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.
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.
Ortiz
Astrid A
AA
Department of Metabolic Disorders Research, Bayer Pharmaceuticals Corporation, West Haven, Connecticut, USA.
Milardo
Lucinda F
LF
DeCarr
Lynn B
LB
Buckholz
Thomas M
TM
Mays
Michelle R
MR
Claus
Thomas H
TH
Livingston
James N
JN
Mahle
Cathy D
CD
Lumb
Kevin J
KJ
D052242:Adiponectin / Q000097:blood; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology*; D019894:Peptide YY / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000819:agonists*; D013329:Structure-Activity Relationship
D052242:Adiponectin; D001067:Appetite Depressants; D001552:Benzazepines; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; C078948:peptide YY (13-36); D019894:Peptide YY; C061785:peptide YY (3-36); D011092:Polyethylene Glycols; D001120:Arginine; D005947:Glucose; C403256:BIIE 0246