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ACS Med Chem Lett. 2011 Feb 28;2(4):303-6. doi: 10.1021/ml100293q. eCollection 2011 Apr 14.

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

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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.
Lundbeck Research USA , 215 College Road, Paramus, New Jersey 07652-1431, United States.


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.


CNS; G-protein coupled receptor; Orphan GPR-139; agonists; hydrazinecarboxamide

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