Parkinson’s disease: no NOP, new hope

Arcuri, Ludovico; Mercatelli, Daniela; Morari, Michele

doi:10.18632/oncotarget.13710

Cited by 7 publications

(6 citation statements)

References 8 publications

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“…In parallel, genetic models have been developed for investigating the biology of the N/OFQ-NOP receptor system including mouse 17 and rat 18,19 knockouts of the NOP receptor gene (NOP(e/e)), a mouse knockout of the ppN/OFQ gene, 20 and more recently a mouse knock-in of the NOP-eGFP fusoprotein in place of the native NOP. 21 Based on a large body of evidence coming from preclinical studies performed using the above tools, NOP receptor agonists have been proposed as innovative drugs for treating anxiety, drug abuse, cough, and urinary incontinence, 3,22,23 whereas NOP selective antagonists have been suggested as novel treatments for Parkinson's disease 24 and depression 25 (Table 2). For some of these indications of NOP ligands, preclinical findings were confirmed by clinical studies that are briefly described in the following sections.…”

Section: Editor's Key Pointsmentioning

confidence: 99%

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

Calò

Lambert

2018

British Journal of Anaesthesia

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Opioids are characterised as classical (mu, delta, and kappa) along with the non-classical nociceptin/orphanin FQ (N/ OFQ) receptor or NOP. Targeting NOP has therapeutic indications in control of the cardiovascular and respiratory systems and micturition, and a profile as an antidepressant. For all of these indications, there are translational human data. Opioids such as morphine and fentanyl (activating the mu receptor) are the mainstay of pain treatment in the perioperative period, despite a challenging side-effect profile. Opioids in general have poor efficacy in neuropathic pain. Moreover, longer term use is associated with tolerance. There is good evidence interactions between opioid receptors, and receptor co-activation can reduce side-effects without compromising analgesia; this is particularly true for mu and NOP co-activation. Recent pharmaceutical development has produced a mixed opioid/NOP agonist, cebranopadol. This new chemical entity is effective in animal models of nociceptive and neuropathic pain with greater efficacy in the latter. In animal models, there is little evidence for respiratory depression, and tolerance (compared with morphine) only develops after long treatment periods. There is now early phase clinical development in diabetic neuropathy, cancer pain, and low back pain where cebranopadol displays significant efficacy. In 1996, N/OFQ was formally identified with an innovative analgesic profile. Approximately 20 yr later, cebranopadol as a clinical ligand is advancing through the human trials process.

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Section: Editor's Key Pointsmentioning

confidence: 99%

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

Calò

Lambert

2018

British Journal of Anaesthesia

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“…UFP-101 is a potent and selective NOP receptor antagonist; since its identification [52] this peptide has been used in a large number of in vitro and in vivo studies (reviewed in [39,53]) contributing to increase our knowledge on the control exerted by the N/OFQ system on several biological functions and on the possible therapeutic indications of NOP selective antagonists particularly as innovative antidepressant agents [54] and as novel drugs to treat Parkinson disease [55]. Thus, the PWT chemical strategy has been applied to the peptide sequence of UFP-101 (see Table 1) to generate the tetrabranched derivative PWT2-UFP-101.…”

Section: Pwt2-ufp-101mentioning

confidence: 99%

Peptide welding technology – A simple strategy for generating innovative ligands for G protein coupled receptors

et al. 2018

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“…The Phase II clinical trial testing the symptomatic efficacy of the NOP antagonist BTRX-246040 in PD will be pivotal in validating that NOP receptor antagonists might really represent a new hope for PD patients (Arcuri, Mercatelli, & Morari, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical data strongly suggest that the N/OFQ-NOP receptor system would be a novel target for PD therapy. Selective and potent NOP receptor antagonists have been developed and characterized, (Arcuri, Mercatelli, & Morari, 2017).…”

Section: Discussionmentioning

confidence: 99%

Managing Parkinson's disease: moving ON with NOP

Mercatelli

Bézard

Eleopra

et al. 2020

British J Pharmacology

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The opioid‐like neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP receptor) contribute to Parkinson's disease (PD) and motor complications associated with levodopa therapy. The N/OFQ–NOP receptor system is expressed in cortical and subcortical motor areas and, notably, in dopaminergic neurons of the substantia nigra compacta. Dopamine depletion, as in rodent models of PD results in up‐regulation of N/OFQ transmission in the substantia nigra and down‐regulation of N/OFQ transmission in the striatum. Consistent with this, NOP receptor antagonists relieve motor deficits in PD models by reinstating the physiological balance between excitatory and inhibitory inputs impinging on nigro‐thalamic GABAergic neurons. NOP receptor antagonists also counteract the degeneration of nigrostriatal dopaminergic neurons, possibly by attenuating the excitotoxicity or modulating the immune response. Conversely, NOP receptor agonists attenuate levodopa‐induced dyskinesia by attenuating the hyperactivation of striatal D1 receptor signalling in neurons of the direct striatonigral pathway. The N/OFQ–NOP receptor system might represent a novel target in the therapy of PD.

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Parkinson’s disease: no NOP, new hope

Cited by 7 publications

References 8 publications

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

Peptide welding technology – A simple strategy for generating innovative ligands for G protein coupled receptors

Managing Parkinson's disease: moving ON with NOP

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