The development of ligands of the thyrotropin receptor transmembrane allosteric site with the activity of antagonists and inverse agonists

Thyroid-stimulating hormone (TSH) is the main regulator of thyroid hormones production. The increased activity of TSH receptors due to mutations or interaction with the stimulating TSH receptor-autoantibodies leads to oncological and autoimmune thyroid diseases. Currently, no effective drugs have been developed to prevent TSH receptor hyperactivation. One of the approaches is the use of low-molecular-weight antagonists and inverse agonists of the transmembrane allosteric site of TSH receptor, in particular, thieno[2,3d]pyrimidine derivatives (TPs). The aim of the study was to explore the new TPs with such activity: 5-amino-N-(tert-butyl)-4-(4-iodophenyl-)-2-(methylthio)thieno[2,3d]pyrimidine-6-carboxamide (TP48) and 5-amino-N-(tert-butyl)-4-(4-(3-methoxyprop-1yn-1-yl)phenyl)-2-(methylthio)thieno[2,3d]pyrimidine-6-carboxamide (TPY1). When TP48 and TPY1 (15 mg/kg, i.p.) were administered to male Wistar rats, thyroliberin-induced production of thyroxine and triiodothyronine was reduced. TP48 and TPY1 also weakened the stimulating effects of thyroliberin on the expression of the Tg, TPO, and Dio2 genes, which encode the enzymes responsible for thyroid hormone synthesis, such as thyroglobulin, thyroid peroxidase and D2-deiodinase, and unexpectedly reduced expression of the Tshr gene encoding TSH receptor. TP48 also decreased basal thyroid hormone levels in control rats. Thus, new allosteric antagonists (TPY1) and inverse agonists (TP48) of TSH receptor have been developed, which can become prototypes for the creation of drugs to treat hyperthyroidism and thyroid cancer. This work was supported by the Russian Science Foundation (No. 19-75-20122).