Characterization of N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4yl]-acrylamide (JNJ-5207787), a small molecule antagonist of the neuropeptide YY2 receptor

The in vitro pharmacological properties of N-(1-Acetyl- 2,3-dihydro- 1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentylethyl)- piperidin-4yl]-acrylamide (JNJ-5207787), a novel neuropeptide Y Y-2 receptor (Y-2) antagonist, were evaluated. JNJ-5207787 inhibited the binding of peptide YY (PYY) to human Y-2 receptor in KAN-Ts cells (pIC(50) = 7.00 +/- 0.10) and to rat Y-2 receptors in rat hippocampus (pIC(50) = 7.10 +/- 0.20). The compound was > 100-fold selective versus human Y-1, Y-4, and Y-5 receptors as evaluated by radioligand binding. In vitro receptor autoradiography data in rat brain tissue sections confirmed the selectivity of JNJ-5207787. [I-125] PYY binding sites sensitive to JNJ-5207787 were found in rat brain regions known to express Y-2 receptor (septum, hypothalamus, hippocampus, substantia nigra, and cerebellum), whereas insensitive binding sites were observed in regions known to express Y-1 receptor (cortex and thalamus). JNJ-5207787 was demonstrated to be an antagonist via inhibition of PYY-stimulated guanosine 5'-O-(3[ S-35] thio) triphosphate binding ([S-35] GTPgammaS) in KAN-Ts cells (pIC(50) corrected = 7.20 +/- 0.12). This was confirmed autoradiographically in rat brain sections where PYY-stimulated guanosine 5'-O-(3-[S-35] thio) triphosphate binding was inhibited by JNJ-5207787 (10 muM) in hypothalamus, hippocampus, and substantia nigra. After intraperitoneal administration in rats (30 mg/kg), JNJ-5207787 penetrated into the brain (C-max = 1351 +/- 153 ng/ml at 30 min) and occupied Y-2 receptor binding sites as revealed by ex vivo receptor autoradiography. Hence, JNJ-5207787 is a potent and selective pharmacological tool available to establish the potential role of central and peripheral Y-2 receptors in vivo.