Food intake inhibition and reduction in body weight gain in rats treated with GI264879A, a non-selective NPY-Y1 receptor antagonist.
Neuropeptide Y has been proposed to play a major role in the hypothalamic regulation of feeding behavior through the activation of specific, central NPY receptor(s). In an effort to design small molecule antagonists of NPY receptors, we have synthesized a series of substituted dipeptides based on defined pharmacophores, previously identified by us and others as essential for the interaction with the peptide receptors. GI264879A behaves as a functional antagonist of Y1 receptors while displaying no binding selectivity for the different NPY receptor subtypes. We demonstrate here that administration of GI264879A to rats causes a significant decrease in food intake and body weight partly through a mechanism dependent on the integrity of the vagus nerve.
Daniels
A J
AJ
Glaxo Wellcome Inc., Departments of Metabolic Diseases and Medicinal Chemistry, Research Triangle Park, NC 27713, USA. ajd32553@glaxowellcome.com
Chance
W T
WT
Grizzle
M K
MK
Heyer
D
D
Matthews
J E
JE
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects*; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D008956:Models, Chemical; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014630:Vagus Nerve / Q000378:metabolism
C430565:GI264879A; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D001120:Arginine