Regulation of ingestive behaviors in the rat by GSK1521498, a novel μ-opioid receptor-selective inverse agonist

Diane M. Ignar, Aaron S. Goetz, Kimberly Nichols Noble, Luz Helena Carballo, Andrea E. Stroup, Julie C. Fisher, Joyce A. Boucheron, Tracy A. Brainard, Andrew L. Larkin, Andrea H. Epperly, Todd W. Shearer, Scott D. Sorensen, Jason D. Speake, Jonathan Hommel

Research output: Contribution to journalArticle

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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 dietinduced 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.

Original languageEnglish (US)
Pages (from-to)24-34
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume339
Issue number1
DOIs
StatePublished - Oct 2011

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Opioid Receptors
Food
Long Evans Rats
Body Weight
Binge-Eating Disorder
Pleasure
N-((3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl)methyl)-2,3-dihydro-1H-inden-2-amine
Autoradiography
Reward
Pharmaceutical Preparations
Oral Administration
Sucrose
Weight Loss
Obesity
Eating
Fats
Pharmacology
Brain

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Regulation of ingestive behaviors in the rat by GSK1521498, a novel μ-opioid receptor-selective inverse agonist. / Ignar, Diane M.; Goetz, Aaron S.; Noble, Kimberly Nichols; Carballo, Luz Helena; Stroup, Andrea E.; Fisher, Julie C.; Boucheron, Joyce A.; Brainard, Tracy A.; Larkin, Andrew L.; Epperly, Andrea H.; Shearer, Todd W.; Sorensen, Scott D.; Speake, Jason D.; Hommel, Jonathan.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 339, No. 1, 10.2011, p. 24-34.

Research output: Contribution to journalArticle

Ignar, DM, Goetz, AS, Noble, KN, Carballo, LH, Stroup, AE, Fisher, JC, Boucheron, JA, Brainard, TA, Larkin, AL, Epperly, AH, Shearer, TW, Sorensen, SD, Speake, JD & Hommel, J 2011, 'Regulation of ingestive behaviors in the rat by GSK1521498, a novel μ-opioid receptor-selective inverse agonist', Journal of Pharmacology and Experimental Therapeutics, vol. 339, no. 1, pp. 24-34. https://doi.org/10.1124/jpet.111.180943
Ignar, Diane M. ; Goetz, Aaron S. ; Noble, Kimberly Nichols ; Carballo, Luz Helena ; Stroup, Andrea E. ; Fisher, Julie C. ; Boucheron, Joyce A. ; Brainard, Tracy A. ; Larkin, Andrew L. ; Epperly, Andrea H. ; Shearer, Todd W. ; Sorensen, Scott D. ; Speake, Jason D. ; Hommel, Jonathan. / Regulation of ingestive behaviors in the rat by GSK1521498, a novel μ-opioid receptor-selective inverse agonist. In: Journal of Pharmacology and Experimental Therapeutics. 2011 ; Vol. 339, No. 1. pp. 24-34.
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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 dietinduced 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.",
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AU - Stroup, Andrea E.

AU - Fisher, Julie C.

AU - Boucheron, Joyce A.

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