Abstract
The role of neuropeptide Y Y2 receptor (Y2R) in human diseases such as obesity, mood disorders, and alcoholism could be better resolved by the use of small-molecule chemical probes that are substantially different from the currently available Y2R antagonist, N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide) (BIIE0246). Presented here are five potent, selective, and publicly available Y2R antagonists identified by a high-throughput screening approach. These compounds belong to four chemical scaffolds that are structurally distinct from the peptidomimetic BIIE0246. In functional assays, IC50 values between 199 and 4400 nM against the Y2R were measured, with no appreciable activity against the related NPY-Y1 receptor (Y1R). Compounds also displaced radiolabeled peptide YY from the Y2R with high affinity (Ki values between 1.55 and 60 nM) while not displacing the same ligand from the Y1R. In contrast to BIIE0246, Schild analysis with NPY suggests that two of the five compounds behave as competitive antagonists. Profiling against a panel of 40 receptors, ion channels, and transporters found in the central nervous system showed that the five Y2R antagonists demonstrate greater selectivity than BIIE0246. Furthermore, the ability of these antagonists to penetrate the blood-brain barrier makes them better suited for pharmacological studies of Y2R function in both the brain and periphery.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. -
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R21-NS056950-01S]; and the National Institutes of Health National Institute of Mental Health [Grant U54-MH084512]. Selectivity binding studies were conducted by the National Institute of Mental Health's Psychoactive Drug Screening Program [Contract N01-MH32004].
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.058677.
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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
- Z′
- 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 identification 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]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide)
- BIBP3226
- (2R)-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl)amino]-N-[(4-hydroxyphenyl)methyl]pentanamide
- SF-11
- N-(4-ethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide
- SF-12
- 4-[hydroxy(diphenyl)methyl]-N-(4-methoxyphenyl)piperidine-1-carbothioamide
- SF-13
- N-(4-chlorophenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide
- SF-14
- N-(3, 5-dimethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide
- SF-15
- 5-dimethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide
- SF-16
- N-(4-fluorophenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide
- SF-21
- 4-chloro-3-[(2,5-dimethylphenyl)sulfamoyl]-N-(2-phenylphenyl)benzamide
- SF-22
- N-2-biphenylyl-3-{[(2,5-dimethylphenyl)amino]sulfonyl}-4-methylbenzamide
- SF-23
- 4-methyl-N-(2-phenylphenyl)-3-(phenylsulfamoyl)benzamide
- SF-24
- 4-chloro-3-[(2-methylphenyl)sulfamoyl]-N-(2-phenylphenyl)benzamide
- SF-31
- 2-(2-methoxyphenyl)-N-[4-[5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide
- SF-32
- N-[4-[5-(2-ethoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl]-2-(2-methoxyphenyl)acetamide
- SF-33
- 2-(4-methoxyphenyl)-N-[4-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide
- SF-34
- N-[4-[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]phenyl]-2-(2-methoxyphenyl)acetamide
- SF-35
- N-[4-[5-(2-ethoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl]-2-(4-methoxyphenyl)acetamide
- SF-36
- N-[4-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]phenyl]-2-(2-methoxyphenyl)acetamide
- SF-37
- 2-(4-methoxyphenyl)-N-[4-[5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide
- SF-38
- 2-(4-methoxyphenyl)-N-[4-[5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide
- SF-39
- N-[4-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]phenyl]-2-(4-methoxyphenyl)acetamide
- SF-41
- 3,5-dimethyl-4-[(4-methylphenyl)sulfonyl-phenylmethyl]-1,2-oxazole
- SF-42
- 4-[benzenesulfonyl(phenyl)methyl]-3,5-dimethyl-1,2-oxazole
- Ro 20-1724
- 4-[(3-butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone
- JNJ-5207787
- (N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4yl]-acrylamide).
- Received June 18, 2009.
- Accepted October 16, 2009.
- © 2010 The American Society for Pharmacology and Experimental Therapeutics
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