NOP-Targeted Nonpeptide Ligands

Zaveri, Nurulain T.; Meyer, Michelle M.

doi:10.1007/164_2019_213

Cited by 12 publications

(8 citation statements)

References 131 publications

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“…NOP receptor agonists are now under clinical development for the treatment of hypertension (Kantola et al, 2017), urinary incontinence (Angelico et al, 2019) and pain (Calo and Lambert, 2018;Tzschentke et al, 2019). Several chemically diverse NOP antagonists have been described in the literature including the peptides [Nphe 1 ]N/OFQ(1-13)-NH2 (Calo et al, 2000) and UFP-101 (Calo et al, 2002), and the small molecules J-113397 (Ozaki et al, 2000), SB-612111 (Zaratin et al, 2004), and Comp 24 (Goto et al, 2006) (for a review see (Toll et al, 2016;Zaveri and Meyer, 2019)). The crystal structure of the NOP receptor in complex with Comp 24 has been described (Thompson et al, 2012;Miller et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Detailed In Vitro Pharmacological Characterization of the Clinically Viable Nociceptin/Orphanin FQ Peptide Receptor Antagonist BTRX-246040

Ferrari

Rizzo

Ruzza

et al. 2020

J Pharmacol Exp Ther

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The peptide nociceptin/orphanin FQ (N/OFQ) is the natural ligand of the N/OFQ receptor (NOP) which is widely expressed in the central and peripheral nervous system. Selective NOP antagonists are worthy of testing as innovative drugs to treat depression, Parkinson's disease, and drug abuse. The aim of this study was to perform a detailed in vitro characterization of BTRX-246040 (also known as LY2940094, [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-pyridyl]methanol)a novel NOP antagonist that has been already studied in humans. BTRX-246040 has been tested in vitro in the following assays: calcium mobilization in cells expressing NOP and classical opioid receptors and chimeric G proteins, BRET assay measuring NOP interaction with G proteins and -arrestins, the label free dynamic mass redistribution assay, and the electrically stimulated mouse vas deferens. BTRX-246040 was systematically compared to the standard NOP antagonist SB-612111. In all assays BTRX-246040 behaves as a pure and selective antagonist at human recombinant and murine native NOP receptors displaying 3-10 fold higher potency than the standard antagonist SB-612111. BTRX-246040 is as an essential pharmacological tool to further investigate the therapeutic potential of NOP antagonists in preclinical and clinical studies. Significance Statement NOP antagonists may be innovative antidepressant drugs. In this research the novel clinically viable NOP antagonist BTRX-246040 has been deeply characterized in vitro in a panel of assays. BTRX-246040 resulted a pure, potent and selective NOP antagonist.

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Section: Introductionmentioning

confidence: 99%

Detailed In Vitro Pharmacological Characterization of the Clinically Viable Nociceptin/Orphanin FQ Peptide Receptor Antagonist BTRX-246040

Ferrari

Rizzo

Ruzza

et al. 2020

J Pharmacol Exp Ther

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“…NOP agonists, upon systemic administration, show significant antinociceptive efficacy comparable to morphine [71]. The N/OFQ peptide precursor (ppN/ OFQ) and the NOP receptor are widely expressed in the nervous system as well as in peripheral organs and immune cells [72].…”

Section: Discussionmentioning

confidence: 99%

Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects

et al. 2021

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“…As bifunctional NOP/MOP agonists exhibit potent analgesic effects in rodents and NHPs, researchers have developed several nonmorphinan compounds that bind to both NOP and MOP receptors (Zaveri, 2011;Zaveri & Meyer, 2019). Among the several nonpeptidic NOP receptor ligands, AT-121 has been identified as a nonmorphinan bifunctional NOP/MOP agonist showing high binding affinity and partial agonist efficacy for both NOP and MOP receptors (Ding et al, 2018).…”

Section: Nonmorphinan Nop/mop Partial Agonistsmentioning

confidence: 99%

Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse

Kiguchi

Ding

2020

J of Neuroscience Research

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Following the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) as an endogenous ligand for the NOP receptor, ample evidence has revealed unique functional profiles of the N/OFQ-NOP receptor system. NOP receptors are expressed in key neural substrates involved in pain and reward modulation. In non-human primates (NHPs), NOP receptor activation effectively exerts antinociception and anti-hypersensitivity at the spinal and supraspinal levels. Moreover, NOP receptor activation inhibits dopaminergic transmission and synergistically enhances mu-opioid peptide (MOP) receptor-mediated analgesia. In this article, we discuss the functional profiles of ligands with dual NOP and MOP receptor agonist activities and highlight their optimal functional efficacy for pain relief and drug abuse treatment. Through coactivation of NOP and MOP receptors, bifunctional NOP/MOP receptor "partial" agonists (e.g., AT-121, BU08028, and BU10038) reveal a wider therapeutic window with fewer side effects. These newly developed ligands potently induce antinociception without MOP receptor agonist-associated side effects such as abuse potential, respiratory depression, itch sensation, and physical dependence. In addition, in both rodent and NHP models, bifunctional NOP/MOP receptor agonists can attenuate reward processing and/or the reinforcing effects of opioids and other abused drugs. While a mixed NOP/opioid receptor "full" agonist cebranopadol is undergoing clinical trials, bifunctional NOP/MOP "partial" agonists exhibit promising therapeutic profiles in translational NHP models for the treatment of pain and opioid abuse. This class of drugs demonstrates the therapeutic advantage of NOP and MOP receptor coactivation, indicating a greater potential for future development.

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NOP-Targeted Nonpeptide Ligands

Cited by 12 publications

References 131 publications

Detailed In Vitro Pharmacological Characterization of the Clinically Viable Nociceptin/Orphanin FQ Peptide Receptor Antagonist BTRX-246040

Detailed In Vitro Pharmacological Characterization of the Clinically Viable Nociceptin/Orphanin FQ Peptide Receptor Antagonist BTRX-246040

Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects

Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse

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