Opioid Receptor Modulation of Hedonic Taste Preference and Food Intake: A Single-Dose Safety, Pharmacokinetic, and Pharmacodynamic Investigation With GSK1521498, a Novel μ-Opioid Receptor Inverse Agonist

• Published in: Journal of clinical pharmacology Vol. 52; no. 4; pp. 464 - 474
• Main Authors: Nathan, Pradeep J., O'Neill, Barry V., Bush, Mark A., Koch, Annelize, Tao, Wenli X., Maltby, Kay, Napolitano, Antonella, Brooke, Allison C., Skeggs, Andrew L., Herman, Craig S., Larkin, Andrew L., Ignar, Diane M., Richards, Duncan B., Williams, Pauline M., Bullmore, Edward T.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2012; SAGE Publications; Wiley Subscription Services, Inc
• Subjects: Administration, Oral; Adult; Area Under Curve; binge eating; Cross-Over Studies; Dairy products; Data processing; Dose-Response Relationship, Drug; Double-Blind Method; Drug Inverse Agonism; Eating - drug effects; Food intake; Food Preferences - drug effects; hedonic; Hedonic response; Humans; Indans - adverse effects; Indans - pharmacokinetics; Indans - pharmacology; Inverse agonists; Male; Obesity; Opioid receptors; Opioid receptors (type mu); pharmacodynamic; Pharmacodynamics; Pharmacokinetics; Receptors, Opioid, mu - agonists; reward; Single-Blind Method; taste preference; Taste preferences; Triazoles - adverse effects; Triazoles - pharmacokinetics; Triazoles - pharmacology; μ-Opioid receptor; reward; taste preference; hedonic; µ-Opioid receptor; pharmacokinetics; pharmacodynamic; obesity; food intake; binge eating
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270011399577

Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (Cmax) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.