JNJ-31020028 is a brain-permeable selective antagonist of the neuropeptide Y (NPY) receptor Y2 (IC50s = 8.51, 6.03, and 6.17 nM for human, rat, and mouse receptors, respectively) with over 100-fold selectivity for Y2 over Y1, Y4, and Y5 receptors. JNJ-31020028 inhibits calcium release induced by peptide YY in a functional assay in KAN-TS cells (pKB = 8.04) and blocks NPY(13-36)-induced decreases in twitch contraction amplitude in isolated rat vas deferens (IC50 = 7.94 nM). Administration of JNJ-31020028 to rats during abstinence (20 mg/kg per day, i.p.) reverses nicotine-induced social anxiety-like behavior and increases hippocampal Y2 receptor mRNA levels. It reverses withdrawal-induced anxiety-like behavior in rats in the elevated plus maze following a single bolus dose of alcohol when administered at a dose of 15 mg/kg. In an olfactory bulbectomized rat model of depression, chronic JNJ-31020028 treatment (10 nmol per day, i.c.v.) decreases immobility time in the forced swim test but has no effect in control animals.
