Low molecular inverse agonist of the thyrotropin receptor is active both intraperitoneal and oral administration

Abstract

Autoimmune hyperthyroidism (Graves’ disease), which is caused by stimulating autoantibodies to the thyroid-stimulating hormone (TSH) receptor, and thyroid gland (TG) tumors, caused by constitutively increased activity of this receptor, are widespread and have a poor prognosis. The drugs used to treat them are not very effective and have many side effects. One of the approaches for the treatment of these thyroid diseases may be the use of allosteric regulators of the TSH receptor with the activity of inverse agonists. The purpose of the work was to study the effects of our previously developed compound TP48 and the new compound TPY5, belonging to the class of thieno[2,3-d]-pyrimidines, on the basal and thyrotropin-releasing hormone (TRH)-stimulated levels of thyroid hormones (THs) in the blood of rats and on the expression of genes responsible for the synthesis of THs in the TG. The effectiveness of TP48 and TPY5 was studied both with intraperitoneal (i.p., 20 mg/kg) and oral (40 mg/kg) administration. Using ELISA, the levels of free (fT4) and total (tT4) thyroxine and free (fT3) and total (tT3) triiodothyronine in the blood were assessed, including during TRH stimulation (intranasally, 300 μg/kg). The gene expression for thyroid peroxidase (Tpo), thyroglobulin (Tg), Na+/I–-symporter (Nis), type 2 deiodinase (Dio2) and TSH receptor (Tshr) in the TG was assessed using PCR. TPY5, with both routes of administration, reduced both basal and TRH-stimulated TH levels, while TP48 suppressed TH production only with i.p. administration. Orally administered TPY5 significantly reduced basal Tpo gene expression and TRH-stimulated Tg and Dio2 gene expression. I.p. administered TP48 reduced only TRH-stimulated expression of the Tg and Dio2 genes. Quite surprisingly, TPY5 (oral) and TP48 (i.p.) reduced basal Tshr gene expression and did not prevent its inhibition by TRH. Thus, the TPY5 compound we developed has the activity of an inverse agonist of the TSH receptor, is effective when administered orally, which is more in demand in medicine, and can be considered as a prototype of drugs to treat autoimmune hyperthyroidism and thyroid tumors.