Effects of the neuropeptide Y Y(2) 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]a cetyl]-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 of 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 IC(50)=4.0+/-1.6 (n=4) for neuropeptide Y receptor binding sites labelled by 125I-neuropeptide Y in rat hippocampal membranes. At a concentration of 1 microM, 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.