Synthesis and pharmacological evaluation of bivalent antagonists of the nociceptin opioid receptor

Giudice, Maria Rosaria Del; Borioni, Anna; Bastanzio, Giuditta; Sbraccia, Maria; Mustazza, Carlo; Sestili, Isabella

doi:10.1016/j.ejmech.2011.01.040

Cited by 8 publications

(4 citation statements)

References 16 publications

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“…Both JTC‐801 and UFP‐101 have been suggested to have complex pharmacological profiles under certain conditions, including inverse agonism (JTC‐801) and partial agonist activity (UFP‐101) . It is also possible that JTC‐801 could interact with a different site on the NOP receptor to the N/OFQ binding site, in effect acting as an allosteric regulator . It is apparent that the potential for differential pharmacological actions in vivo must be a consideration for all NOP antagonists.…”

Section: Discussionmentioning

confidence: 99%

Role of Nociceptin/Orphanin FQ and NOP Receptors in the Response to Acute and Repeated Restraint Stress in Rats

Delaney

Dawe

Hogan

et al. 2012

J Neuroendocrinology

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Central nociceptin/orphanin FQ (N/OFQ)-expressing neurones are abundantly expressed in the hypothalamus and limbic system and are implicated in the regulation of activity of the hypothalamic-pituitary-adrenal axis (HPA) and stress responses. We investigated the role of the endogenous N/OFQ receptor (NOP) system using the nonpeptidic NOP antagonist, JTC-801 [N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxy-methyl)benzamide monohydrochloride], during the HPA axis response to acute physical/psychological stress (60 min of restraint). Although i.v. JTC-801 (0.05 mg/kg in 100 μl) had no significant effect on restraint-induced plasma corticosterone release at 30 or 60 min post-injection, i.v. JTC-801 (0.05 mg/kg in 100 μl) in quiescent rats significantly increased basal plasma corticosterone at the 30-min time-point compared to i.v. vehicle (1% dimethysulphoxide in sterile saline). Central injection of JTC-801 i.c.v. was associated with increased Fos expression in the parvocellular paraventricular nucleus 90 min after infusion compared to vehicle control. These findings contrast to the effects of i.c.v. UFP-101, a NOP antagonist that we have previously shown to have no effect on HPA activity in quiescent rats. To determine whether restraint stress was associated with compensatory changes in N/OFQ precursor (ppN/OFQ) or NOP receptor mRNAs, in a separate study, we undertook reverse transcriptase-polymerase chain reaction and in situ hybridisation analysis of ppN/OFQ and NOP transcripts in the brains of male Sprague–Dawley rats. In support of an endogenous role for central N/OFQ in psychological stress, we found that acute restraint significantly decreased preproN/OFQ transcript expression in the hippocampus 2 h after stress compared to unstressed controls. PpN/OFQ mRNA was also reduced in the mediodorsal forebrain 4 h after stress. NOP mRNA was reduced in the hypothalamus 2 h after restraint and at 4 h in mediodorsal forebrain and hippocampus. In situ hybridisation analysis showed that acute restraint significantly decreased ppNN/OFQ in the central amygdala, with significantly increased expression in bed nucleus and reticular thalamus associated with repeated restraint. There was a strong trend for reduced NOP mRNA in the bed nucleus of acute and repeated restraint groups, although there were no other significant changes seen. Although the exact mechanisms require elucidation, the findings obtained in the present study provide evidence indicating that the endogenous N/OFQ system is involved in both acute and chronic restraint stress responses. In summary, our findings confirm the significant role of endogenous NOP receptors and tonic N/OFQ function in the response to the psychological stress of restraint.

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Section: Discussionmentioning

confidence: 99%

Role of Nociceptin/Orphanin FQ and NOP Receptors in the Response to Acute and Repeated Restraint Stress in Rats

Delaney

Dawe

Hogan

et al. 2012

J Neuroendocrinology

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“…Even if JTC-801 bound to the μ-opioid receptor, its low affinity suggests that it would rapidly dissociate and not produce antinociception 16-18 h after each administration. However, results from binding and in vivo experiments suggest that JTC-801 has competitive and non-competitive binding properties at the NOP receptor that may account for its long-lasting antinociceptive effects (Yamada et al, 2002;Mabuchi et al, 2003;Marti et al, 2003;Sestili et al, 2004;Del Giudice et al, 2011).…”

Section: Figurementioning

confidence: 99%

Nociceptin/orphanin FQ peptide receptor antagonist JTC‐801 reverses pain and anxiety symptoms in a rat model of post‐traumatic stress disorder

Zhang

Simpson-Durand

Standifer

2014

British J Pharmacology

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BACKGROUND AND PURPOSESingle-prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), also induces long-lasting hyperalgesia associated with hypocortisolism and elevated nociceptin/orphanin FQ (N/OFQ) levels in serum and CSF. Here, we determined the effect of JTC-801 (N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride), a nociceptin/orphanin FQ peptide (NOP) receptor antagonist, on symptoms of pain and anxiety in rats after SPS exposure, and examined N/OFQ-NOP receptor system changes. EXPERIMENTAL APPROACHMale Sprague Dawley rats received JTC-801 (6 mg kg −1 i.p., once daily) during days 7-21 of SPS. The ability of JTC-801 to inhibit N/OFQ-stimulated [ 35 S]-GTPγS binding was confirmed in rat brain membranes. Anxiety-like behaviour and pain sensitivity were monitored by changes in elevated plus maze performance and withdrawal responses to thermal and mechanical stimuli. Serum corticosterone and N/OFQ content in CSF, serum and brain tissues were determined by radioimmunoassay; NOP receptor protein and gene expression in amygdala, hippocampus and periaqueductal grey (PAG) were examined by immunoblotting and real-time PCR respectively. KEY RESULTSJTC-801 treatment reversed SPS-induced mechanical allodynia, thermal hyperalgesia, anxiety-like behaviour and hypocortisolism. Elevated N/OFQ levels in serum, CSF, PAG and hippocampus at day 21 of SPS were blocked by JTC-801; daily JTC-801 treatment also reversed NOP receptor protein and mRNA up-regulation in amygdala and PAG. CONCLUSION AND IMPLICATIONSJTC-801 reversed SPS-induced anxiety-and pain-like behaviours, and NOP receptor system up-regulation. These findings suggest that N/OFQ plays an important role in hyperalgesia and allodynia maintenance after SPS. NOP receptor antagonists may provide effective treatment for co-morbid PTSD and pain. LINKED ARTICLESThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx

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“…This suggested that nociceptin tonically regulates, in an inhibitory fashion, basal activity of the HPA axis (Delaney et al, 2012), which contrasted with other evidence that UFP-101 did not alter basal HPA axis activity (Leggett et al, 2007). Once again, however, and like other NOP-R antagonists, JTC-801 exhibits a complex pharmacological profile including antagonist and inverse agonist actions (Mahmoud et al, 2010), and allosteric regulation (Sestili et al, 2004; Del Giudice et al, 2011). Therefore, other experimental factors could have influenced the effect of JTC-801 on the HPA axis including route of drug administration, dose-response characteristics, and the selectivity profile of JTC-801 at NOP-R (Delaney et al, 2012).…”

Section: Ofq/n and The Hypothalamic-pituitary-adrenal Axismentioning

confidence: 99%

The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

Mallimo

Kusnecov

2013

Front. Cell. Neurosci.

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The neuropeptide, orphanin FQ/nociceptin (OFQ/N or simply, nociceptin), is expressed in both neuronal and non-neuronal tissue, including the immune system. In the brain, OFQ/N has been investigated in relation to stress, anxiety, learning and memory, and addiction. More recently, it has also been found that OFQ/N influences glial cell functions, including oligodendrocytes, astrocytes, and microglial cells. However, this latter research is relatively small, but potentially important, when observations regarding the relationship of OFQ/N to stress and emotional functions is taken into consideration and integrated with the growing evidence for its involvement in cells that mediate inflammatory events. This review will first provide an overview and understanding of how OFQ/N has been implicated in the HPA axis response to stress, followed by an understanding of its influence on natural and learned anxiety-like behavior. What emerges from an examination of the literature is a neuropeptide that appears to counteract anxiogenic influences, but paradoxically, without attenuating HPA axis responses generated in response to stress. Studies utilized both central administration of OFQ/N, which was shown to activate the HPA axis, as well as antagonism of NOP-R, the OFQ/N receptor. In contrast, antagonist or transgenic OFQ/N or NOP-R knockout studies, showed augmentation of HPA axis responses to stress, suggesting that OFQ/N may be needed to control the magnitude of the HPA axis response to stress. Investigations of behavior in standard exploratory tests of anxiogenic behavior (eg., elevated plus maze) or learned fear responses have suggested that OFQ/N is needed to attenuate fear or anxiety-like behavior. However, some discrepant observations, in particular, those that involve appetitive behaviors, suggest a failure of NOP-R deletion to increase anxiety. However, it is also suggested that OFQ/N may operate in an anxiolytic manner when initial anxiogenic triggers (eg., the neuropeptide CRH) are initiated. Finally, the regulatory functions of OFQ/N in relation to emotion-related behaviors may serve to counteract potential neuroinflammatory events in the brain. This appears to be evident within the glial cell environment of the brain, since OFQ/N has been shown to reduce the production of proinflammatory cellular and cytokine events. Given that both OFQ/N and glial cells are activated in response to stress, it is possible that there is a possible convergence of these two systems that has important repercussions for behavior and neuroplasticity.

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Synthesis and pharmacological evaluation of bivalent antagonists of the nociceptin opioid receptor

Cited by 8 publications

References 16 publications

Role of Nociceptin/Orphanin FQ and NOP Receptors in the Response to Acute and Repeated Restraint Stress in Rats

Role of Nociceptin/Orphanin FQ and NOP Receptors in the Response to Acute and Repeated Restraint Stress in Rats

Nociceptin/orphanin FQ peptide receptor antagonist JTC‐801 reverses pain and anxiety symptoms in a rat model of post‐traumatic stress disorder

The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

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