A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

Statnick, Michael A.; Chen, Yanyun; Ansonoff, Michael; Witkin, Jeffrey M.; Rorick-Kehn, Linda; Suter, Todd M.; Song, Min Kyung; Hu, Charlie C.; Lafuente, Celia; Jiménez, Alma; Benito, Ana; Dı́az, Nuria; Martinez-Grau, Marìa Ángeles; Toledo, Miguel Ángel; Pintar, John E.

doi:10.1124/jpet.115.228221

Cited by 45 publications

(36 citation statements)

References 48 publications

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“…In contrast, high doses of fluoxetine (FLX) almost completely blocked binge consumption with a concomitant reduction in the animal's 24-hour total intake. This is consistent with a previous study [25] and a recent study that used the 5HT2C agonist mCPP [52]; however, we attribute this reduction in overall food intake to the potent acute anxiogenic capacity of these doses of FLX [54–56]. Although SSRIs like FLX are one of the most common drugs used to treat binge eating disorder [4](Also see AHRQ Systematic Review - Management and Outcomes of Binge Eating Disorder), not all patient's symptoms improve with SSRI treatment[4].…”

Section: Discussionsupporting

confidence: 94%

“…Central injections of this peptide or NOP agonists produces a dose-dependent increase in feeding behavior [15,17,19,20,46–48], and chronic infusions of this peptide are capable of producing changes in body weight [49]. Interestingly, three studies demonstrate that 1) N/OFQ induced hyperphagia is present only in Sprague-Dawley rats that have been previously established as “fat-preferring”; 2) NOP/Oprl1 knockout mice consume significantly less high-fat containing food than their wildtype littermate controls, and 3) that a novel NOP antagonist LY2940094 increases lipid utilization metabolism in mice [50–52]. Taken together, we hypothesized that NOP/Oprl1 signaling is recruited during and required for binge eating of high fat containing foods.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a novel set of orally available highly selective NOP/Oprl1 antagonists have been developed, and one of these compounds, LY2940094, has subnanomolar potency for human NOP, has sustained brain occupancy, and has been tested in rodent models of feeding [52,69]. This compound was found to reduce fasting-induced hyperphagia of chow in wildtype 129S6 mice, but not those with genetic deletion of the Oprl1 gene (NOP KO mice).…”

Section: Discussionmentioning

confidence: 99%

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Nociceptin receptor antagonist SB 612111 decreases high fat diet binge eating

Hardaway

Jensen

Kim

et al. 2016

Behavioural Brain Research

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Binge eating is a dysregulated form of feeding behavior that occurs in multiple eating disorders including binge-eating disorder, the most common eating disorder. Feeding is a complex behavioral program supported through the function of multiple brain regions and influenced by a diverse array of receptor signaling pathways. Previous studies have shown the overexpression of the opioid neuropeptide nociceptin (orphanin FQ, N/OFQ) can induce hyperphagia, but the role of endogenous nociceptin receptor (NOP) in naturally occurring palatability-induced hyperphagia is unknown. In this study we adapted a simple, replicable form of binge eating of high fat food (HFD). We found that male and female C57BL/6J mice provided with daily one-hour access sessions to HFD eat significantly more during this period than those provided with continuous 24 hour access. This form of feeding is rapid and entrained. Chronic intermittent HFD binge eating produced hyperactivity and increased light zone exploration in the open field and light-dark assays respectively. Treatment with the potent and selective NOP antagonist SB 612111 resulted in a significant dose-dependent reduction in binge intake in both male and female mice, and, unlike treatment with the serotonin selective reuptake inhibitor fluoxetine, produced no change in total 24-hour food intake. SB 612111 treatment also significantly decreased non-binge-like acute HFD consumption in male mice. These data are consistent with the hypothesis that high fat binge eating is modulated by NOP signaling and that the NOP system may represent a promising novel receptor to explore for the treatment of binge eating.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nociceptin receptor antagonist SB 612111 decreases high fat diet binge eating

Hardaway

Jensen

Kim

et al. 2016

Behavioural Brain Research

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“…We assessed binding affinity of LY2940094 in the membrane of CHO cells expressing recombinant human NOP receptor, and membranes isolated from whole rat brain, with Ki values of 0.11 and 0.71 nM, respectively (Statnick et al, 2016).…”

Section: Preclinical To Clinical Translation Of Nop Romentioning

confidence: 99%

Occupancy of Nociceptin/Orphanin FQ Peptide Receptors by the Antagonist LY2940094 in Rats and Healthy Human Subjects

Raddad

Chappell

Meyer

et al. 2016

Drug Metabolism and Disposition

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Therapeutic benefits from nociceptin opioid peptide receptor (NOP) antagonism were proposed for obesity, eating disorders, and depression. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) is a novel, orally bioavailable, potent, and selective NOP antagonist. We studied NOP receptor occupancy (RO) after single oral LY2940094 doses in rat hypothalamus and human brain by use of liquid chromatography with tandem mass spectrometry (LC-MS/MS) (LSN2810397) and positron emission tomography (PET) ([(11)C]NOP-1A) tracers, respectively. A bolus plus constant infusion tracer protocol with PET was employed in humans at 2.5 and 26.5 hours after administration of the LY2940094 dose. The RO was calculated from the change in regional distributional volume (VT) corrected for nondisplaceable volume using Lasson plots. The RO followed a simple Emax relationship to plasma LY2940094 concentration, reaching near complete occupancy in both species. For rat hypothalamus, the plasma concentration at half-maximum RO (EC50) was 5.8 ng/ml. In humans, LY2940094 was well tolerated and safe over the 4-40 mg dose range, and it peaked in plasma at 2 to 6 hours after a 1- to 2-hour lag, with approximate dose-proportional exposure. After 4-40 mg doses, NOP RO was similar across the prefrontal cortex, occipital cortex, putamen, and thalamus, with EC50 of 2.94 to 3.46 ng/ml, less than 2-fold lower than in rats. Over 4-40 mg doses, LY2940094 mean plasma levels at peak and 24 hours were 7.93-102 and 1.17-14.1 ng/ml, corresponding to the cross-region average NOP RO of 73%-97% and 28%-82%, respectively. The rat EC50 translates well to humans. LY2940094 readily penetrates the human brain, and a once-daily oral dose of 40 mg achieves sustainably high (>80%) NOP RO levels suitable for testing clinical efficacy.

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“…Receptor-binding affinity (Ki) and functional antagonist potency of SB-612111 and LY2817412 (Table 1) were determined in Chinese Hamster Ovary cells expressing the NOP receptor according to previously published methods (Statnick et al, 2016).…”

Section: Alcohol and Saccharin Self-administration Under Prmentioning

confidence: 99%

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

Kallupi

Scuppa

Guglielmo

et al. 2016

Neuropsychopharmacol

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The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the NOP/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal, and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (− / − ) rats to study the motivation for cocaine, heroin, and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP ( − / − ) rats selfadminister less cocaine (0.25, 0.125, or 0.5 mg/infusion) both under a fixed ratio 1 and a progressive ratio schedule of reinforcement compared with wild-type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP ( − / − ). When NOP ( − / − ) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showed significantly lower drug intake compared with Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP ( − / − ) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol selfadministration in Wt rats but not in NOP ( − / − ) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.

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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

Cited by 45 publications

References 48 publications

Nociceptin receptor antagonist SB 612111 decreases high fat diet binge eating

Nociceptin receptor antagonist SB 612111 decreases high fat diet binge eating

Occupancy of Nociceptin/Orphanin FQ Peptide Receptors by the Antagonist LY2940094 in Rats and Healthy Human Subjects

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

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