PEPTIDE YY DERIVATIVES AS SELECTIVE NEUROPEPTIDE-Y PEPTIDE YY Y-1 AND Y-2 AGONISTS DEVOIDED OF ACTIVITY FOR THE Y-3 RECEPTOR SUB-TYPE

Peptide YY derivatives were evaluated for their respective ability to bind and activate the NPY/PYY receptor sub-types (Y-1, Y-2 and Y-3) present in various preparations. The analogue [Leu(31),Pro(34)]PYY demonstrated high (nM) affinity in rat frontoparietal cortical membrane preparations (Y-1-enriched tissue) and the rabbit saphenous vein (Y-1 in vitro bioassay) but only low affinity in a Y-2-enriched preparation (rat hippocampus). In contrast, PYY C-terminal fragments such as PYY3-36, and PYY13-36 were more potent in Y-2 than Y-1 assays. Interestingly, and in contrast to [Leu(31),Pro(34)]NPY and NPY13-36 the PYY derivatives [Leu(31),Pro(34)]PYY and PYY3-36 were inactive in a purported Y-3 bioassay (rat colon). These results suggest that [Leu(31),Pro(34)]PYY and PYY3-36 respectively represent the first selective and potent Y-1 and Y-2 agonists, devoided of significant affinity/activity for the Y-3 receptor class.