Development of Thieno[2,3-d]-pyrimidine-based Positive Allosteric Modulators of Thyroid Stimulating Hormone Receptor and Their Effect on Thyroid Status in Rats

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Abstract Thyroid stimulating hormone (TSH) levels in hypothyroidism, both autoimmune and caused by inactivating mutations in the TSH receptor gene, are either normal or elevated due to increased thyroliberin (TRH)-stimulated TSH production in thyroid hormone (TH) deficiency. Since the main cause of hypothyroidism is an attenuated thyroid response to TSH, it appears reasonable to develop approaches to increasing the sensitivity of thyrocytes to TSH. One of such approaches implies the use of TSH receptor positive allosteric modulators (PAMs), able to enhance TSH effects on TH production. However, such PAMs are currently unavailable. This work was aimed to synthesize the new thieno[2,3-d]-pyrimidine-based derivatives, TPYox and TPYmp, sharing a TSH receptor PAM activity, and to study their effects on basal and TRH-stimulated blood TH levels, as well as the expression of genes involved in TH synthesis, in the rat thyroid. When administered to rats, TPYox and TPYmp (20 mg/kg) had little effect on blood TH levels and the expression of TH synthesis genes, except for an increase in tT3 concentration and the expression of the Dio2 gene encoding type 2 deiodinase when using TPYmp. At the same time, despite no differences versus controls, blood TH levels and the expression of Tg, Tpo, Dio2, and Tshr genes in the TPYox-treated group decreased compared to TPYmp-treated rats, which we assume is due to a high reactivity of the oxirane cycle in the TPYox molecule and the inhibitory effect of this compound on some components of the thyroid system. Rat pretreatment with TPYox and TPYmp preserved the stimulating effects of TRH on TH concentration and thyroid gene expression, while significantly enhancing them in some cases. Meanwhile, the dynamics and severity of TPYox and TPYmp potentiating effects differed, namely TPYox potentiated TRH stimulating effects on blood tT4, fT3, and tT3 levels 1.5 h after TRH treatment, whereas TPYmp enhanced these effects on blood fT3 and tT3 levels 3 h later, when the potentiating effect of TPYox had already faded away. In the thyroid gland, TPYox enhanced TRH-induced Tpo expression, while TPYmp enhanced Dio2 and Nis expression. Thus, it was concluded that the most promising drug for increasing the TSH receptor response to endogenous TSH is TPYmp, 5-amino-N-(tert-butyl)-4-{4-[3-(2-hydroxy-3-morpholinopropoxy)pro-1-yn-1-yl]phenyl}-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxamide, the first functionally active PAM of the TSH receptor.

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