A new synthetic approach of N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide (JTC-801) and its analogues and their pharmacological evaluation as nociceptin receptor (NOP) antagonists

Sestili, Isabella; Borioni, Anna; Mustazza, Carlo; Rodomonte, Andrea; Turchetto, Luciana; Sbraccia, Maria; Riitano, Daniela; Giudice, Maria Rosaria Del

doi:10.1016/j.ejmech.2004.09.009

Cited by 39 publications

(18 citation statements)

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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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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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“…[5] Cyanine dyes derived from substituted 2-methylquinolines are utilized as electronic and optoelectronic materials. [6] Tris(8-quinolinolato)aluminum is most widely used as an excellent green-emitting material, [7a,b] and functionalization of the quinoline ring provides full-spectrum fluorescent materials.…”

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confidence: 99%

Assembly of Substituted 2‐Alkylquinolines by a Sequential Palladium‐Catalyzed CN and CC Bond Formation

et al. 2011

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“…JTC‐801 also attenuates N/OFQ‐induced suppression of [ 3 H]‐5‐HT and noradrenaline release in the rat brain, showing time‐dependent profiles . JTC‐801 is relatively nonpolar and appears to have good bioavailability, readily crossing the blood–brain barrier , and has been suggested to lack partial agonist activity .…”

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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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A new synthetic approach of N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide (JTC-801) and its analogues and their pharmacological evaluation as nociceptin receptor (NOP) antagonists

Cited by 39 publications

References 30 publications

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

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

Assembly of Substituted 2‐Alkylquinolines by a Sequential Palladium‐Catalyzed CN and CC Bond Formation

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

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