Development of Low-Molecular-Weight Allosteric Agonist of Thyroid-Stimulating Hormone Receptor with Thyroidogenic Activity

Abstract

To normalize the thyroid status in hypothyroidism caused by resistance to thyroid-stimulating hormone (TSH), low-molecular-weight allosteric agonists of TSH receptor can be used. A new compound ethyl-2-(4-(4-(5-amino-6-(tert-butylcarbamoyl)-2-(methylthio)thieno[2,3-d]-pyrimidine-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) acetate (TPY3m), which stimulated the production of thyroxine when administered to rats (25 mg/kg, i.p.) and also increased the expression of thyroidogenic genes in the cultured FRTL-5 thyrocytes (30 μM) and the rat thyroid gland. The in vitro and in vivo treatment with TPY3m did not lead to a decrease in the expression of the TSH receptor gene in thyrocytes, restoring it under the conditions of receptor hyperactivation by the hormone. This determines the retaining and, in some cases, potentiation of the thyroidogenic effects of TSH (FRTL-5) or thyroliberin (rats) when they are coadministered with TPY3m. TPY3m is a prototype drug for correcting thyroid system functions in subclinical hypothyroidism.

Keywords: allosteric agonist; hypothyroidism; receptor of thyroid-stimulating hormone; thyroid gland; thyroid hormone.

Fig. 1.

Effects of TSH and TPY3m on the expression of thyroglobulin (Tg), Na⁺/I^– cotransporter (Nis), and TSH receptor (TshR) genes in FRTL-5 thyrocyte culture preincubated in TSH-free medium. Designations: TSH, TPY3m, and TPY3m + TSH—cells incubated with TSH (6 mIU/mL), TPY3m (30 µM), and TSH and TPY3m together. Differences with C (^a), with TSH (^b), and between TPY3m and TPY3m+TSH (^c) are statistically significant at p < 0.05. Data are presented as M ± SEM, n = 5.

Fig. 2.

Effects of thyroliberin and TPY3m on the expression of genes encoding thyroidogenic proteins and TSH receptor in rat thyroid gland. Designations: C—control; TRH, TPY3m and TPY3m+TRH—the groups of rats treated with TRH (100 μg/rat, intranasally), TPY3m (25 mg/kg, i.p.) and with TRH + TPY3m. The differences with the control (a) and with the TRH group (b) and between the TPY3m and TPY3m+TRH groups (c) are statistically significant at p < 0.05. M ± SEM, n = 5.