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.

Thyroid-Stimulating Hormone Receptor: the Role in the Development of Thyroid Pathology and Its Correction

“…The thienopyrimidine derivatives with an activity of TSHR agonists and inverse antagonists, we created in our laboratory, also did not affect the activity of the LH receptor, both in vitro and in vivo [11,52,58,59]. At the same time, in terms of hydrophobicity, they significantly exceeded the corresponding derivatives with an activity of LH receptor agonists and had a smaller volume of side radicals, which completely matched the structural characteristics of the TSHR allosteric site [11,59].…”

“…For example, a relatively hydrophobic compound S37 with an activity of a TSHR allosteric inverse agonist, devel oped in 2019 and having a rigid framework struc ture, suppresses TSHR stimulation both by the hormone and by stimulatory antibodies, but does not affect the functional activity of LH and FSH receptors [57]. The thienopyrimidine derivatives with an activity of TSHR agonists and inverse antagonists, we created in our laboratory, also did not affect the activity of the LH receptor, both in vitro and in vivo [11,52,58,59]. At the same time, in terms of hydrophobicity, they significantly exceeded the corresponding derivatives with an activity of LH receptor agonists and had a smaller volume of side radicals, which completely matched the structural characteristics of the TSHR allosteric site [11,59].…”

“…The development of selective agonists of thy roid hormone receptors [10] and allosteric ago nists of the TSHR are promising approaches that can become an alternative to the existing thera peutic standard [11]. The mechanism of action of thyroid hormone receptor agonists consists in their specific binding to the β isoform of these receptors, which results in the potentiation of physiological effects of the thyroid hormones thy roxine and triiodothyronine.…”

“…Compound ethyl 2 (4 (4 (5 amino 6 (tert butylcarbamoyl) 2 (methylthio)thieno[2,3 d] pyrimidin 4 yl)phenyl) 1H 1,2,3 triazol 1 yl) acetate (TPY3m) demonstrated the activity of a full TSHR agonist, which increases the expression of genes involved in the synthesis of thyroid hor mones [11]. When administered to male rats (15 mg/kg, i.p.…”

Thyroid diseases and new approaches for their treatment

“…Нами разработаны препараты, являющиеся производными тиено[2,3-d]-пиримидина, которые способны в условиях in vitro при действии на культуру тироцитов крысы FRTL-5 повышать экспрессию генов, вовлеченных в синтез тиреоидных гормонов. В условиях in vivo при введении крысам данные препараты повышают у них уровень тиреоидных гормонов в крови, а также усиливают экспрессию тиреопероксидазы и дейодиназы 2-го типа в ткани ЩЖ, как это продемонстрировано для наиболее активного из них -соединения TPY3m [54]. Важно, что производные тиено [2,3-d]-пиримидина сохраняют свою активность не только при внутрибрюшинном, но и при пероральном введении, что делает их прототипами препаратов для стимуляции тиреоидогенеза.…”