Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65168510.31857/S0869813924010078WJZCXEEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleLow molecular inverse agonist of the thyrotropin receptor is active both intraperitoneal and oral administrationНизкомолекулярный инверсионный агонист рецептора тиреотропина активен как при внутрибрюшинном, так и при пероральном введенииDerkachK. V.ДеркачК. В.
Russian Federation
derkatch_k@list.ruBakhtyukovA. A.БахтюковА. А.
Russian Federation
derkatch_k@list.ruSorokoumovV. N.СорокоумовВ. Н.
Russian Federation
derkatch_k@list.ruLebedevI. A.ЛебедевИ. А.
Russian Federation
derkatch_k@list.ruDidenkoE. A.ДиденкоЕ. А.
Russian Federation
derkatch_k@list.ruShpakovA. O.ШпаковА. О.
Russian Federation
derkatch_k@list.ruSechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesИнститут эволюционной физиологии и биохимии им. И.М. Сеченова РАНInstitute of Chemistry, St. Petersburg State UniversityИнститут химии Санкт-Петербургского государственного университета15012024110110812101022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/651685

Autoimmune hyperthyroidism (Graves’ disease), which is caused by stimulating autoantibodies to the thyroid-stimulating hormone (TSH) receptor, and thyroid gland (TG) tumors, caused by constitutively increased activity of this receptor, are widespread and have a poor prognosis. The drugs used to treat them are not very effective and have many side effects. One of the approaches for the treatment of these thyroid diseases may be the use of allosteric regulators of the TSH receptor with the activity of inverse agonists. The purpose of the work was to study the effects of our previously developed compound TP48 and the new compound TPY5, belonging to the class of thieno[2,3-d]-pyrimidines, on the basal and thyrotropin-releasing hormone (TRH)-stimulated levels of thyroid hormones (THs) in the blood of rats and on the expression of genes responsible for the synthesis of THs in the TG. The effectiveness of TP48 and TPY5 was studied both with intraperitoneal (i.p., 20 mg/kg) and oral (40 mg/kg) administration. Using ELISA, the levels of free (fT4) and total (tT4) thyroxine and free (fT3) and total (tT3) triiodothyronine in the blood were assessed, including during TRH stimulation (intranasally, 300 μg/kg). The gene expression for thyroid peroxidase (Tpo), thyroglobulin (Tg), Na+/I–-symporter (Nis), type 2 deiodinase (Dio2) and TSH receptor (Tshr) in the TG was assessed using PCR. TPY5, with both routes of administration, reduced both basal and TRH-stimulated TH levels, while TP48 suppressed TH production only with i.p. administration. Orally administered TPY5 significantly reduced basal Tpo gene expression and TRH-stimulated Tg and Dio2 gene expression. I.p. administered TP48 reduced only TRH-stimulated expression of the Tg and Dio2 genes. Quite surprisingly, TPY5 (oral) and TP48 (i.p.) reduced basal Tshr gene expression and did not prevent its inhibition by TRH. Thus, the TPY5 compound we developed has the activity of an inverse agonist of the TSH receptor, is effective when administered orally, which is more in demand in medicine, and can be considered as a prototype of drugs to treat autoimmune hyperthyroidism and thyroid tumors.

Аутоиммунный гипертиреоз (болезнь Грейвса), причиной которого являются стимулирующие аутоантитела к рецептору тиреотропного гормона (ТТГ), и опухоли щитовидной железы, обусловленные конститутивно повышенной активностью этого рецептора, имеют широкое распространение и неблагоприятный прогноз. Препараты, используемые для их лечения, малоэффективны и имеют множество побочных эффектов. Одним из подходов для лечения этих заболеваний может стать применение аллостерических регуляторов рецептора ТТГ с активностью инверсионных агонистов. Цель работы состояла в изучении эффектов ранее разработанного нами соединения TP48 и нового соединения TPY5, относящихся к классу тиено[2,3-d]-пиримидинов, на базальные и стимулированные тиролиберином (TRH) уровни тиреоидных гормонов (ТГ) в крови крыс и на экспрессию генов, ответственных за синтез ТГ в щитовидной железе. Эффективность TP48 и TPY5 изучали как при внутрибрюшинном (в/б, 20 мг/кг), так и при пероральном (40 мг/кг) введении. С помощью иммуноферментного анализа оценивали уровни свободного (fT4) и общего (tT4) тироксина и свободного (fT3) и общего (tT3) трийодтиронина в крови, в том числе при стимуляции TRH (интраназально, 300 мкг/кг), с помощью ПЦР – экспрессию генов тиреопероксидазы (Tpo), тиреоглобулина (Tg), Na+/I–-симпортера (Nis), дейодиназы 2-го типа (Dio2) и рецептора ТТГ (Tshr) в щитовидной железе. TPY5 при обоих способах введения снижал как базальные, так и стимулированные TRH уровни ТГ, в то время как TP48 подавлял продукцию ТГ только при в/б введении. Перорально вводимый TPY5 в значительной степени снижал базальную экспрессию гена Tpo и TRH-стимулированную экспрессию генов Tg и Dio2. Внутрибрюшинно вводимый TP48 снижал только TRH-стимулированную экспрессию генов Tg и Dio2. Достаточно неожиданно, что TPY5 (перорально) и TP48 (в/б) снижали базальную экспрессию гена Tshr и не предотвращали ее ингибирование, вызываемое TRH. Тем самым разработанное нами соединение TPY5 наделено активностью инверсионного агониста рецептора ТТГ, эффективно при пероральном способе доставки, который в большей степени востребован в медицине, и может рассматриваться как прототип фармакологических препаратов для лечения аутоиммунного гипертиреоза и опухолей щитовидной железы.

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