Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents

1 The novel Y1-selective argininamide derivative BIBO 3304 ((R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N-2-(diphenylacetyl)-argininamide trifluoroacetate) has been synthesized and was examined for its subtype selectivity, its in vitro antagonistic properties and its food intake inhibitory properties. 2 BIBO 3304 displayed subnanomolar affinity for both the human and the rat Y1 receptor (IC50 values 0.38+/-0.06 nM and 0.72+/-0.42 nM, respectively). The inactive enantiomer of BIBO 3304 (BIBO 3457) had low affinity for both the human and rat Y1 receptor subtype (IC50 >1000 nM). BIBO 3304 showed low affinity for the human Y2 receptor, human and rat Y4 receptor as well as for the human and rat Y5 receptor (IC50 values > 1000 nM). 3 30 mu g BIBO 3304 administered into the paraventricular nucleus inhibited the feeding response induced by 1 mu g NPY as well as the hyperphagia induced by a 24 h fast implying a role for Y1 receptors in NPY mediated feeding. The inactive enantiomer had no effect. 4 BIBO 3304 inhibits neither the galanin nor the noradrenaline induced orexigenic response, but it blocked feeding behaviour elicited by both [Leu(31) Pro(34)]NPY and NPY (3-36) suggesting an interplay between different NPY receptor subtypes in feeding behavior. 5 The present study reveals that BIBO 3304 is a subtype selective nonpeptide antagonist with subnanomolar affinity for the Y1 receptor subtype that significantly inhibits food intake induced by application of NPY or by fasting.