title: Selective antagonism of the NPY Y5 receptor does not have a major effect on feeding in rats.
abstract: Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of NPY have been ascribed to actions at the NPY Y5 receptor, we have determined the role of this receptor in feeding in rats, using a small molecule antagonist of this receptor. NPY5RA-972 is a selective and potent (<10 nmol/l) NPY Y5 receptor antagonist. This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC(50) (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats. Chronic administration of NPY5RA-972 (10 mg/kg twice daily) had no effect on food intake or body weight in either free-feeding Wistar rats or dietary obese rats. These data indicate that NPY5RA-972 is a potent, selective, orally active, and CNS-penetrant antagonist of the NPY Y5 receptor that prevents feeding driven by activation of this receptor. The data obtained with this antagonist indicate that the NPY Y5 receptor is not a major regulator of feeding in the rat.
authors.affiliation: Cardiovascular and Gastrointestinal Discovery Department, AstraZeneca, Mereside, Alderley Park, Macclesfield, UK. andrew.turnbull@astrazeneca.com
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Turnbull
authors.forename: Laraine
authors.initials: L
authors.lastname: Ellershaw
authors.forename: Dave J
authors.initials: DJ
authors.lastname: Masters
authors.forename: Susan
authors.initials: S
authors.lastname: Birtles
authors.forename: Scott
authors.initials: S
authors.lastname: Boyer
authors.forename: Debbie
authors.initials: D
authors.lastname: Carroll
authors.forename: Paul
authors.initials: P
authors.lastname: Clarkson
authors.forename: Sue J G
authors.initials: SJ
authors.lastname: Loxham
authors.forename: Pat
authors.initials: P
authors.lastname: McAulay
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Teague
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Foote
authors.forename: J Elizabeth
authors.initials: JE
authors.lastname: Pease
authors.forename: Michael H
authors.initials: MH
authors.lastname: Block
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D003503:Cyclobutanes / Q000008:administration & dosage / Q000494:pharmacology*; D002149:Energy Intake / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D007276:Injections, Intraventricular; D007700:Kinetics; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*
chemical_list: D001067:Appetite Depressants; D003503:Cyclobutanes; D009478:Neuropeptide Y; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; C058254:sibutramine