title: Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents.
abstract: 1. The novel Y1-selective argininamide derivative BIBO 3304 ((R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2-(diphen ylacetyl)-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 microg BIBO 3304 administered into the paraventricular nucleus inhibited the feeding response induced by 1 microg 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 [Leu31, Pro24]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.
authors.affiliation: Department of Biology, Boehringer Ingelheim Pharma KG, Biberach an der Riss, Germany.
authors.forename: H A
authors.initials: HA
authors.lastname: Wieland
authors.forename: W
authors.initials: W
authors.lastname: Engel
authors.forename: W
authors.initials: W
authors.lastname: Eberlein
authors.forename: K
authors.initials: K
authors.lastname: Rudolf
authors.forename: H N
authors.initials: HN
authors.lastname: Doods
mesh_terms: D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000032:analysis; D004435:Eating / Q000187:drug effects*; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000145:classification; D014407:Tumor Cells, Cultured
chemical_list: D017476:Receptors, Neuropeptide Y; D001120:Arginine; D000242:Cyclic AMP; C117416:BIBO 3304