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

被引：86

作者：

Neumann, Susanne ^{[1
]}

Kleinau, Gunnar ^{[4
]}

Costanzi, Stefano ^{[3
]}

Moore, Susanna ^{[1
]}

Jiang, Jian-kang ^{[2
]}

Raaka, Bruce M. ^{[1
]}

Thomas, Craig J. ^{[2
]}

Krause, Gerd ^{[4
]}

Gershengorn, Marvin C. ^{[1
]}

机构：

[1] NIDDKD, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA

[2] NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA

[3] NIDDKD, Lab Biol Modeling, Bethesda, MD 20892 USA

[4] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany

来源：

ENDOCRINOLOGY | 2008年 / 149卷 / 12期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1210/en.2008-0836

中图分类号：

R5 [内科学];

学科分类号：

1002 [临床医学]; 100201 [内科学];

摘要：

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. (Endocrinology 149: 5945-5950, 2008)

引用

页码：5945 / 5950

页数：6

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