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 (IC 50 values 0.38±0.06 n M and 0.72±0.42 n M , respectively). The inactive enantiomer of BIBO 3304 (BIBO 3457) had low affinity for both the human and rat Y1 receptor subtype (IC 50 >1000 n M ). 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 (IC 50 values >1000 n M ). 3 30 μg BIBO 3304 administered into the paraventricular nucleus inhibited the feeding response induced by 1 μg 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.British Journal of Pharmacology (1998) 125 , 549–555; doi: 10.1038/sj.bjp.0702084