Details

Autor(en) / Beteiligte

• Shi, Feng
• Shen, Jing Kang
• Chen, Danqi
• Fog, Karina
• Thirstrup, Kenneth
• Hentzer, Morten
• Karlsson, Jens-Jakob
• Menon, Veena
• Jones, Kenneth A
• Smith, Kelli E
• Smith, Garrick

Titel

Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139

Ist Teil von

• ACS medicinal chemistry letters, 2011-04, Vol.2 (4), p.303-306

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2011

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• GPR139 is an orphan G-protein coupled receptor (GPCR) which is primarily expressed in the central nervous system (CNS). In order to explore the biological function of this receptor, selective tool compounds are required. A screening campaign identified compound 1a as a high potency GPR139 agonist with an EC50 = 39 nM in a calcium mobilization assay in CHO-K1 cells stably expressing the GPR139 receptor. In the absence of a known endogenous ligand, the maximum effect was set as 100% for 1a. Screening against 90 diverse targets revealed no cross-reactivity issues. Assessment of the pharmacokinetic properties showed limited utility as in vivo tool compound in rat with a poor whole brain exposure of 61 ng/g and a brain/plasma (b/p) ratio of 0.03. Attempts to identify a more suitable analogue identified the des-nitrogen analogue 1s with a reduced polar surface area of 76.7 Å2 and an improved b/p ratio of 2.8. The whole brain exposure remained low at 95 ng/g due to a low plasma exposure.