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This version published online on July 31, 2008
Endocrinology, doi:10.1210/en.2008-0836
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Submitted on June 4, 2008
Accepted on July 22, 2008

A Low Molecular Weight Antagonist for the Human Thyrotropin Receptor with Therapeutic Potential for Hyperthyroidism

Susanne Neumann, Gunnar Kleinau, Stefano Costanzi, Susanna Moore, Jian-kang Jiang, Bruce M. Raaka, Craig J. Thomas, Gerd Krause, and Marvin C. Gershengorn*

Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892; Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Str.10, D-13125 Berlin, Germany; Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA; NIH Chemical Genomics Center, National Human Genome Research Institute, NIH 9800 Medical Center Drive, MSC 3370 Bethesda, MD 20892-3370 USA

* To whom correspondence should be addressed. E-mail: marving{at}intra.niddk.nih.gov.

Low molecular weight (LMW) antagonists for thyroid-stimulating hormone receptor (TSHR) may have therapeutic potential as orally active drugs to block stimulating antibodies in Graves' hyperthyroidism (TsAbs). We describe an approach to identify LMW ligands for TSHR based on Org41841, a LMW partial agonist for the luteinizing hormone/choriogonadotropin receptor and TSHR. We used molecular modeling and functional experiments to guide the chemical modification of Org41841. We identified an antagonist (NIDDK/CEB-52) that selectively inhibits activation of TSHR both by TSH and by TsAbs. While initially characterized in cultured cells overexpressing TSHRs, the antagonist was also active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs where it inhibited TSH- and TsAb-induced up-regulation of mRNA transcripts for thyroperoxidase. Our results establish this LMW compound as a lead for the development of higher potency antagonists and serve as "proof-of-principle" that LMW ligands that target TSHR could serve as drugs in patients with Graves' disease.




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