Selective and brain penetrant neuropeptide Y Y2 receptor antagonists discovered by whole-cell high-throughput screening

Shaun P Brothers, S. Adrian Saldanha, Timothy P. Spicer, Michael Cameron, Becky A. Mercer, Peter Chase, Patricia McDonald, Claes R Wahlestedt, Peter S. Hodder

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)46-57
Number of pages12
JournalMolecular Pharmacology
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

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Neuropeptide Y Receptors
Brain
Peptidomimetics
Aptitude
Blood-Brain Barrier
Mood Disorders
Ion Channels
Alcoholism
Inhibitory Concentration 50
Central Nervous System
Obesity
Pharmacology
Ligands
neuropeptide Y2 receptor
BIIE 0246

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Selective and brain penetrant neuropeptide Y Y2 receptor antagonists discovered by whole-cell high-throughput screening. / Brothers, Shaun P; Saldanha, S. Adrian; Spicer, Timothy P.; Cameron, Michael; Mercer, Becky A.; Chase, Peter; McDonald, Patricia; Wahlestedt, Claes R; Hodder, Peter S.

In: Molecular Pharmacology, Vol. 77, No. 1, 01.01.2010, p. 46-57.

Research output: Contribution to journalArticle

Brothers, Shaun P ; Saldanha, S. Adrian ; Spicer, Timothy P. ; Cameron, Michael ; Mercer, Becky A. ; Chase, Peter ; McDonald, Patricia ; Wahlestedt, Claes R ; Hodder, Peter S. / Selective and brain penetrant neuropeptide Y Y2 receptor antagonists discovered by whole-cell high-throughput screening. In: Molecular Pharmacology. 2010 ; Vol. 77, No. 1. pp. 46-57.
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