ABSTRACT
Selective activation of the NPY2 receptor to suppress appetite provides an approach to obesity management. Selective NPY2 PEGylated peptide agonists are described that consist of a peptide core corresponding to residues 25-36 of PYY and a nonpeptidic moiety at the peptide N-terminus that contributes to in vitro potency and in vivo efficacy and provides a PEGylation site. The lead peptide elicits a dose-dependent reduction of food intake in lean mice and of food intake, body weight, and fat mass in DIO mice.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Body Weight/drug effects , Eating/drug effects , Oligopeptides/chemical synthesis , Peptide YY/chemistry , Polyethylene Glycols/chemistry , Receptors, Neuropeptide Y/agonists , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Cyclic AMP/biosynthesis , Humans , Male , Mice , Mice, Inbred C57BL , Oligopeptides/chemistry , Oligopeptides/pharmacology , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Peptide YY/pharmacology , Radioligand Assay , Structure-Activity RelationshipABSTRACT
Activation of the NPY2 receptor to reduce appetite while avoiding stimulation of the NPY1 and NPY5 receptors that induce feeding provides a pharmaceutical approach to modulate food intake. The naturally occurring peptide PYY(3-36) is a nonselective NPY1, NPY2, and NPY5 agonist. N-terminal truncation of PYY to abrogate affinity for the NPY1 and NPY5 receptors and subsequent N-terminal modification with aminobenzoic analogs to restore NPY2 receptor potency results in a series of highly selective NPY2 receptor peptide agonists.
