title: A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder.
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 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.) m.statnick@lilly.com.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Statnick
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Michael
authors.initials: M
authors.lastname: Ansonoff
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Linda
authors.initials: L
authors.lastname: Rorick-Kehn
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Todd M
authors.initials: TM
authors.lastname: Suter
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Min
authors.initials: M
authors.lastname: Song
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Charlie
authors.initials: C
authors.lastname: Hu
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Celia
authors.initials: C
authors.lastname: Lafuente
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Alma
authors.initials: A
authors.lastname: Jiménez
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Ana
authors.initials: A
authors.lastname: Benito
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Nuria
authors.initials: N
authors.lastname: Diaz
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Martínez-Grau
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Toledo
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.A.S., Y.C., J.M.W., L.R.K., T.M.S., M.S., C.H.); Eli Lilly and Company, Madrid, Spain (C.L., A.J., A.B., N.D., M.A.M.G., M.A.T.); and Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854 (M.A., J.E.P.).
authors.forename: John E
authors.initials: JE
authors.lastname: Pintar
mesh_terms: D000818:Animals; D056912:Binge-Eating Disorder / Q000188:drug therapy / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D002149:Energy Intake / Q000187:drug effects / Q000502:physiology*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009292:Narcotic Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D011957:Receptors, Opioid / Q000502:physiology*; D016896:Treatment Outcome; D000094942:Nociceptin Receptor
chemical_list: D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor