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

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Selective and Brain Penetrant Neuropeptide Y Y2 Receptor Antagonists Discovered by Whole-Cell High-Throughput Screening□S Supplemental Material can be found at: http://molpharm.aspetjournals.org/content/suppl/2009/10/16/mol.109.05 8677.DC1.html 0026-895X/10/7701-46–57$20.00 MOLECULAR PHARMACOLOGY Vol. 77, No. 1 Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics 58677/3545841 Mol Pharmacol 77:46–57, 2010 Printed in U.S.A. Selective and Brain Penetrant Neuropeptide Y Y2 Receptor Antagonists Discovered by Whole-Cell High-Throughput Screening□S Shaun P. Brothers, S. Adrian Saldanha, Timothy P. Spicer, Michael Cameron, Becky A. Mercer, Peter Chase, Patricia McDonald, Claes Wahlestedt, and Peter S. Hodder Department of Neuroscience (S.P.B., C.W.), Lead Identification Division, Molecular Screening Center (S.A.S., T.P.S., B.A.M., P.C., P.S.H.), Drug Metabolism and Pharmacokinetics (M.C.), Discovery Biology (P.M.), and Department of Molecular Therapeutics (P.S.H.), the Scripps Research Institute, Jupiter, Florida Downloaded from Received June 18, 2009; accepted October 16, 2009 ABSTRACT The role of neuropeptide Y Y2 receptor (Y2R) in human diseases measured, with no appreciable activity against the related NPY-Y1 molpharm.aspetjournals.org such as obesity, mood disorders, and alcoholism could be better receptor (Y1R). Compounds also displaced radiolabeled peptide resolved by the use of small-molecule chemical probes that are YY from the Y2R with high affinity (Ki values between 1.55 and 60 substantially different from the currently available Y2R antagonist, nM) while not displacing the same ligand from the Y1R. In contrast N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2- to BIIE0246, Schild analysis with NPY suggests that two of the five diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4- compounds behave as competitive antagonists. Profiling against (6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]- a panel of 40 receptors, ion channels, and transporters found in 2-oxoethyl]-cyclopentaneacetamide) (BIIE0246). Presented here the central nervous system showed that the five Y2R antagonists are five potent, selective, and publicly available Y2R antagonists demonstrate greater selectivity than BIIE0246. Furthermore, the identified by a high-throughput screening approach. These com- ability of these antagonists to penetrate the blood-brain barrier pounds belong to four chemical scaffolds that are structurally makes them better suited for pharmacological studies of Y2R by guest on February 15, 2012 distinct from the peptidomimetic BIIE0246. In functional assays, function in both the brain and periphery. IC50 values between 199 and 4400 nM against the Y2R were Neuropeptide Y (NPY) is one of the most abundant neu- and pancreatic polypeptide (50% homology with PP) (Tate- ropeptides in the mammalian brain (Catapano and Manji, moto, 1982). Each of these 36-residue peptides is processed 2007) and was originally identified in 1982 based on its from a 94- to 95-residue prohormone (Balasubramaniam, structural similarity to peptide YY (70% homology with PYY) 1997). Four related type 1 G protein-coupled receptor (GPCR) family members (Y1, Y2, Y4, and Y5) mediate biological ␣ This work was supported by the National Institutes of Health National responses to NPY. These receptors couple to the G i signal- Institute of Neurological Disorders and Stroke [Grant R21-NS056950-01S]; ing pathway and inhibit adenylate cyclase, preventing cAMP and the National Institutes of Health National Institute of Mental Health production. [Grant U54-MH084512]. Selectivity binding studies were conducted by the National Institute of Mental Health’s Psychoactive Drug Screening Program Although NPY receptors have mainly been of interest to [Contract N01-MH32004]. the pharmaceutical industry as therapeutic targets for obe- S.P.B. and S.A.S. contributed equally to this work. Article, publication date, and citation information can be found at sity and feeding disorders, NPY has numerous roles in the http://molpharm.aspetjournals.org. body, including modulation of feeding behavior, circadian doi:10.1124/mol.109.058677. □S The online version of this article (available at http://molpharm. rhythm, learning, memory, vascular remodeling, cell prolif- aspetjournals.org) contains supplemental material. eration, and angiogenesis (Tatemoto, 1982). Human studies ABBREVIATIONS: NPY, neuropeptide Y; Y2R, neuropeptide Y Y2 receptor; Y1R, neuropeptide Y Y1 receptor; 125I-PPY, radiolabeled peptide YY; MLPCN, Molecular Probe Production Center Network; MLSMR, Molecular Libraries Small Molecule Repository; CNS, central nervous system; HTS, high-throughput screening; GPCR, G protein-coupled receptor; ZЈ, Z-factor; DMSO, dimethyl sulfoxide; HEK, human embryonic kidney; AID, bioassay identification number; PSA, polar surface area; 5-HT, 5-hydroxytryptamine; NIMH PDSP, National Institute of Mental Health Psychoactive Drug Screening Program; LC-MS/MS, liquid chromatography-tandem mass spectrometry; CNG, cyclic nucleotide-gated; SID, substance iden- tification number; BIIE0246, N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]- 46 Novel Y2 Receptor Antagonists 47 suggest that NPY is involved in mood disorders and in alco- the small molecule JNJ-5207787 has improved properties holism (Wahlestedt et al., 1989; Thorsell et al., 2006). In over T4-[NPY 33-36]4 and BIIE0246. For example, ex vivo patients with major depression, several studies show that receptor autoradiography studies reveal that JNJ-5207787 is NPY levels in the central nervous system (CNS) are low and able to cross the blood-brain barrier and occupy Y2R receptor correlate inversely to anxiety (Widerlo¨v et al., 1988; Heilig, binding sites (Bonaventure et al., 2004). However, the lack of 2004; Nikisch et al., 2005). In addition to major depressive commercial availability of JNJ-520778 prevents further in- disorders, human genetic studies show that polymorphisms vestigation into its pharmacology. in the NPY gene also associate with alcoholism (Wahlestedt As a result of the drawbacks of current antagonists, there et al., 1986; Zhu et al., 2003; Mottagui-Tabar et al., 2005). is a need to identify brain-penetrant Y2R antagonists to The NPY-Y2 receptor (Y2R) is located presynaptically on better define the role of the receptor in the CNS. This report neurons and in part serves to negatively regulate neuro- presents five novel, selective, brain-penetrant small-mole- transmitter release in the brain (King et al., 1999). Antago- cule Y2R antagonists, discovered from a high-throughput nism of Y2R would thus be expected to increase NPY levels in screening (HTS) approach, that seem to have a different the CNS and may prove useful in treating certain psychiatric mechanism of action from BIIE0246 and are better suited for diseases. Consistent with this, Y2R-null mice demonstrate neuropharmacology studies. reduced anxiety-like behavior compared with wild type (Redrobe et al., 2003). In addition, administration of the Y2R Materials and Methods antagonist BIIE0246 decreased ethanol consumption in rats and induced antidepressant-like effects in mice (Rimondini Unless otherwise stated, reagents were purchased from commer- Downloaded from et al., 2005). cial sources. The cAMP biosensor assay, ACTOne Membrane Poten- tial assay kit, was purchased from BD Biosciences (Rockville, MD). Few efforts have focused on developing Y2R antagonists, Puromycin, Ro 20-1724, and isoproterenol were from Sigma-Aldrich with only two selective Y2R antagonists being reported other (St. Louis, MO). Neuropeptide Y was from American Peptide (Sunny- than BIIE0246: the peptide ligand T4-[NPY 33-36]4 (Grouz- vale, CA). BIIE0246 and BIBP3226 were from Tocris Bioscience mann et al., 1997); and the small molecule JNJ-5207787 (Ellisville, MO). Human liver microsomes were from Xenotech (Le- (Bonaventure et al., 2004). Small-molecule diamines have nexa, KS). Black, clear-bottomed 1536-well tissue culture-treated molpharm.aspetjournals.org also been reported as Y2R ligands. However, these com- microtiter plates were from Greiner Bio-One (Longwood, FL). The pounds have not been shown to be functionally active or National Institutes of Health Molecular Libraries Small-Molecule selective for the Y2R (Andres et al., 2003). Repository (MLSMR, San Francisco, CA) provided compound collec- The most widely used Y2R antagonist, BIIE0246, is selec- tions (dissolved at concentrations up to 10 mM in DMSO) for the tive with high receptor affinity and is efficacious both in vitro primary and follow-up assays. For dose-response assays, compounds were provided by the MLSMR or were ordered as powders and and in vivo (Doods et al., 1999). However, there are signifi- prepared as 10 mM stock solutions in DMSO. cant drawbacks associated with this compound. For instance, For studies involving powders, the compounds SF-11, SF-21, and it has been suggested that BIIE0246 behaves as an insur- SF-22 were obtained from ChemBridge (San Diego, CA). The com- by guest on February 15, 2012 mountable antagonist (Dautzenberg and Neysari, 2005), an pounds SF-31 and SF-41 were purchased from Chemical Diversity undesirable trait for a probe or potential therapeutic agent, (San Diego, CA) and Specs (Delft, Holland), respectively. Reference because this mode of inhibition might block the Y2R from and ordering information for all compounds can be obtained from further activation, which would lead to long-term loss of Y2R PubChem (available at http://pubchem.ncbi.nlm.nih.gov/) by con- function. As a consequence,
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