Modulating effect of low-molecular allosteric regulators of the thyroid-stimulating hormonereceptor on thyroid function in rats exposed to low temperatures

Antithyroid drugs are widely used for the pharmacological correction of hyperthyroidism; however, they have numerous side effects and do not act on the key component of the thyroid axis—thyroid-stimulating hormone receptors (TSHR). Allosteric antagonists and negative modulators of TSHR can be used to reduce TSHR activity, including the thieno[2,3-d]thienopyrimidine derivatives TPY1 and TPY4, which we developed previously [1]. The most suitable model of physiologically induced hyperthyroidism is cold-induced triiodothyronine (T3) hyperthyroidism. The aim of this study was to evaluate the pharmacological properties of TPY1 and TPY4 as negative modulators of TSHR in a rat model of cold-induced T3 hyperthyroidism. After 10 days of low-temperature exposure (+5 °C), T3 hyperthyroidism with increased total T3 (tT3) levels and the tT3/tT4 ratio was observed, while after 15 days, the tT3 level did not differ from the control, but the tT3/tT4 ratio remained high due to T4 deficiency. A single treatment with TPY1, an allosteric antagonist of TSHR (15 mg/kg, intraperitoneally), prevented T3 hyperthyroidism after 10 days, but caused a pronounced thyroxine deficiency and suppression of thyroid function after 15 days of cold exposure. TPY4 (15 mg/kg, intraperitoneally) attenuated, albeit to a lesser extent, T3 hyperthyroidism after 10 days, but after 15 days of cold exposure it did not worsen, but restored, thyroxine deficiency, exhibiting the properties of a negative allosteric modulator and TSHR agonist (ago-NAM). This effect was maintained after five days of TPY4 administration. Thus, TPY4, the N-tert-butylamide of 5-amino-4-(4-bromophenyl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylic acid, can be used to correct moderate hyperthyroidism without causing thyroid hormone deficiency.

The work was supported by the state assignment of the Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences (No. 075-00264-26-00).

[1]. Derkach K.V., Didenko E.A., Sorokoumov V.N., Zakharova I.O., Shpakov A.O. Low-molecular-weight ligand of the thyroid-stimulating hormone receptor with the activity of a partial agonist and a negative allosteric modulator // Doklady Biological Sciences. - 2025. - Vol. 520. - N. 1. - P. 122-127. doi: 10.31857/S2686738925010208