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Tuesday, October 20, 2009

Selective and Brain Penetrant Neuropeptide Y Y2 Receptor Antagonists Discovered by Whole-Cell High Throughput Screening
Molecular Pharmacology Fast Forward First published on October 16, 2009

The role of neuropeptide Y Y2 receptor (Y2R) in human diseases such as obesity, mood disorders and alcoholism could be better resolved by use of small molecule chemical probes that are substantially different from the currently available Y2R antagonist, BIIE0246.

Presented here are five potent, selective and publicly available Y2R antagonists identified by a high throughput screening (HTS) approach. These compounds belong to four chemical scaffolds that are structurally distinct from the peptidomimetic BIIE0246.

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 pharmacologic studies of Y2R function in both the brain and periphery.


Request Reprint E-Mail: hodderp@scripps.edu

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