Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139
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 wi...
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Published in | ACS medicinal chemistry letters Vol. 2; no. 4; pp. 303 - 306 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
14.04.2011
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1948-5875 1948-5875 |
DOI: | 10.1021/ml100293q |