Thyroid stimulating hormone (TSH) receptor antagonists are required for the treatment of TSH-dependent tumors and Graves disease. We developed the compound 5-amino-N-(tert-butyl)-4-(4-iodophenyl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxamide (TP48) and showed that it reduces the TSH-stimulated adenylate cyclase activity in rat thyroid membranes. Pretreatment of rats with compound TP48 (ip, 40 mg/kg) reduced the increase in the levels of total and free thyroxin in blood and the increase in the expression of thyroglobulin and D2 deiodinase genes in the thyroid gland, which are responsible for the synthesis of thyroid hormones, which were caused by intranasal administration of thyroliberin to animals (300 μg/kg). These data indicate that compound TP48 is a functional antagonist of the TSH receptor and can be used to correct the thyroid status in hyperthyroidism.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Rowe, C.W., Paul, J.W., Gedye, C., et al., Endocr. Relat. Cancer, 2017, vol. 24, pp. R191–R202. https://doi.org/10.1530/ERC-17-0010
Rapoport, B. and McLachlan, S.M., Thyroid, 2007, vol. 17, pp. 911–922.
Neumann, S. and Gershengorn, M.C., Ann. Endocrinol. (Paris), 2011, vol. 72, pp. 74–76. https://doi.org/10.1016/j.ando.2011.03.002
Nunez, MiguelR. Sanders, J., et al., Auto Immun. Highlights, 2017, vol. 8, p. 2. https://doi.org/10.1007/s13317-016-0090-1
Marcinkowski, P., Hoyer, I., Specker, E., et al., Thyroid, 2019, vol. 29, pp. 111–123. https://doi.org/10.1089/thy.2018.0349
Kleinau, G., Worth, C.L., Kreuchwig, A., et al., Front. Endocrinol. (Lausanne), 2017, vol. 8, p. 86. https://doi.org/10.3389/fendo.2017.00086
van Koppen, C.J., Zaman, G.J., Timmers, C.M., et al., Naunyn Schmiedebergs Arch. Pharmacol., 2008, vol. 378, pp. 503–514. https://doi.org/10.1007/s00210-008-0318-3
Nataraja, S.G., Yu, H.N., and Palmer, S.S., Front. Endocrinol. (Lausanne), 2015, vol. 6, p. 142. https://doi.org/10.3389/fendo.2015.00142
Derkach, K.V., Dar’in, D.V., Bakhtyukov, A.A., et al., Biochemistry (Moscow)Suppl. Ser. A: Memb. Cell. Biol., 2016, vol. 10, pp. 294–300. https://doi.org/10.1134/S1990747816030132
Hoyer, I., Haas, A.K., Kreuchwig, A., et al., Biochem. Soc. Trans., 2013, vol. 41, pp. 213–217. https://doi.org/10.1042/BST20120319
Neumann, S., Kleinau, G., Costanzi, S., et al., Endocrinology, 2008, vol. 149, pp. 5945–5950. https://doi.org/10.1210/en.2008-0836
Shpakov, A.O., Shpakova, E.A., Tarasenko, I.I., et al., Cell Tissue Biol., 2014, vol. 8, pp. 488–498. https://doi.org/10.1134/S1990519X1406008X
Derkach, K.V., Bogush, I.V., Berstein, L.M., et al., Horm. Metab. Res., 2015, vol. 47, pp. 916–924. https://doi.org/10.1055/s-0035-1547236
Carvalho, D.P. and Dupuy, C., Mol. Cell. Endocrinol., 2017, vol. 458, pp. 6–15. https://doi.org/10.1016/j.mce.2017.01.038
This work was supported by the Russian Science Foundation (no. 19-75-20122). The NMR and mass spectrometric studies were carried out using the resource centers of St. Petersburg State University “Magnetic resonance research methods” and “Methods of analysis of the composition of the substance.”
COMPLIANCE WITH ETHICAL STANDARDS
Statement on the welfare of animals. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
About this article
Cite this article
Derkach, K.V., Bakhtyukov, A.A., Sorokoumov, V.N. et al. New Thieno-[2,3-d]pyrimidine-Based Functional Antagonist for the Receptor of Thyroid Stimulating Hormone. Dokl Biochem Biophys 491, 77–80 (2020). https://doi.org/10.1134/S1607672920020064
- thyroid stimulating hormone receptor, antagonist, thienopyrimidine, thyroid gland