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

Clinical Endocrinology Branch (S.N., S.M., B.M.R., M.C.G.), National Institute of Diabetes and Digestive and Kidney Diseases, and Chemical Genomics Center (J.J., C.J.T.), National Human Genome Research Institute, National Institutes of Health, Laboratory of Biological Modeling (S.C.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892; and Leibniz-Institut für Molekulare Pharmakologie (G.Kl., G.Kr.), D-13125 Berlin, Germany

Address all correspondence and requests for reprints to: Marvin C. Gershengorn, National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Endocrinology Branch, National Institutes of Health, 50 South Drive, Bethesda, Maryland 20892-8029. E-mail: marving{at}intra.niddk.nih.gov.

Low-molecular-weight (LMW) antagonists for TSH receptor (TSHR) may have therapeutic potential as orally active drugs to block stimulating antibodies (TsAbs) in Graves’ hyperthyroidism. We describe an approach to identify LMW ligands for TSHR based on Org41841, a LMW partial agonist for the LH/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 by both TSH and TsAbs. Whereas 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 in which 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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