Laboratory of Molecular Endocrinology and Neurochemistry, I. M. Se-chenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
Bull Exp Biol Med. 2022 Apr;172(6):713-717. doi: 10.1007/s10517-022-05462-x. Epub 2022 May 2.
The development of low-molecular-weight antagonists of thyroid-stimulating hormone (TSH) receptor is a promising trend in the treatment of autoimmune hyperthyroidism. We studied the effect of thieno[2,3-d]-pyrimidine derivative TPY1 on TSH-stimulated synthesis of thyroid hormones in the culture of FRTL-5 thyrocytes and on thyroliberin-stimulated production of thyroid hormones in rat blood. Preincubation of FRTL-5 cells with TPY1 suppressed the stimulatory effect of TSH on the synthesis of thyroxine and triiodothyronine. Intraperitoneal injection of TPY1 in a dose of 25 mg/kg reduced thyroliberin-stimulated levels of thyroid hormones in the blood and inhibited the expression of genes encoding thyroid peroxidase, thyroglobulin, and Na/I- cotransporter responsible for thyroxine synthesis. In the absence of thyroliberin stimulation, TPY1 did not affect the levels of thyroid hormones and expression of thyroidogenesis genes. Thus, a new TPY1 antagonist of TSH receptor can be a prototype of a drug for the treatment of autoimmune hyperthyroidism.
甲状腺刺激激素（TSH）受体的小分子拮抗剂的开发是治疗自身免疫性甲状腺功能亢进症的一个有前途的趋势。我们研究了噻吩并[2,3-d]嘧啶衍生物 TPY1 对 FRTL-5 甲状腺细胞培养中 TSH 刺激甲状腺激素合成的影响，以及对大鼠血液中促甲状腺素释放激素刺激甲状腺激素产生的影响。TPY1 对 FRTL-5 细胞的预孵育抑制了 TSH 对甲状腺素和三碘甲状腺原氨酸合成的刺激作用。以 25mg/kg 的剂量腹腔注射 TPY1 可降低促甲状腺素释放激素刺激的血液中甲状腺激素水平，并抑制编码甲状腺过氧化物酶、甲状腺球蛋白和负责甲状腺素合成的 Na+/I-共转运体的基因表达。在没有促甲状腺素释放激素刺激的情况下，TPY1 不影响甲状腺激素水平和甲状腺生成基因的表达。因此，新型 TSH 受体 TPY1 拮抗剂可能成为治疗自身免疫性甲状腺功能亢进症的药物原型。
