BIIE0246, a potent and highly selective non-peptide neuropeptide YY2 receptor antagonist

1 BIIE0246, a newly synthesized non-peptide neuropeptide Y (NPY) Y-2 receptor antagonist, was able to compete with high affinity (8 to 15 nM) for specific [I-125]PYY3-36 binding sites in HEK293 cells transfected with the rat Y-2 receptor cDNA, and in rat brain and human frontal cortex membrane homogenates. 2 Interestingly, in rat brain homogenates while NPY, C2-NPY and PYY3-36 inhibited all specific [I-125]PYY3-36 labelling, BIIE0246 failed to compete for all specific binding suggesting that [I-125]PYY3-36 recognized, in addition to the Y-2 subtype, another population of specific NPY binding sites, most likely the Y-5 receptor. 3 Quantitative receptor autoradiographic data confirmed the presence of [I-125]PYY3-36/BIIE0246-sensitive (Y-2) and-insensitive (Y-5) binding sites in the rat brain as well as in the marmoset monkey and human hippocampal formation. 4 In the rat vas deferens and dog saphenous vein (two prototypical Y-2 bioassays), BIIE0246 induced parallel shifts to the right of NPY concentration-response curves with pA(2) values of 8.1 and 8.6, respectively. In the rat colon (a Y-2/Y-4 bioassay), BIIE0246 (1 mu M) completely blocked the contraction induced by PYY3-36, but not that of [Leu(31),Pro(34)]NPY (a Y-1, Y-4 and Y-5 agonist) and hPP (a Y-4 and Y-5 agonist). Additionally, BIIE0246 failed to alter the contractile effects of NPY in prototypical Y-1 in vitro bioassays. 5 Taken together, these results demonstrate that BIIE0246 is a highly potent, high affinity antagonist selective for the Y-2 receptor subtype. It should prove most useful to establish further the functional role of the Y-2 receptor in the organism.