PT  - JOURNAL ARTICLE
AU  - Michael A. Statnick
AU  - Yanyun Chen
AU  - Michael Ansonoff
AU  - Jeffrey M. Witkin
AU  - Linda Rorick-Kehn
AU  - Todd M. Suter
AU  - Min Song
AU  - Charlie Hu
AU  - Celia Lafuente
AU  - Alma Jiménez
AU  - Ana Benito
AU  - Nuria Diaz
AU  - Maria Angeles Martínez-Grau
AU  - Miguel A. Toledo
AU  - John E. Pintar
TI  - A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder
AID  - 10.1124/jpet.115.228221
DP  - 2016 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 493--502
VI  - 356
IP  - 2
4099  - http://jpet.aspetjournals.org/content/356/2/493.short
4100  - http://jpet.aspetjournals.org/content/356/2/493.full
SO  - J Pharmacol Exp Ther2016 Feb 01; 356
AB  - 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.