Low-molecular-weight Ligand of the Thyroid-stimulating Hormone Receptor with the Activity of a Partial Agonist and a Negative Allosteric Modulator.

IF 0.8 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Doklady Biochemistry and Biophysics Pub Date : 2025-01-22 DOI:10.1134/S1607672924600799

K V Derkach, E A Didenko, V N Sorokoumov, I O Zakharova, A O Shpakov

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引用次数: 0

Abstract

Graves' disease is caused by overactivation of the thyroid-stimulating hormone receptor (TSHR). One approach for its treatment may be the use of negative allosteric modulators (NAM) of TSHR, which normalize TSHR activity and do not cause thyroid hormone (TH) deficiency. The aim of the work was to study the effect of a new compound 5-amino-4-(4-bromophenyl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylic acid N-tert-butylamide (TPY4) on the basal and TSH-stimulated TH production in cultured FRTL-5 thyrocytes and on basal and thyrotropin-releasing hormone (TRH)-stimulated TH levels in the blood of rats. TPY4 stimulated TH production by thyrocytes and increased TH levels when administered intraperitoneally and orally in rats. It also decreased the TSH-stimulated TH production in thyrocytes and the TRH-stimulated TH levels in rats. Thus, TPY4 is the first known allosteric regulator of TSHR, combining the properties of NAM and a partial agonist, and can be considered as a prototype of drugs for the treatment of Graves' disease.

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具有部分激动剂和负变构调节剂活性的促甲状腺激素受体的低分子配体。

Graves病是由促甲状腺激素受体（TSHR）过度激活引起的。治疗方法之一可能是使用TSHR的负变构调节剂（NAM），使TSHR活性正常化，不会引起甲状腺激素（TH）缺乏。本研究的目的是研究新化合物5-氨基-4-（4-溴苯基）-2-（甲基硫）噻吩[2,3-d]嘧啶-6-羧酸n-叔丁基酰胺（TPY4）对培养的FRTL-5甲状腺细胞基础和tsh刺激的TH产生以及大鼠血液基础和促甲状腺素释放激素（TRH）刺激的TH水平的影响。大鼠腹腔和口服TPY4刺激甲状腺细胞产生促甲状腺激素，并增加促甲状腺激素水平。它还能降低大鼠甲状腺细胞中tsh刺激的TH产生和trh刺激的TH水平。因此，TPY4是第一个已知的TSHR变构调节因子，结合了NAM和部分激动剂的特性，可以被认为是治疗Graves病的药物原型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Doklady Biochemistry and Biophysics 生物-生化与分子生物学

CiteScore

1.60

自引率

12.50%

发文量

审稿时长

6-12 weeks

期刊介绍： Doklady Biochemistry and Biophysics is a journal consisting of English translations of articles published in Russian in biochemistry and biophysics sections of the Russian-language journal Doklady Akademii Nauk. The journal''s goal is to publish the most significant new research in biochemistry and biophysics carried out in Russia today or in collaboration with Russian authors. The journal accepts only articles in the Russian language that are submitted or recommended by acting Russian or foreign members of the Russian Academy of Sciences. The journal does not accept direct submissions in English.