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

Abstract

The -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 -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 -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: , and naloxone. After long-acting antagonist treatment, pJNK-ir did not increase in mice lacking the -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 -opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the -receptor does not require sustained JNK activation.

Pharmacological Characterization of 2-Methyl-N-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a High-Affinity Antagonist Selective for κ-Opioid Receptors

“…A number of selective KOR antagonists, including nor-BNI and JDTic, have been shown to have an exceptionally long duration of action in vivo, which might constrain their therapeutic value (see Metcalf and Coop, 2005). Receptor occupancy time-course data showed that PF-04455242 was no longer bound to KORs after 8 h, suggesting a relatively short duration of action, which has subsequently been confirmed using a warm water tail-withdrawal assay (Melief et al, 2011).…”

Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

“…The mechanism of this effect is not fully understood, but may involve ligand-directed signaling (also known as biased agonism), a process by which a drug can act as an antagonist of some downstream intracellular signaling pathways while simultaneously acting as an agonist at others. The long-lasting effects of KOR antagonists in general may be related to their ability to activate c-Jun N-terminal kinase-1 (JNK), leading to a de-coupling of KORs from their intracellular signaling cascades (Melief et al, 2010;Melief et al, 2011), rather than long-term persistence of these drugs in the brain (Munro et al, 2012). From a drug development perspective, such long-lasting effects may be ultimately desirable once safety and efficacy are established, but they complicate early-phase clinical studies in humans ).…”

Dynorphin–Still an Extraordinarily Potent Opioid Peptide

“…Both norBNI and JDTic have antidepressant-like and anxiolyticlike properties in rodent models of stress behaviors Knoll and Carlezon, 2010), and these actions may be therapeutically useful. However, both norBNI and JDTic have very long durations of action (.3 weeks in rodents after a single dose), and this long-duration of effect is likely to be a consequence of kappa receptor inactivation through a c-Jun N-terminal kinase 1-dependent mechanism (Melief et al, 2011). Short-acting, selective kappa antagonists that do not activate c-Jun kinase have more recently been developed by scientists working at AstraZeneca (Peters et al, 2011), Pfizer , and Eli Lilly , and further development of these and related compounds is ongoing.…”