Titre du document / Document title

Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist

Auteur(s) / Author(s)

DANIELS A. J. ⁽¹⁾ ; GRIZZLE M. K. ⁽¹⁾ ; WIARD R. P. ⁽¹⁾ ; MATTHEWS J. E. ⁽¹⁾ ; HEYER D. ⁽²⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ GlaxoSmithKline, Department of Metabolic Diseases, Research Triangle Park, NC 27709, ETATS-UNIS
⁽²⁾ GlaxoSmithKline, Department of Medicinal Chemistry, Research Triangle Park, NC 27709, ETATS-UNIS

Résumé / Abstract

Numerous reports have implicated theY5 receptor as the 'feeding' receptor mediating the orexigenic action of neuropeptide Y (NPY). This notion is supported by the correlation between the in vitro functional and binding activities of different peptide agonists and their potent stimulation of food intake in rodents. We have discovered a series of small molecule heterocycles with high affinity, selectivity, and functional antagonism for Y5 receptors. Intraperitoneal (i.p.) administration of GW438014A into rodents, resulted in a potent reduction of NPY-induced and normal overnight food intake. Brain levels of GW438014A were detected well in excess of its binding IC₅₀ for up to 3 h post-dosing. Daily (i.p., BID, 10 mg/kg) administration of this compound to Zucker Fatty rats for a period of 4 days resulted in a marked decrease in the rate of weight gain and a reduction in fat mass. No effect on food intake was observed following oral administration of GW438014A (25-100 mg/kg), consistent with the poor oral bioavailability (<3%) and low brain levels observed.

Revue / Journal Title

Regulatory peptides   ISSN 0167-0115   CODEN REPPDY 

Source / Source

2002, vol. 106, n^o1-3, pp. 47-54 (37 ref.)

Langue / Language

Anglais

Editeur / Publisher

Elsevier, Amsterdam, PAYS-BAS  (1980) (Revue)

Mots-clés anglais / English Keywords

Vertebrata ; Mammalia ; Rodentia ; Metabolic disorder ; Central nervous system ; Brain (vertebrata) ; Feeding behavior ; Rat ; Obesity ; Y5 neuropeptide Y receptor ; Antagonist ; Neuropeptide Y ; Body weight ; Food intake ; Hypothalamus ;

Mots-clés français / French Keywords

Vertebrata ; Mammalia ; Rodentia ; Trouble métabolisme ; Système nerveux central ; Encéphale ; Comportement alimentaire ; Rat ; Obésité ; Récepteur neuropeptide Y Y5 ; Antagoniste ; Neuropeptide Y ; Poids corporel ; Consommation alimentaire ; Hypothalamus ;

Mots-clés espagnols / Spanish Keywords

Vertebrata ; Mammalia ; Rodentia ; Trastorno metabolismo ; Sistema nervioso central ; Encéfalo ; Conducta alimenticia ; Rata ; Obesidad ; Receptor neuropéptido Y Y5 ; Antagonista ; Neuropéptido Y ; Peso corporal ; Consumo alimenticio ; Hipotálamo ;

Localisation / Location

INIST-CNRS, Cote INIST : 18854, 35400010168368.0080