Characterization ofN-(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 Y₂Receptor

Abstract

Neuropeptide Y (NPY) is a 36-amino acid peptide discovered in the early 1980s that belongs to a family of peptides that includes pancreatic polypeptides (PP) and peptide YY (PYY) (Tatemoto and Mutt, 1980). NPY is widely distributed in the central and peripheral nervous systems (for reviews, see Blomqvist and Herzog, 1997;Gehlert, 1999;Wieland et al., 2000;Kask et al., 2002;Malmstrom, 2002;Thorsell and Heilig, 2002). In the brain, NPY is the most abundant neuropeptide yet identified and its localization suggests an involvement in a variety of physiological processes, including anxiety, food intake, water consumption, circadian rhythms, hormone release, learning, and memory.The use of various cloning techniques has resulted in the identification of five receptors to date (Y 1 , Y 2 , Y 4 , Y 5 , and y 6 ) (Herzog et al., 1992;Larhammar et al., 1992;Bard et al., 1995;Gerald et al., 1995Gerald et al., , 1996Gregor et al., 1996;Hu et al., 1996;Matsumoto et al., 1996;Weinberg et al., 1996), all of them belong to the superfamily of G protein-coupled receptors. All NPY receptor subtypes are expressed in several species, including human, except the y 6 , which is absent in rat and not functional in the human and primates (Blomqvist and Herzog, 1997

Selective and Brain Penetrant Neuropeptide Y Y2 Receptor Antagonists Discovered by Whole-Cell High-Throughput Screening

“…Brain penetration for all five HTS antagonists was high, signifying their potential for in vivo neurological studies. Brain concentrations determined for all five compounds (0.4 -4.5 M) are comparable with levels achieved by the small molecule JNJ-5207787 (C max of 2.6 M at 30 min) (Bonaventure et al, 2004). Because of the potential for rapid hepatic metabolism, SF-21, SF-22, and SF-41 may not be suitable for rodent in vivo efficacy studies.…”

“…In contrast, the small molecule JNJ-5207787 has improved properties over T4- 4 and BIIE0246. For example, ex vivo receptor autoradiography studies reveal that JNJ-5207787 is able to cross the blood-brain barrier and occupy Y2R receptor binding sites (Bonaventure et al, 2004). However, the lack of commercial availability of JNJ-520778 prevents further investigation into its pharmacology.…”

“…Few efforts have focused on developing Y2R antagonists, with only two selective Y2R antagonists being reported other than BIIE0246: the peptide ligand T4- 4 (Grouzmann et al, 1997); and the small molecule JNJ-5207787 (Bonaventure et al, 2004). Small-molecule diamines have also been reported as Y2R ligands.…”

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

“…A first small-molecule Y2-R antagonist, JNJ-5207787 (20) (Figure 4), had been reported by Bonaventure et al [108]. The compound showed a modest affinity and a receptor occupancy of 50%.…”

“…This forces the interest in NPY-R ligands suitable for treatment of anxiety disorders. The NPY1-R receptor is also localized in cerebral cortex, caudate-putamen and thalamus [108], while NPY2-R is found primarily in hypothalamus, hippocampus, substantia nigra and cerebellum. Moreover, the NPY2-R has been found as pre-and postsynaptic receptor [109][110][111].…”