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
Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
Neuroscience Drug Discovery Denmark , H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen, Valby, Denmark.
ACS Med Chem Lett. 2011 Feb 28;2(4):303-6. doi: 10.1021/ml100293q. eCollection 2011 Apr 14.
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 Å(2) 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.
GPR139是一种孤儿G蛋白偶联受体（GPCR），主要在中枢神经系统（CNS）中表达。为了探索该受体的生物学功能，需要选择性工具化合物。一项筛选活动确定化合物1a是一种高效的GPR139激动剂，在稳定表达GPR139受体的CHO-K1细胞的钙动员试验中，其EC50 = 39 nM。在没有已知内源性配体的情况下，将1a的最大效应设定为100%。针对90种不同靶点的筛选未发现交叉反应问题。药代动力学性质评估显示，作为大鼠体内工具化合物，其效用有限，全脑暴露量低至61 ng/g，脑/血浆（b/p）比值为0.03。尝试鉴定更合适的类似物时，发现了去氮类似物1s，其极性表面积减少至76.7 Å(2)，b/p比值提高至2.8。由于血浆暴露量低，全脑暴露量仍低至95 ng/g。
