• Article

Duration of Action of a Broad Range of Selective kappa-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

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

Citation

Melief, E. J., Miyatake, M., Carroll, F., Beguin, C., Carlezon, W. A., Cohen, B. M., ... Chavkin, C. (2011). Duration of Action of a Broad Range of Selective kappa-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation. Molecular Pharmacology, 80(5), 920-929.