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Nurulain T Zaveri - One of the best experts on this subject based on the ideXlab platform.
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Discovery and Structure-Activity Relationships of Nociceptin Receptor Partial Agonists That Afford Symptom Ablation in Parkinson's Disease Models.
Journal of medicinal chemistry, 2020Co-Authors: Uma Gayathri Kamakolanu, Willma E Polgar, Dennis Yasuda, Michael E. Meyer, Matteo Marti, Daniela Mercatelli, Clarissa Anna Pisanò, Alberto Brugnoli, Michele Morari, Nurulain T ZaveriAbstract:A novel series of C(3)-substituted piperdinylindoles were developed as Nociceptin opioid Receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induced dyskinesias. SAR around the C-3 substituents investigated effects on NOP binding, intrinsic activity, and selectivity and showed that while the C(3)-substituted indoles are selective, high affinity NOP ligands, the steric, polar, and cationic nature of the C-3 substituents affected intrinsic activity to afford partial agonists with a range of efficacies. Compounds 4, 5, and 9 with agonist efficacies between 25% and 35% significantly attenuated motor deficits in the 6-OHDA-hemilesioned rat model of PD. Further, unlike NOP antagonists, which appear to worsen dyskinesia expression, these NOP partial agonists did not attenuate or worsen dyskinesia expression. The NOP partial agonists and their SAR reported here may be useful to develop nondopaminergic treatments for PD.
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The Nociceptin Receptor as an Emerging Molecular Target for Cocaine Addiction.
Progress in molecular biology and translational science, 2015Co-Authors: Kabirullah Lutfy, Nurulain T ZaveriAbstract:Cocaine addiction is a global public health and socioeconomic issue that requires pharmacological and cognitive therapies. Currently there are no FDA-approved medications to treat cocaine addiction. However, in preclinical studies, interventions ranging from herbal medicine to deep-brain stimulation have shown promise for the therapy of cocaine addiction. Recent developments in molecular biology, pharmacology, and medicinal chemistry have enabled scientists to identify novel molecular targets along the pathways involved in drug addiction. In 1994, a Receptor that showed a great deal of homology to the traditional opioid Receptors was characterized. However, endogenous and exogenous opioids failed to bind to this Receptor, which led scientists to name it opioid Receptor-like Receptor, now referred to as the Nociceptin Receptor. The endogenous ligand of NOPr was identified a year later and named orphanin FQ/Nociceptin. Nociceptin and NOPr are widely distributed throughout the CNS and are involved in many physiological responses, such as food intake, nociceptive processing, neurotransmitter release, etc. Furthermore, exogenous Nociceptin has been shown to regulate the activity of mesolimbic dopaminergic neurons, glutamate, and opioid systems, and the stress circuit. Importantly, exogenous Nociceptin has been shown to reduce the rewarding and addictive actions of a number of drugs of abuse, such as psychostimulants, alcohol, and opioids. This paper reviews the existing literature on the role of endogenous Nociceptin in the rewarding and addictive actions of cocaine. The effect of exogenous Nociceptin on these processes is also reviewed. Furthermore, the effects of novel small-molecule NOPr ligands on these actions of cocaine are discussed. Overall, a review of the literature suggests that NOPr could be an emerging target for cocaine addiction pharmacotherapy.
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small molecule Nociceptin Receptor agonist ameliorates mast cell activation and pain in sickle mice
Haematologica, 2015Co-Authors: Derek Vang, Nurulain T Zaveri, Jinny Paul, Julia Nguyen, Huy Tran, Lucile Vincent, Dennis Yasuda, Kalpna GuptaAbstract:Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule Nociceptin opioid Receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity Nociceptin opioid Receptor agonist with low efficacy at the mu opioid Receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice. The antinociceptive effect of AT-200 was antagonized by SB-612111, a Nociceptin opioid Receptor antagonist, but not naloxone, a non-selective mu opioid Receptor antagonist. Daily 7-day treatment with AT-200 did not develop tolerance and showed a sustained anti-nociceptive effect, which improved over time and led to reduced plasma serum amyloid protein, neuropeptides, inflammatory cytokines and mast cell activation in the periphery. These data suggest that AT-200 ameliorates pain in sickle mice via the Nociceptin opioid Receptor by reducing inflammation and mast cell activation without causing tolerance. Thus, Nociceptin opioid Receptor agonists are promising drugs for treating pain in sickle cell anemia.
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the Nociceptin orphanin fq Receptor nop as a target for drug abuse medications
Current Topics in Medicinal Chemistry, 2011Co-Authors: Nurulain T ZaveriAbstract:Several studies show that the Nociceptin Receptor NOP plays a role in the regulation of reward and motivation pathways related to substance abuse. Administration of the NOP’s natural peptide ligand, Nociceptin/Orphanin FQ (N/OFQ) or synthetic agonist Ro 64-6198 has been shown to block rewarding effects of cocaine, morphine, amphetamines and alcohol, in various behavioral models of drug reward and reinforcement, such as conditioned place preference and drug self-administration. Administration of N/OFQ has been shown to reduce drug-stimulated levels of dopamine in mesolimbic pathways. The NOP-N/OFQ system has been particularly well examined in the development of alcohol abuse in animal models. Furthermore, the efficacy of the mixed-action opioid buprenorphine, in attenuating alcohol consumption in human addicts and in alcohol-preferring animal models, at higher doses, has been attributed to its partial agonist activity at the NOP Receptor. These studies suggest that NOP Receptor agonists may have potential as drug abuse medications. However, the pathophysiology of addiction is complex and drug addiction pharmacotherapy needs to address the various phases of substance addiction (craving, withdrawal, relapse). Further studies are needed to clearly establish how NOP agonists may attenuate the drug addiction process and provide therapeutic benefit. Addiction to multiple abused drugs (polydrug addiction) is now commonplace and presents a treatment challenge, given the limited pharmacotherapies currently approved. Polydrug addiction may not be adequately treated by a single agent with a single mechanism of action. As with the case of buprenorphine, a mixed-action profile of NOP/opioid activity may provide a more effective drug to treat addiction to various abused substances and/or polydrug addiction.
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comparison of the antinociceptive and antirewarding profiles of novel bifunctional Nociceptin Receptor μ opioid Receptor ligands implications for therapeutic applications
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Lawrence Toll, Taline V Khroyan, Willma E Polgar, Faming Jiang, Cris M Olsen, Nurulain T ZaveriAbstract:The Nociceptin Receptor (NOPr), a member of the opioid Receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the μ-opioid Receptor (MOPr), may function as nonaddicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphine-induced CPP. 1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one) (SR14150), a high-affinity NOPr partial agonist, with low MOPr affinity and efficacy, produced analgesia that was naloxone-reversible. SR14150 did not induce CPP alone, nor did it attenuate morphine-induced CPP. 3-Ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), which has high affinity for both NOPr and MOPr, full agonist activity at NOPr, and partial agonist activity at MOPr, was also a potent analgesic and produced CPP alone, but also modestly attenuated morphine CPP. 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835), a NOPr full agonist and low-affinity MOPr partial agonist, was not antinociceptive, did not produce CPP alone, but attenuated morphine CPP. Our results suggest that NOPr full-agonist activity is required to modulate opioid-induced reward, whereas a bifunctional NOPr/MOPr partial agonist profile may be suitable as a nonaddicting analgesic. The opioid-modulating effects of the NOPr ligands may be used effectively to produce better medications for treatment of drug abuse and pain.
Diego A Pizzagalli - One of the best experts on this subject based on the ideXlab platform.
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social defeat disrupts reward learning and potentiates striatal Nociceptin orphanin fq mrna in rats
Psychopharmacology, 2017Co-Authors: Andre Deravakian, Manoranjan S Dsouza, David N Potter, Elena H Chartoff, William A Carlezon, Diego A PizzagalliAbstract:RATIONALE Mood disorders can be triggered by stress and are characterized by deficits in reward processing, including disrupted reward learning (the ability to modulate behavior according to past rewards). Reward learning is regulated by the anterior cingulate cortex (ACC) and striatal circuits, both of which are implicated in the pathophysiology of mood disorders. OBJECTIVES Here, we assessed in rats the effects of a potent stressor (social defeat) on reward learning and gene expression in the ACC, ventral tegmental area (VTA), and striatum. METHODS Adult male Wistar rats were trained on an operant probabilistic reward task (PRT) and then exposed to 3 days of social defeat before assessment of reward learning. After testing, the ACC, VTA, and striatum were dissected, and expression of genes previously implicated in stress was assessed. RESULT Social defeat blunted reward learning (manifested as reduced response bias toward a more frequently rewarded stimulus) and was associated with increased Nociceptin/orphanin FQ (N/OFQ) peptide mRNA levels in the striatum and decreased Fos mRNA levels in the VTA. Moreover, N/OFQ peptide and Nociceptin Receptor mRNA levels in the ACC, VTA and striatum were inversely related to reward learning. CONCLUSIONS The behavioral findings parallel previous data in humans, suggesting that stress similarly disrupts reward learning in both species. Increased striatal N/OFQ mRNA in stressed rats characterized by impaired reward learning is consistent with accumulating evidence that antagonism of Nociceptin Receptors, which bind N/OFQ, has antidepressant-like effects. These results raise the possibility that Nociceptin systems represent a molecular substrate through which stress produces reward learning deficits in mood disorders.
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social defeat disrupts reward learning and potentiates striatal Nociceptin orphanin fq mrna in rats
Psychopharmacology, 2017Co-Authors: Andre Deravakian, Manoranjan S Dsouza, David N Potter, Elena H Chartoff, William A Carlezon, Diego A PizzagalliAbstract:Mood disorders can be triggered by stress and are characterized by deficits in reward processing, including disrupted reward learning (the ability to modulate behavior according to past rewards). Reward learning is regulated by the anterior cingulate cortex (ACC) and striatal circuits, both of which are implicated in the pathophysiology of mood disorders. Here, we assessed in rats the effects of a potent stressor (social defeat) on reward learning and gene expression in the ACC, ventral tegmental area (VTA), and striatum. Adult male Wistar rats were trained on an operant probabilistic reward task (PRT) and then exposed to 3 days of social defeat before assessment of reward learning. After testing, the ACC, VTA, and striatum were dissected, and expression of genes previously implicated in stress was assessed. Social defeat blunted reward learning (manifested as reduced response bias toward a more frequently rewarded stimulus) and was associated with increased Nociceptin/orphanin FQ (N/OFQ) peptide mRNA levels in the striatum and decreased Fos mRNA levels in the VTA. Moreover, N/OFQ peptide and Nociceptin Receptor mRNA levels in the ACC, VTA and striatum were inversely related to reward learning. The behavioral findings parallel previous data in humans, suggesting that stress similarly disrupts reward learning in both species. Increased striatal N/OFQ mRNA in stressed rats characterized by impaired reward learning is consistent with accumulating evidence that antagonism of Nociceptin Receptors, which bind N/OFQ, has antidepressant-like effects. These results raise the possibility that Nociceptin systems represent a molecular substrate through which stress produces reward learning deficits in mood disorders.
Karel Guillemyn - One of the best experts on this subject based on the ideXlab platform.
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bifunctional peptide based opioid agonist Nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain
Pain, 2017Co-Authors: Camille Lagard, Lucie Chevillard, Karel Guillemyn, Patricia Risede, Jeanlouis Laplanche, Mariana Spetea, Steven Ballet, Bruno MegarbaneAbstract:Drugs able to treat both nociceptive and neuropathic pain effectively without major side effects are lacking. We developed a bifunctional peptide-based hybrid (KGNOP1) that structurally combines a mu-opioid Receptor agonist (KGOP1) with antinociceptive activity and a weak Nociceptin Receptor antagonist (KGNOP3) with anti-neuropathic pain activity. We investigated KGNOP1-related behavioral effects after intravenous administration in rats by assessing thermal nociception, cold hyperalgesia in a model of neuropathic pain induced by chronic constriction injury of the sciatic nerve, and plethysmography parameters including inspiratory time (TI) and minute ventilation (VM) in comparison to the well-known opioid analgesics, tramadol and morphine. Time-course and dose-dependent effects were investigated for all behavioral parameters to determine the effective doses 50% (ED50). Pain-related effects on cold hyperalgesia were markedly increased by KGNOP1 as compared to KGNOP3 and tramadol (ED50: 0.0004, 0.32, and 12.1 μmol/kg, respectively), whereas effects on thermal nociception were significantly higher with KGNOP1 as compared to morphine (ED50: 0.41 and 14.7 μmol/kg, respectively). KGNOP1 and KGOP1 produced a larger increase in TI and deleterious decrease in VM in comparison to morphine and tramadol (ED50(TI): 0.63, 0.52, 12.2, and 50.9 μmol/kg; ED50(VM): 0.57, 0.66, 10.6, and 50.0 μmol/kg, respectively). Interestingly, the calculated ratios of anti-neuropathic pain/antinociceptive to respiratory effects revealed that KGNOP1 was safer than tramadol (ED50 ratio: 5.44 × 10 vs 0.24) and morphine (ED50 ratio: 0.72 vs 1.39). We conclude that KGNOP1 is able to treat both experimental neuropathic and nociceptive pain, more efficiently and safely than tramadol and morphine, respectively, and thus should be a candidate for future clinical developments.
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bifunctional peptide based opioid agonist Nociceptin antagonist ligands for dual treatment of acute and neuropathic pain
Journal of Medicinal Chemistry, 2016Co-Authors: Karel Guillemyn, Camille Lagard, Joanna Starnowska, Jolanta Dyniewicz, Ewelina Rojewska, Joanna Mika, Nga N Chung, Valerie Utard, Piotr Kosson, Andrzej W LipkowskiAbstract:Herein, the opioid pharmacophore H-Dmt-d-Arg-Aba-β-Ala-NH2 (7) was linked to peptide ligands for the Nociceptin Receptor. Combination of 7 and NOP ligands (e.g., H-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) led to binding affinities in the low nanomolar domain. In vitro, the hybrids behaved as agonists at the opioid Receptors and antagonists at the Nociceptin Receptor. Intravenous administration of hybrid 13a (H-Dmt-d-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) to mice resulted in potent and long lasting antinociception in the tail-flick test, indicating that 13a was able to permeate the BBB. This was further supported by a cell-based BBB model. All hybrids alleviated allodynia and hyperalgesia in neuropathic pain models. Especially with respect to hyperalgesia, they showed to be more effective than the parent compounds. Hybrid 13a did not result in significant respiratory depression, in contrast to an equipotent analgesic dose of morphine. These hybrids hence represent a promising avenue toward analgesics for the dual treatment of acute and neuropathic pain.
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Bifunctional Peptide-Based Opioid Agonist–Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain
2016Co-Authors: Karel Guillemyn, Camille Lagard, Joanna Starnowska, Jolanta Dyniewicz, Ewelina Rojewska, Joanna Mika, Nga N Chung, Valerie Utard, Piotr Kosson, Andrzej W LipkowskiAbstract:Herein, the opioid pharmacophore H-Dmt-d-Arg-Aba-β-Ala-NH2 (7) was linked to peptide ligands for the Nociceptin Receptor. Combination of 7 and NOP ligands (e.g., H-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) led to binding affinities in the low nanomolar domain. In vitro, the hybrids behaved as agonists at the opioid Receptors and antagonists at the Nociceptin Receptor. Intravenous administration of hybrid 13a (H-Dmt-d-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) to mice resulted in potent and long lasting antinociception in the tail-flick test, indicating that 13a was able to permeate the BBB. This was further supported by a cell-based BBB model. All hybrids alleviated allodynia and hyperalgesia in neuropathic pain models. Especially with respect to hyperalgesia, they showed to be more effective than the parent compounds. Hybrid 13a did not result in significant respiratory depression, in contrast to an equipotent analgesic dose of morphine. These hybrids hence represent a promising avenue toward analgesics for the dual treatment of acute and neuropathic pain
Camille Lagard - One of the best experts on this subject based on the ideXlab platform.
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bifunctional peptide based opioid agonist Nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain
Pain, 2017Co-Authors: Camille Lagard, Lucie Chevillard, Karel Guillemyn, Patricia Risede, Jeanlouis Laplanche, Mariana Spetea, Steven Ballet, Bruno MegarbaneAbstract:Drugs able to treat both nociceptive and neuropathic pain effectively without major side effects are lacking. We developed a bifunctional peptide-based hybrid (KGNOP1) that structurally combines a mu-opioid Receptor agonist (KGOP1) with antinociceptive activity and a weak Nociceptin Receptor antagonist (KGNOP3) with anti-neuropathic pain activity. We investigated KGNOP1-related behavioral effects after intravenous administration in rats by assessing thermal nociception, cold hyperalgesia in a model of neuropathic pain induced by chronic constriction injury of the sciatic nerve, and plethysmography parameters including inspiratory time (TI) and minute ventilation (VM) in comparison to the well-known opioid analgesics, tramadol and morphine. Time-course and dose-dependent effects were investigated for all behavioral parameters to determine the effective doses 50% (ED50). Pain-related effects on cold hyperalgesia were markedly increased by KGNOP1 as compared to KGNOP3 and tramadol (ED50: 0.0004, 0.32, and 12.1 μmol/kg, respectively), whereas effects on thermal nociception were significantly higher with KGNOP1 as compared to morphine (ED50: 0.41 and 14.7 μmol/kg, respectively). KGNOP1 and KGOP1 produced a larger increase in TI and deleterious decrease in VM in comparison to morphine and tramadol (ED50(TI): 0.63, 0.52, 12.2, and 50.9 μmol/kg; ED50(VM): 0.57, 0.66, 10.6, and 50.0 μmol/kg, respectively). Interestingly, the calculated ratios of anti-neuropathic pain/antinociceptive to respiratory effects revealed that KGNOP1 was safer than tramadol (ED50 ratio: 5.44 × 10 vs 0.24) and morphine (ED50 ratio: 0.72 vs 1.39). We conclude that KGNOP1 is able to treat both experimental neuropathic and nociceptive pain, more efficiently and safely than tramadol and morphine, respectively, and thus should be a candidate for future clinical developments.
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bifunctional peptide based opioid agonist Nociceptin antagonist ligands for dual treatment of acute and neuropathic pain
Journal of Medicinal Chemistry, 2016Co-Authors: Karel Guillemyn, Camille Lagard, Joanna Starnowska, Jolanta Dyniewicz, Ewelina Rojewska, Joanna Mika, Nga N Chung, Valerie Utard, Piotr Kosson, Andrzej W LipkowskiAbstract:Herein, the opioid pharmacophore H-Dmt-d-Arg-Aba-β-Ala-NH2 (7) was linked to peptide ligands for the Nociceptin Receptor. Combination of 7 and NOP ligands (e.g., H-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) led to binding affinities in the low nanomolar domain. In vitro, the hybrids behaved as agonists at the opioid Receptors and antagonists at the Nociceptin Receptor. Intravenous administration of hybrid 13a (H-Dmt-d-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) to mice resulted in potent and long lasting antinociception in the tail-flick test, indicating that 13a was able to permeate the BBB. This was further supported by a cell-based BBB model. All hybrids alleviated allodynia and hyperalgesia in neuropathic pain models. Especially with respect to hyperalgesia, they showed to be more effective than the parent compounds. Hybrid 13a did not result in significant respiratory depression, in contrast to an equipotent analgesic dose of morphine. These hybrids hence represent a promising avenue toward analgesics for the dual treatment of acute and neuropathic pain.
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Bifunctional Peptide-Based Opioid Agonist–Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain
2016Co-Authors: Karel Guillemyn, Camille Lagard, Joanna Starnowska, Jolanta Dyniewicz, Ewelina Rojewska, Joanna Mika, Nga N Chung, Valerie Utard, Piotr Kosson, Andrzej W LipkowskiAbstract:Herein, the opioid pharmacophore H-Dmt-d-Arg-Aba-β-Ala-NH2 (7) was linked to peptide ligands for the Nociceptin Receptor. Combination of 7 and NOP ligands (e.g., H-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) led to binding affinities in the low nanomolar domain. In vitro, the hybrids behaved as agonists at the opioid Receptors and antagonists at the Nociceptin Receptor. Intravenous administration of hybrid 13a (H-Dmt-d-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) to mice resulted in potent and long lasting antinociception in the tail-flick test, indicating that 13a was able to permeate the BBB. This was further supported by a cell-based BBB model. All hybrids alleviated allodynia and hyperalgesia in neuropathic pain models. Especially with respect to hyperalgesia, they showed to be more effective than the parent compounds. Hybrid 13a did not result in significant respiratory depression, in contrast to an equipotent analgesic dose of morphine. These hybrids hence represent a promising avenue toward analgesics for the dual treatment of acute and neuropathic pain
Michael A Statnick - One of the best experts on this subject based on the ideXlab platform.
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a selective Nociceptin Receptor antagonist to treat depression evidence from preclinical and clinical studies
Neuropsychopharmacology, 2016Co-Authors: Anke Post, Trevor S Smart, Judith Krikkeworkel, Gerard R Dawson, Catherine J Harmer, Michael Browning, Kimberley Jackson, Rishi Kakar, Richard C Mohs, Michael A StatnickAbstract:Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) Receptor, which is a G protein-coupled Receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP Receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP Receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo-controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of LY2940094 being better than placebo⩾88%) was not met (82.9%). LY2940094 also had an early effect on the processing of emotional stimuli at Week 1 as shown by an increased recognition of positive relative to negative facial expressions in an emotional test battery. LY2940094 was safe and well tolerated. Overall, these are the first human data providing evidence that the blockade of NOP Receptor signaling represents a promising strategy for the treatment of MDD.
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proof of concept study to assess the Nociceptin Receptor antagonist ly2940094 as a new treatment for alcohol dependence
Alcoholism: Clinical and Experimental Research, 2016Co-Authors: Anke Post, Trevor S Smart, Kimberley Jackson, Richard C Mohs, Michael A Statnick, Joanne Mann, Linda M Rorickkehn, Raymond F Anton, Stephanie S Omalley, Conrad J WongAbstract:Background This was a proof-of-concept study to evaluate the efficacy of LY2940094, a Nociceptin/orphanin FQ peptide Receptor antagonist, in reducing alcohol consumption in actively alcohol-drinking patients with alcohol dependence. Methods Eighty-eight patients, 21 to 66 years of age, diagnosed with alcohol dependence, reporting 3 to 6 heavy drinking days per week, were randomized (1:1) to 8 weeks of treatment with once-daily oral placebo (N = 44) or 40 mg/d of LY2940094 (N = 44). The primary efficacy analysis was the change from baseline in number of drinks per day (NDD) utilizing mixed-model repeated measures comparing LY2940094 and placebo in Month 2 of the 8-week double-blind treatment period. The probability that the difference relative to placebo in NDD was ≤0 at endpoint was calculated, and a probability ≥80% was considered to be evidence that LY2940094 was associated with the reduction in NDD. Results After 8 weeks of treatment, reduction in mean NDD did not differ between LY2940094 versus placebo (−1.4 vs. −1.5, respectively, 44% probability of greater reduction relative to placebo), but there was a greater reduction in the mean percentage of heavy drinking days in a month with LY2940094 versus placebo (−24.5 vs. −15.7%, respectively, 93% probability of a greater reduction relative to placebo), and an increase in the mean percentage of abstinent days in a month compared to placebo (9.1 vs. 1.9%, respectively, 91% probability of a greater increase relative to placebo). Patients who were treated with LY2940094 showed decreased plasma levels of gamma-glutamyl transferase with probabilities ≥98% for greater reduction compared with placebo at Weeks 1, 4, 6, and 8. Treatment-emergent adverse events in ≥5% of patients treated with LY2940094 included insomnia, vomiting, and anxiety. There were no serious adverse events or significant changes in laboratory assessments or vital signs with LY2940094. Conclusions Although not reducing the NDD, LY2940094, compared to placebo, did reduce heavy drinking days and increased abstinence days in patients with alcohol dependence.
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a novel Nociceptin Receptor antagonist ly2940094 inhibits excessive feeding behavior in rodents a possible mechanism for the treatment of binge eating disorder
Journal of Pharmacology and Experimental Therapeutics, 2016Co-Authors: Michael A Statnick, Yanyun Chen, Michael Ansonoff, Jeffrey M Witkin, Linda Rorickkehn, Todd M Suter, Min Song, Celia Lafuente, Alma Jimenez, Ana BenitoAbstract:Nociceptin/orphanin FQ (N/OFQ), a 17 amino acid peptide, is the endogenous ligand of the ORL1/Nociceptin-opioid-peptide (NOP) Receptor. N/OFQ appears to regulate a variety of physiologic functions including stimulating feeding behavior. Recently, a new class of thienospiro-piperidine-based NOP antagonists was described. One of these molecules, LY2940094 has been identified as a potent and selective NOP antagonist that exhibited activity in the central nervous system. Herein, we examined the effects of LY2940094 on feeding in a variety of behavioral models. Fasting-induced feeding was inhibited by LY2940094 in mice, an effect that was absent in NOP Receptor knockout mice. Moreover, NOP Receptor knockout mice exhibited a baseline phenotype of reduced fasting-induced feeding, relative to wild-type littermate controls. In lean rats, LY2940094 inhibited the overconsumption of a palatable high-energy diet, reducing caloric intake to control chow levels. In dietary-induced obese rats, LY2940094 inhibited feeding and body weight regain induced by a 30% daily caloric restriction. Last, in dietary-induced obese mice, LY2940094 decreased 24-hour intake of a high-energy diet made freely available. These are the first data demonstrating that a systemically administered NOP Receptor antagonist can reduce feeding behavior and body weight in rodents. Moreover, the hypophagic effect of LY2940094 is NOP Receptor dependent and not due to off-target or aversive effects. Thus, LY2940094 may be useful in treating disorders of appetitive behavior such as binge eating disorder, food choice, and overeating, which lead to obesity and its associated medical complications and morbidity.