Therapeutic Approaches for NOP Receptor Antagonists in Neurobehavioral Disorders: Clinical Studies in Major Depressive Disorder and Alcohol Use Disorder with BTRX-246040 (LY2940094)

Witkin, Jeffrey M.; Wallace, Tanya L.; Martin, William J.

doi:10.1007/164_2018_186

Cited by 21 publications

(21 citation statements)

References 53 publications

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“…These pharmacodynamic features are associated with great pharmacokinetic properties demonstrated in rodents and humans (Raddad et al, 2016). In addition, the tolerability and safety of BTRX-246040 once-daily dosing of 40 mg up to 8 weeks have been already demonstrated in clinical studies (Witkin et al, 2019). Collectively these features candidate BTRX-246040 as an essential pharmacological tool to further investigate the therapeutic potential of NOP antagonists as innovative drugs to treat depression (Gavioli and Calo, 2013), Parkinson's disease (Mercatelli et al, 2019), and possibly drug abuse 14 (Ciccocioppo et al, 2019) as well as to identify novel conditions/diseases where the blockade of the NOP receptor is associated with beneficial effects, including traumatic injuries of the central nervous system (Awwad et al, 2018;Sekine et al, 2018), post-traumatic stress disorders (Zhang et al, 2015;Genovese and Dobre, 2017), and sepsis (Carvalho et al, 2008;Williams et al, 2008).…”

Section: Discussionmentioning

confidence: 94%

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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: Discussionmentioning

confidence: 94%

“…Moreover, in small proof of concept clinical studies BTRX-246040 was safe and well tolerated and showed efficacy in depressed (Post et al, 2016b) and alcohol dependent (Post et al, 2016a) patients (for an updated review on this NOP ligand see Witkin et al, 2019).…”

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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“…Consistent with these findings, NOP receptor antagonists show antidepressant-like effects in animal models of depression [4]. Moreover, recent clinical studies demonstrate that LY2940094, NOP receptor antagonist administered per oral, displays antidepressant effects in depressed patients [56], providing evidence that blockade of NOP receptor signaling could represent a promising strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ and explore the underlying mechanism of NOP receptor antagonists as potential antidepressants.…”

Section: Introductionmentioning

confidence: 77%

Role of nociceptin/orphanin FQ and nociceptin opioid peptide receptor in depression and antidepressant effects of nociceptin opioid peptide receptor antagonists

Park

Chae

Kim

et al. 2019

Korean J Physiol Pharmacol

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Nociceptin/orphanin FQ (N/OFQ) and its receptor, nociceptin opioid peptide (NOP) receptor, are localized in brain areas implicated in depression including the amygdala, bed nucleus of the stria terminalis, habenula, and monoaminergic nuclei in the brain stem. N/OFQ inhibits neuronal excitability of monoaminergic neurons and monoamine release from their terminals by activation of G protein-coupled inwardly rectifying K+ channels and inhibition of voltage sensitive calcium channels, respectively. Therefore, NOP receptor antagonists have been proposed as a potential antidepressant. Indeed, mounting evidence shows that NOP receptor antagonists have antidepressant-like effects in various preclinical animal models of depression, and recent clinical studies again confirmed the idea that blockade of NOP receptor signaling could provide a novel strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ in relation to depression and explore the possible mechanism of NOP receptor antagonists as potential antidepressants.

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“…BTRX-246040 was also found to reduce depression symptoms in a second trial with heavy alcohol drinkers. Given the comorbidity of major depression and alcohol use disorder, a compound with such effects in patients could be a valuable addition to the medications available [ 255 ]. In addition, NOP antagonists have already been used to identify novel conditions/diseases for which the blockade of NOP receptor is associated with beneficial effects (traumatic injuries of the central nervous system, post-traumatic stress disorders, sepsis) [ 255 , 256 , 257 , 258 , 259 ].…”

Section: Anti-opioid Peptides: Potential Therapeutic Interestmentioning

confidence: 99%

Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance

Gibuła‐Tarłowska

Kotlińska

2020

Biomolecules

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Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.

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Therapeutic Approaches for NOP Receptor Antagonists in Neurobehavioral Disorders: Clinical Studies in Major Depressive Disorder and Alcohol Use Disorder with BTRX-246040 (LY2940094)

Cited by 21 publications

References 53 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

Role of nociceptin/orphanin FQ and nociceptin opioid peptide receptor in depression and antidepressant effects of nociceptin opioid peptide receptor antagonists

Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance

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