (JDTic) 7 的作用持续时间较短，并且不会增加磷酸-JNK-ir： RTI-5989-212[(3R)-N-[(1S)-1-[(3R,4R)-4-(3羟基苯基)-3,4-二甲基-1-哌啶基]甲基}-(2-甲基丙基]-7-甲氧基-1,2,3,4-四氢异喹啉-3-甲酰胺]，RTI-5989-240 [(3R)-7-羟基-N-[(1S)-1-[(3R,4R)-4-(3-羟基苯基)-3,4-二甲基哌啶-1-基]甲基}-(2-甲基丙基]-3-甲基-1,2,3,4-四氢异喹啉-3-甲酰胺], JSPA0658 [(S)-3-氟-4-(4-((2-(3,5-二甲基苯基)吡咯烷-1-基)甲基)苯氧基)苯甲酰胺]，JSPA071B[(S)-3-氟-4-(4-((2-(3,5-双(三氟甲基)苯基)吡咯烷-1-基)甲基)苯氧基)苯甲酰胺] PF-4455242。 [2-甲基-N-((2'-(吡咯烷-1-基磺酰基)联苯-4-基)甲基)丙-1-胺]，PF-4455242 [2-甲基-N-((2'(吡咯烷-1-基磺酰基)联苯-4-基)甲基)丙-1-胺]，FP3FBZ [(S)-3-氟-4-(4-((2-(3-氟苯基)吡咯烷-1-基)甲基)苯氧基)苯甲酰胺]和纳洛酮治疗后，缺乏κ-阿片受体的小鼠中pJNK-ir没有增加；治疗后48小时pJNK-ir恢复到基线；并且在第一次攻击72小时后第二次使用nor-BNI没有增加。在缺乏 JNK1 同工型的动物中没有观察到 pJNK-ir 的持久拮抗作用和磷酸化 JNK-ir 的增加。这些结果支持了这样的假设：小分子 kappa-阿片受体拮抗剂的体内作用持续时间取决于其激活 JNK1 的功效，并且 kappa-受体的持续失活不需要持续的 JNK 激活。
The kappa-opioid receptor is a widely expressed G-protein-coupled receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective kappa-opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we used C57BL/6 wild type mice to determine the durations of antagonist action of novel kappa-opioid receptor ligands and examined their efficacies for JNK1 activation compared with conventional competitive antagonists. Of the 12 compounds tested, 5 had long durations of action that positively correlated with JNK activation: RTI-5989-97 [(3S)-7-hydroxy-N-[(1S)-1-[(3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl] methyl}-(2-methylpropyl]-2-methyl-1,2, 3,4-tetrahydro-3-isoquinolinecarboxamide], RTI-5989-194 [(3R)-7hydroxy- N-[(1S)-1-[(3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl] methyl}-(2-methylbutyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide], RTI-5989-241 [(3R)-7-hydroxy-N-[(1S)-1-{[(3R, 4R)-4-(3-methoxyphenyl)-3,4-dimethyl-1-piperidinyl] methyl}-2methylpropyl]- 1,2,3,4-tetrahydroisoquinoline-3-carboxamide)], nor-binaltorphimine (nor-BNI); and (3R)-7-hydroxy-N-((1S)1-{[(3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl] methyl}2- methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic). Seven had short durations of action and did not increase phospho-JNK-ir: RTI-5989-212[(3R)-N-[(1S)-1-[(3R, 4R)-4-(3hydroxyphenyl)-3,4-dimethyl-1-piperidinyl] methyl}-(2-methylpropyl]- 7-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide], RTI-5989-240 [(3R)-7-hydroxy-N-[(1S)-1-[(3R, 4R)-4-(3-hydroxyphenyl)- 3,4-dimethylpiperidin-1-yl] methyl}-(2-methylpropyl]-3-methyl- 1,2,3,4-tetrahydroisoquinoline-3-carboxamide], JSPA0658 [(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl) pyrrolidin-1-yl) methyl) phenoxy) benzamide], JSPA071B [(S)-3-fluoro-4-(4-((2-(3, 5-bis(trifluoromethyl) phenyl) pyrrolidin-1-yl) methyl) phenoxy) benzamide]. PF-4455242 [2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl) biphenyl- 4-yl) methyl) propan-1-amine], PF-4455242 [2-methyl-N-((2'(pyrrolidin-1-ylsulfonyl) biphenyl-4-yl) methyl) propan-1-amine], FP3FBZ [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl) pyrrolidin-1-yl) methyl) phenoxy) benzamide], and naloxone. After long-acting antagonist treatment, pJNK-ir did not increase in mice lacking the kappa-opioid receptor; increased pJNK-ir returned to baseline by 48 h after treatment; and a second challenge with nor-BNI 72 h after the first did not increase pJNK-ir. Long-lasting antagonism and increased phospho-JNK-ir were not seen in animals lacking the JNK1 isoform. These results support the hypothesis that the duration of action of small molecule kappa-opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the kappa-receptor does not require sustained JNK activation.