Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 7, Pages 2036-2042Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm801561h
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- Top Institute Pharma [D1-105]
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The luteinizing hormone (LH) receptor plays an important role in fertility and certain cancers. The endogenous ligands human chorionic gonadotropin (hCG) and LH bind to the large N terminal domain of the receptor. We recently reported on the first radiolabeled low molecular weight (LMW) agonist for this receptor, [H-3]Org 43553, which was now used to screen for new LMW ligands. We identified a terphenyl derivative that inhibited [H-3]Org 43553 binding to the receptor, which led us to synthesize a number of derivatives. The most potent compound of this terphenyl series, 24 (LUF5771), was able to increase the dissociation rate of [H-3]Org 43553 by 3.3-fold (at 10 mu M). In a functional assay, the presence of 24 resulted in a 2- to 3-fold lower potency of both Org 43553 and LH. Thus, the compounds presented in this paper are the first LMW ligands that allosterically inhibit the LH receptor.
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