Low Molecular Weight Thyrotropin Receptor Inverse Agonist Is Active upon Both Intraperitoneal and Oral Administration

Autoimmune hyperthyroidism (Graves’ disease), which is caused by stimulating autoantibodies to the thyroid-stimulating hormone receptor (TSHR), and thyroid tumors, caused by a constitutively increased activity of this receptor, are widespread and have a poor prognosis. The drugs used to treat them are low effective and have many side effects. One of the therapeutic approaches to these thyroid diseases may be the use of TSH receptor allosteric regulators with an activity of inverse agonists. This work was aimed to study the effects of the compound TP48, previously synthesized in our laboratory, and a newly synthesized compound TPY5, with both of them referring to thieno[2,3-d]-pyrimidines, on basal and thyrotropin-releasing hormone (TRH)-stimulated levels of thyroid hormones (THs) in the rat blood and on the expression of genes responsible for TH synthesis in the rat thyroid gland. TP48 and TPY5 effectiveness was studied upon both intraperitoneal (20 mg/kg) and peroral (40 mg/kg) administration. Using ELISA, blood levels of free (fT4) and total (tT4) thyroxine, as well as free (fT3) and total (tT3) triiodothyronine, were assessed, including during stimulation with intranasal TRH (300 µg/kg). Gene expression for thyroid peroxidase ( Tpo ), thyroglobulin ( Tg ), Na + /I – symporter ( Nis ), type 2 deiodinase ( Dio2 ), and TSH receptor ( Tshr ) in the thyroid gland was assessed by PCR. TPY5, administered via both routes, reduced both basal and TRH-stimulated plasma TH levels, while TP48 suppressed TH production only after intraperitoneal administration. Peroral TPY5 significantly reduced basal Tpo expression, as well as TRH-stimulated Tg and Dio2 expression. Intraperitoneal TP48 reduced only TRH-stimulated Tg and Dio2 expression. Quite surprisingly, peroral TPY5 and intraperitoneal TP48 reduced basal Tshr expression but did not prevent its inhibition by TRH. Thus, the novel compound TPY5 exhibits the activity of a TSH receptor inverse agonist and is effective when administered perorally, which is more in demand in medicine; it can be considered as a prototype of drugs to treat autoimmune hyperthyroidism and thyroid tumors.