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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

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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 JPET Fast Forward. Published on December 9, 2015 as DOI: 10.1124/jpet.115.228221 This article has not been copyedited and formatted. The final version may differ from this version. JPET#228221 A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism For The Treatment of Binge Eating Disorder. Michael A. Statnick, Yanyun Chen, Michael Ansonoff, Jeffrey M. Witkin, Linda Rorick-Kehn, Todd M. Suter, Min Song, Charlie Hu, , Celia Lafuente, Alma Jiménez, Ana Benito, Nuria Diaz, Maria Angeles Martínez-Grau, Miguel A. Toledo and John E. Pintar Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.), Eli Lilly and Company, Avenida de la Industria 30, 28108- Downloaded from Alcobendas, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.), Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.) jpet.aspetjournals.org at ASPET Journals on September 26, 2021 JPET Fast Forward. Published on December 9, 2015 as DOI: 10.1124/jpet.115.228221 This article has not been copyedited and formatted. The final version may differ from this version. JPET #228221 Running Title: LY2940094 inhibits food intake in rodents Address Correspondence to: Michael A Statnick, Ph.D. Lilly Research Laboratories Lilly Corporate Center Downloaded from Indianapolis, IN 46285 Email: [email protected] Phone: 317-277-1123 jpet.aspetjournals.org Number of: 1. Text pages = 15 at ASPET Journals on September 26, 2021 2. Tables = 2 3. Figures = 6 4. References = 56 Word Count 1. Abstract = 244 2. Introduction = 571 3. Discussion = 1486 Non-Standard Abbreviations ANOVA: Analysis of Variance CV: Caloric Value CO2: Carbon Dioxide CHO: Chinese hamster ovary DIO: Dietary Induced Obese 2 JPET Fast Forward. Published on December 9, 2015 as DOI: 10.1124/jpet.115.228221 This article has not been copyedited and formatted. The final version may differ from this version. JPET #228221 EE: Energy Expenditure GIRK: G-protein activated, inwardly rectifying K+ channel GPCR: G-protein-coupled receptor HEK293: Human embryonic kidney HED: high energy diet (diet high in both fat and sucrose) Hr: hour 5-HT: 5-hydroxytryptamine or serotonin IP: Intraperitoneal J-113397: (±)trans-1-[1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3- Downloaded from dihydro-2H-benzimidazol-2-one, a NOP receptor antagonist JTC-801: N-(4-amino-2-methylquinolin-6-yl)-2-(4- ethylphenoxymethyl)benzamidehydrochloride jpet.aspetjournals.org Kg: Kilogram KO: Knockout LY2940094: [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'- at ASPET Journals on September 26, 2021 yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol MAP: mitogen-activated-protein mCPP: meta-Chlorophenylpiperazine mg: Milligram N/OFQ: Nociceptin/Orphinan FQ (F:phenylalanine;Q:glutamine; the amino acids that begin and end the peptide sequence) NOP: Nociceptin opioid peptide receptor ORL-1: Opioid-Receptor-Like-1 PO: Oral POMC: Pro-opiomelanocortin RO: Receptor Occupancy Ro 64-6198: (1S,3aS)-8- (2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza- spiro[4.5]decan-4-one, a NOP receptor agonist RQ: Respiratory Quotient 3 JPET Fast Forward. Published on December 9, 2015 as DOI: 10.1124/jpet.115.228221 This article has not been copyedited and formatted. The final version may differ from this version. JPET #228221 SB-612111: [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9- tetrahydro-5H-benzocyclohepten-5-ol, a NOP receptor antagonist SPA: scintillation proximity assay VCO2: CO2 production VO2: Oxygen consumption W212393: 2-{3-[1-((1R)-acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1- yl}-N-methylacetamide, a NOP receptor agonist WT: Wildtype Downloaded from Recommended Section Assignment: Drug Discovery and Translational Medicine jpet.aspetjournals.org at ASPET Journals on September 26, 2021 4 JPET Fast Forward. Published on December 9, 2015 as DOI: 10.1124/jpet.115.228221 This article has not been copyedited and formatted. The final version may differ from this version. JPET #228221 Abstract 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 physiological 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 Downloaded from exhibited a baseline phenotype of reduced fasting-induced feeding, relative to wild-type littermate controls. In lean rats, LY2940094 inhibited the over consumption of a palatable high energy diet, reducing caloric intake to control chow levels. In dietary-induced obese rats, LY2940094 inhibited feeding and body weight re-gain induced by a 30% daily caloric jpet.aspetjournals.org restriction. Lastly, in dietary-induced obese (DIO) mice, LY2940094 decreased 24 hr 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 at ASPET Journals on September 26, 2021 behavior such as binge eating disorder, food choice and over-eating, which lead to obesity and its associated medical complications and morbidity. 5 JPET Fast Forward. Published on December 9, 2015 as DOI: 10.1124/jpet.115.228221 This article has not been copyedited and formatted. The final version may differ from this version. JPET #228221 Introduction Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid neuropeptide with high homology to the opioid peptide dynorphin. N/OFQ was identified as the natural ligand for the orphan receptor ORL1 (today referred to as the NOP receptor) (Meunier et al., 1995; Reinscheid et al., 1995). The NOP receptor is a Class A G-protein-coupled receptor (GPCR) that is functionally coupled Downloaded from to inhibition of adenylate cyclase, activation of mitogen-activated-protein (MAP) kinases, activation of K+ conductance and inhibition of Ca+2 conductance (see reviews by Mogil and Pasternak, 2001; New and Wong, 2002). The NOP receptor is widely expressed in the central jpet.aspetjournals.org nervous system (CNS) including the cortex, hippocampus, medial septum, amygdala, thalamus, hypothalamus, and the nucleus of the solitary tract. Moreover, NOP is expressed in the peripheral nervous system as well as in the gastrointestinal tract, smooth muscles and in cells of at ASPET Journals on September 26, 2021 the immune system. Initially, N/OFQ was found to produce hyperalgesia, leading to the naming the peptide nociceptin (Meunier et al., 1995), however, in addition to pain, N/OFQ modulates other CNS behaviors, including stress and anxiety, depression, substance abuse, prolactin secretion, locomotor activity, body temperature, memory and feeding (Mustazza and Bastanzio, 2011; Gavioli and Calo', 2013; Singh et al., 2013; Witkin et al., 2014). Numerous studies have reported that activation of NOP receptors produces a robust orexigenic effect in rodents. Indeed, fasting regulates N/OFQ and NOP receptor gene expression in the CNS (Rodi et al., 2002; Przydzial et al., 2010). Highly potent and efficacious orexigenic effects are produced by administration of either N/OFQ peptide analogues or small molecule agonists 6 JPET Fast Forward. Published on December 9, 2015 as DOI: 10.1124/jpet.115.228221 This article has not been copyedited and formatted. The final version may differ from this version. JPET #228221 (Pomonis et al., 1996; Polidori et al., 2000), leading the authors to hypothesize that the feeding effects of N/OFQ are mediated at the level of the forebrain and/or hypothalamus (Polidori et al., 2000). Microinjection studies confirmed this hypothesis and identified the nucleus accumbens and ventromedial hypothalamic nucleus as specific sites of the orexigenic actions of N/OFQ (Stratford et al., 1997). It is postulated that the orexigenic effects of N/OFQ are the result of inhibition of anorexigenic signaling (Farhang et al., 2010). These data support the hypothesis that inhibitors to NOP receptor signaling will regulate food intake and might therefore be useful Downloaded from in the treatment of obesity and eating disorders. jpet.aspetjournals.org Several NOP selective antagonists (J113367, JTC-801 and SB612111) and agonists (Ro 64,6198 and W212393) have been developed (Zaveri et al., 2005; Largent-Milnes and Vanderah, 2010). at ASPET Journals on September 26, 2021 Recently, we identified a novel series of NOP receptor antagonists based on a dihydrospiro(piperidine-4,7’thieno[2,3-c]pyran) scaffold (Toledo et al., 2014). These antagonists were found to have high affinity and antagonist activity for the human NOP receptor. In vivo, we found that the antagonists had good oral bioavailability and exhibited CNS activity. One of these molecules, LY2940094 (Toledo et al., 2014), exhibited subnanomolar antagonist potency (Kb = 0.17 nM) in vitro at the human NOP receptor. Moreover, LY2940094 was orally bioavailable in rats (F = 57%, T1/2 = 3.8 hrs) in vivo and demonstrated sustained NOP receptor occupancy in the brain (24 hr RO = 62% at 10 mg/kg, po). When tested in vivo LY2940094 potently inhibited the hypothermic effects of exogenously administered NOP agonist, Ro 64,6198, confirming its on-target activity.
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