title: Regulation of ingestive behaviors in the rat by GSK1521498, a novel micro-opioid receptor-selective inverse agonist.
abstract: μ-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with κ-opioid receptors (KOR) and δ-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with μ receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.
authors.affiliation: Metabolic Diseases Department, GlaxoSmithKline, Research Triangle Park, North Carolina, USA. diane.m.ignar@gsk.com
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ignar
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Goetz
authors.forename: Kimberly Nichols
authors.initials: KN
authors.lastname: Noble
authors.forename: Luz Helena
authors.initials: LH
authors.lastname: Carballo
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Stroup
authors.forename: Julie C
authors.initials: JC
authors.lastname: Fisher
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Boucheron
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Brainard
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Larkin
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Epperly
authors.forename: Todd W
authors.initials: TW
authors.lastname: Shearer
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sorensen
authors.forename: Jason D
authors.initials: JD
authors.lastname: Speake
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Hommel
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002138:Calibration; D003216:Conditioning, Operant / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004327:Drinking Behavior / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects*; D005518:Food Preferences / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D007189:Indans / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012528:Satiety Response / Q000187:drug effects; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D007189:Indans; C568078:N-((3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl)methyl)-2,3-dihydro-1H-inden-2-amine; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D014230:Triazoles; D016244:Guanosine 5'-O-(3-Thiotriphosphate)