title: Selective and brain penetrant neuropeptide y y2 receptor antagonists discovered by whole-cell high-throughput screening.
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, IC(50) 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 (K(i) 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.
authors.affiliation: Department of Neuroscience, Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Brothers
authors.forename: S Adrian
authors.initials: SA
authors.lastname: Saldanha
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.forename: Michael
authors.initials: M
authors.lastname: Cameron
authors.forename: Becky A
authors.initials: BA
authors.lastname: Mercer
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Patricia
authors.initials: P
authors.lastname: McDonald
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D001552:Benzazepines / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004355:Drug Stability; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D006571:Heterocyclic Compounds; D006575:Heterocyclic Compounds, 3-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D001120:Arginine; C403256:BIIE 0246