1279654-88-4Relevant academic research and scientific papers
Discovery and SAR of a series of agonists at orphan G protein-coupled receptor 139
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
, p. 303 - 306 (2011/06/21)
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 A2 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.
