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 Y Y2 receptor.
The in vitro pharmacological properties 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 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. [(125)I]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-[(35)S]thio)triphosphate binding ([(35)S]GTPgammaS) in KAN-Ts cells (pIC(50) corrected = 7.20 +/- 0.12). This was confirmed auto-radiographically in rat brain sections where PYY-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding was inhibited by JNJ-5207787 (10 microM) 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.
Bonaventure
Pascal
P
Johnson & Johnson Pharmaceutical Research and Development, San Diego, CA 92121, USA. pbonave1@prdus.jnj.com
Nepomuceno
Diane
D
Mazur
Curt
C
Lord
Brian
B
Rudolph
Dale A
DA
Jablonowski
Jill A
JA
Carruthers
Nicholas I
NI
Lovenberg
Timothy W
TW
D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001812:Blood-Brain Barrier; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*
D000178:Acrylamides; C483241:N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-(1-(2-cyclopentyl-ethyl)-piperidin-4yl)acrylamide; D010880:Piperidines; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D016244:Guanosine 5'-O-(3-Thiotriphosphate)