Effects of the neuropeptide YY2 receptor antagonist BIIE0246 on presynaptic inhibition by neuropeptide Y in rat hippocampal slices

We previously reported that (S)-N-2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cylopentyl]acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]argininamid, BIIE0246, is a potent and highly selective neuropeptide Y Y-2 receptor antagonist. Neuropeptide Y Y-2 receptors have been proposed to mediate the inhibition by neuropeptide Y or excitatory synaptic transmission in rat hippocampus. Therefore, we investigated the effects of BIIE0246 on the electrophysiological properties of neuropeptide Y in rat hippocampal slices and determined the affinity of this novel antagonist for rat hippocampal neuropeptide Y Y-2 receptors. BIIE0246 displayed an affinity of IC50 = 4.0 +/- 1.6 (n = 4) fur neuropeptide Y receptor binding sites labelled by I-125-neuropeptide Y in rat hippocampal membranes. At a concentration of 1 mu M, BIIE0246 completely antagonized the inhibitory effects of 300 nM neuropeptide Y on synaptic transmission in rat hippocampal slices. This is the first study showing that a selective neuropeptide Y Y-2 receptor antagonist is able to block neuropeptide Y mediated effects in the hippocampus and unambiguously characterizes the presynaptic receptor in the rat hippocampus as the neuropeptide Y Y-2 receptor. (C) 2000 Elsevier Science B.V. All rights reserved.