A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice.
A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice.
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DOI：
10.1210/en.2013-1835
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发表时间：
2014
期刊：
影响因子：
4.8
通讯作者：
S. Neumann;Eshel A. Nir;E. Eliseeva;Wenwei Huang;J. Marugan;Jingbo Xiao;Andrés E Dulcey;M. Gershengorn
中科院分区：
文献类型：
--
作者：
S. Neumann;Eshel A. Nir;E. Eliseeva;Wenwei Huang;J. Marugan;Jingbo Xiao;Andrés E Dulcey;M. Gershengorn
由于TSH受体(TSHR)在甲状腺疾病的发病机制中起重要作用，TSHR拮抗剂可能成为一种新的治疗方法。我们试图开发一种小分子、类药物的TSHR信号通路拮抗剂，这种拮抗剂在体内具有选择性和活性。我们对已报道的一种TSHR拮抗剂进行化学修饰，合成了NCGC00242364(ANTAG3)。我们在体外模型细胞系统中通过测量其抑制TSH、LH或FSH刺激的cAMP产生的活性来测试其效力、有效性和选择性。我们检测了ANTAG3对BALB/c雌性小鼠血清游离T4和甲状腺基因表达的影响，并测定了ANTAG3对BALB/c雌性小鼠血清游离T4和甲状腺基因表达的影响。ANTAG3对促性腺激素释放激素受体具有选择性抑制作用，半数抑制剂量为2.1μM，对促黄体生成素和卵泡刺激素受体的抑制剂量大于30μM。在TRH治疗的小鼠中，ANTAG3使血清游离T4降低了44%，钠碘共转运体和甲状腺过氧化物酶的mRNAs分别降低了75%和83%。在服用M22的小鼠中，ANTAG3使血清游离T4降低了38%，钠碘共转运体和甲状腺过氧化物酶的mRNAs分别降低了73%和40%。总之，我们开发了一种在小鼠体内有效的选择性TSHR拮抗剂。这是首次报道体内活性的小分子TSHR拮抗剂，并可能导致治疗Graves病的药物。
Because the TSH receptor (TSHR) plays an important role in the pathogenesis of thyroid disease, a TSHR antagonist could be a novel treatment. We attempted to develop a small molecule, drug-like antagonist of TSHR signaling that is selective and active in vivo. We synthesized NCGC00242364 (ANTAG3) by chemical modification of a previously reported TSHR antagonist. We tested its potency, efficacy, and selectivity in a model cell system in vitro by measuring its activity to inhibit stimulation of cAMP production stimulated by TSH, LH, or FSH. We tested the in vivo activity of ANTAG3 by measuring its effects to lower serum free T4 and thyroid gene expression in female BALB/c mice continuously treated with ANTAG3 for 3 days and given low doses of TRH continuously or stimulated by a single administration of a monoclonal thyroid-stimulating antibody M22. ANTAG3 was selective for TSHR inhibition; half-maximal inhibitory doses were 2.1 μM for TSHR and greater than 30 μM for LH and FSH receptors. In mice treated with TRH, ANTAG3 lowered serum free T4 by 44% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 75% and 83%, respectively. In mice given M22, ANTAG3 lowered serum free T4 by 38% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 73% and 40%, respectively. In conclusion, we developed a selective TSHR antagonist that is effective in vivo in mice. This is the first report of a small-molecule TSHR antagonist active in vivo and may lead to a drug to treat Graves' disease.