PT  - JOURNAL ARTICLE
AU  - Astrid A. Ortiz
AU  - Lucinda F. Milardo
AU  - Lynn B. DeCarr
AU  - Thomas M. Buckholz
AU  - Michelle R. Mays
AU  - Thomas H. Claus
AU  - James N. Livingston
AU  - Cathy D. Mahle
AU  - Kevin J. Lumb
TI  - A Novel Long-Acting Selective Neuropeptide Y2 Receptor Polyethylene Glycol-Conjugated Peptide Agonist Reduces Food Intake and Body Weight and Improves Glucose Metabolism in Rodents
AID  - 10.1124/jpet.107.125211
DP  - 2007 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 692--700
VI  - 323
IP  - 2
4099  - http://jpet.aspetjournals.org/content/323/2/692.short
4100  - http://jpet.aspetjournals.org/content/323/2/692.full
SO  - J Pharmacol Exp Ther2007 Nov 01; 323
AB  - Selective activation of the neuropeptide Y (NPY)2 receptor to suppress appetite provides a promising approach to obesity management. A selective NPY2 polyethylene glycol-conjugated (PEGylated) peptide agonist is described that consists of a peptide core corresponding to residues 13 to 36 of human peptide YY (PYY) and a nonpeptidic moiety (2-mercaptonicotinic acid) at the peptide N terminus that is derivatized with 20-kDa monomethoxypolyethylene glycol. The PEGylated peptide elicits a dose-dependent reduction in food intake in lean C57BL/6 mice and Wistar rats that persists for 72 and 48 h, respectively. The effect on food intake in lean C57BL/6 mice is blocked by the selective NPY2 antagonist BIIE0246 (N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide formate). A dose-dependent reduction in body weight in diet-induced obese (DIO) mice is seen following daily dosing for 14 days. The reduction in body weight is sustained following dosing for 40 days, and it is accompanied by an increase in plasma adiponectin. Improvements in glucose disposal and in plasma insulin and glucose levels that are risk factors for type II diabetes are observed following once-daily subcutaneous dosing in DIO mice. The results provide evidence from two animal species that the long-acting selective NPY2 peptide agonist has potential for obesity management. The American Society for Pharmacology and Experimental Therapeutics