A POTENT NONPEPTIDE NEUROPEPTIDE-Y Y1 RECEPTOR ANTAGONIST, A BENZODIAZEPINE DERIVATIVE

We describe here a nonpeptide neuropeptide Y Y1 receptor antagonist, e ido}-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine (Compound 1), which was previously synthesized as a linked type of dual cholecystokinin (C CK)-B and histamine H-2 receptor antagonist. Compound 1 competitively inhibited [I-125] peptide YY (PYY) binding to Y1 receptors in human ne uroblastoma SK-N-MC cells with K-i of 6.4 +/- 1.0 nM, while it had no effect on [I-125]PYY binding to Y2 or Y5 receptors even at 1 mu M. Fun ctionally, compound 1 inhibited and Y1 receptor-mediated increase in c ytosolic free Ca2+ concentration and Y1 receptor-mediated attenuation of cAMP accumulation in a dose-dependent manner with IC50 values of 95 +/- 5 and 320 +/- 10 nm in SK-N-MC cells, respectively. Neither its C CK-B receptor antagonistic moiety of Compound 1 (Compound 2) nor its h istamine H-2 receptor antagonistic moiety of Compound 1 (Compound 3) h ad any effect on [I-125]PYY binding, suggesting that the entire struct ure of Compound 1 is essential for Y1 receptor blocking activity. It s howed no significant activity (IC50 > 1 mu M) in 30 receptor binding a ssays and 5 enzyme assays, with the exception of CCK-B and histamine H -2 receptors. We conclude that Compound 1 is a useful molecule not onl y for studying the physiological role of neuropeptide Y but also for e xploring more specific Y1 receptor antagonists. (C) 1998 Elsevier Scie nce Inc.