Low-molecular-weight ligand of the thyroid-stimulating hormone receptor with the activity of a partial agonist and a negative allosteric modulator

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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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作者简介

K. Derkach

I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: alex_shpakov@list.ru
俄罗斯联邦, St. Petersburg

E. Didenko

I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences; St. Petersburg State University

Email: alex_shpakov@list.ru

Institute of Chemistry, St. Petersburg State University

俄罗斯联邦, St. Petersburg; St. Petersburg

V. Sorokoumov

I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences; St. Petersburg State University

Email: alex_shpakov@list.ru

Institute of Chemistry, St. Petersburg State University

俄罗斯联邦, St. Petersburg; St. Petersburg

I. Zakharova

I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: alex_shpakov@list.ru
俄罗斯联邦, St. Petersburg

A. Shpakov

I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

编辑信件的主要联系方式.
Email: alex_shpakov@list.ru
俄罗斯联邦, St. Petersburg

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2. Fig. 1. Levels of thyroid hormones and TSH in the blood of rats treated with intraperitoneal and oral administration of TPY4 and thyroliberin separately and together. Note. Differences with the control (a) and between groups treated with TRH only or sequentially with TPY4 and TRH (b) are statistically significant at P < 0.05. M ± SEM, n = 6.

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