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Abstract <p><b>Objective:</b> Despite the fact that hypothyroid conditions, including autoimmune thyroiditis, are widespread pathologies, the possibilities of their pharmacological correction are very limited, including, mainly, the replacement therapy with thyroid hormones (THs). However, such therapy is characterized by many side effects, in connection with which alternative ways of stimulating the thyroid system are being developed, including the use of low-molecular regulators. Their target is allosteric sites located in the transmembrane domain of the thyroid-stimulating hormone (TSH) receptor. The aim of the study was the synthesis and physicochemical characterization of a new compound TPY7, methyl 2-(4-(4-(5-amino-6-(<i>tert</i>-butylcarbamoyl)-2-(methylthio)thieno[2,3-<i>d</i>]pyrimidin-4-yl)phenyl)-1<i>H</i>-1,2,3-triazol-1-yl) acetate, a methylated analogue of TPY3m, a TSH receptor agonist developed by us earlier, and to study the ability of TPY7 (in comparison with TPY3m) to influence the levels of total (tT4) and free (fT4) thyroxine and free triiodothyronine (fT3) and the expression of thyroglobulin (<i>Tg</i>), thyroid peroxidase (<i>Tpo</i>), and type 2 deiodinase (<i>Dio2</i>) genes in the thyroid gland of rats with one- and five-day administration, including stimulation of the thyroid system with thyroliberin (TRH). <b>Material and methods:</b> Blood levels of TG and TSH were assessed using enzyme immunoassay. Expression of genes responsible for TG synthesis was measured using real-time PCR. <b>Results and discussion:</b> When administered to rats, TPY7 dose-dependently increased the production of tT4 and fT3, and at a dose of 15 mg/kg (i.p.) also increased the expression of the <i>Tpo</i> and <i>Dio2</i> genes responsible for the synthesis and conversion of THs. Its stimulating effect was maintained after five days of administration, indicating the absence of significant desensitization of the TSH receptor and its signaling cascades with long-term exposure to TPY7. In terms of the effectiveness of the stimulating effect on the thyroid system, TPY7 was inferior to TPY3m, although to a small extent. At the same time, unlike TPY3m, TPY7 potentiated the effects of TRH, increasing its stimulating effect on the levels of tT4 and fT3 in the blood and on the expression of the <i>Dio2</i> gene in the thyroid gland. <b>Conclusions:</b> Thus, we have developed for the first time an active <i>in vivo</i> allosteric ligand of the TSH receptor with the activity of a partial agonist and a positive allosteric modulator (ago-PAM). TPY7 is a prototype for the creation of drugs that can be used to treat hypothyroidism and as stimulators of radioactive iodine uptake by thyrocytes in thyroid cancer radiotherapy.</p>

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Substitution of an Ethyl Group with a Methyl Group in the Variable Moiety of TPY3m, a Thyroid-Stimulating Hormone Receptor Agonist, Modifies the Effect of This Analogue on the Basal and Thyroliberin-Stimulated Levels of Thyroid Hormones in Rats

  • 期刊论文

  • 发表日期：

    2025年2月10日

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  • K. V. Derkach,
  • E. A. Didenko,
  • V. N. Sorokoumov,
  • A. O. Shpakov

摘要

Abstract

Objective: Despite the fact that hypothyroid conditions, including autoimmune thyroiditis, are widespread pathologies, the possibilities of their pharmacological correction are very limited, including, mainly, the replacement therapy with thyroid hormones (THs). However, such therapy is characterized by many side effects, in connection with which alternative ways of stimulating the thyroid system are being developed, including the use of low-molecular regulators. Their target is allosteric sites located in the transmembrane domain of the thyroid-stimulating hormone (TSH) receptor. The aim of the study was the synthesis and physicochemical characterization of a new compound TPY7, methyl 2-(4-(4-(5-amino-6-(tert-butylcarbamoyl)-2-(methylthio)thieno[2,3-d]pyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) acetate, a methylated analogue of TPY3m, a TSH receptor agonist developed by us earlier, and to study the ability of TPY7 (in comparison with TPY3m) to influence the levels of total (tT4) and free (fT4) thyroxine and free triiodothyronine (fT3) and the expression of thyroglobulin (Tg), thyroid peroxidase (Tpo), and type 2 deiodinase (Dio2) genes in the thyroid gland of rats with one- and five-day administration, including stimulation of the thyroid system with thyroliberin (TRH). Material and methods: Blood levels of TG and TSH were assessed using enzyme immunoassay. Expression of genes responsible for TG synthesis was measured using real-time PCR. Results and discussion: When administered to rats, TPY7 dose-dependently increased the production of tT4 and fT3, and at a dose of 15 mg/kg (i.p.) also increased the expression of the Tpo and Dio2 genes responsible for the synthesis and conversion of THs. Its stimulating effect was maintained after five days of administration, indicating the absence of significant desensitization of the TSH receptor and its signaling cascades with long-term exposure to TPY7. In terms of the effectiveness of the stimulating effect on the thyroid system, TPY7 was inferior to TPY3m, although to a small extent. At the same time, unlike TPY3m, TPY7 potentiated the effects of TRH, increasing its stimulating effect on the levels of tT4 and fT3 in the blood and on the expression of the Dio2 gene in the thyroid gland. Conclusions: Thus, we have developed for the first time an active in vivo allosteric ligand of the TSH receptor with the activity of a partial agonist and a positive allosteric modulator (ago-PAM). TPY7 is a prototype for the creation of drugs that can be used to treat hypothyroidism and as stimulators of radioactive iodine uptake by thyrocytes in thyroid cancer radiotherapy.