Reviews on Clinical Pharmacology and Drug TherapyReviews on Clinical Pharmacology and Drug TherapyОбзоры по клинической фармакологии и лекарственной терапии1683-41002542-1875Eco-Vector63592410.17816/RCF635924YJIEMOOriginal study articlesОригинальные исследованияResearch ArticleComparative analysis of steroidogenic effects of thienopyrimidine derivatives and partial agonists for luteinizing hormone receptorСравнительный анализ стероидогенных эффектов тиенопиримидиновых производных с активностью частичных агонистов рецептора лютеинизирующего гормонаhttps://orcid.org/0000-0001-6555-95406925-1558DerkachKira V.ДеркачКира Викторовна
Russian Federation

Cand. Sci. (Biology)

канд. биол. наук

derkatch_k@list.ruhttps://orcid.org/0000-0002-4917-21751042-8142SorokoumovViktor N.СорокоумовВиктор Николаевич
Russian Federation

Cand. Sci. (Chemistry)

канд. хим. наук

sorokoumov@gmail.comhttps://orcid.org/0000-0002-4293-31626335-8311ShpakovAlexander O.ШпаковАлександр Олегович
Russian Federation

Dr. Sci. (Biology)

д-р биол. наук

alex_shpakov@list.ruSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of SciencesИнститут эволюционной физиологии и биохимии им. И.М. Сеченова Российской академии наукSaint Petersburg State UniversityСанкт-Петербургский государственный университет281120242004202523159691109202428112024Copyright ©; 2025, Eco-VectorCopyright ©; 2025, Эко-Вектор2025Eco-VectorЭко-Векторhttps://journals.eco-vector.com/RCF/article/view/635924

Background: Luteinizing hormone and human chorionic gonadotropin are widely used in medicine for the treatment of reproductive disorders. However, these hormones are associated with numerous adverse effects. Therefore, low-molecular-weight allosteric luteinizing hormone receptor agonists are currently being developed, with the most active compounds being thieno[2,3-d]pyrimidine derivatives.

Aim: To investigate the stimulatory effects of the synthetic compound TP03 on the activity of membrane adenylate cyclase in vitro and on testicular and ovarian steroidogenesis in vivo as compared to those of Org43553, considered the gold standard among low-molecular-weight luteinizing hormone receptor agonists.

Methods: The effects of TP03 and Org43553 (10–8–10–3 M) on the basal and human chorionic gonadotropin-stimulated (10–9 M) adenylate cyclase activity in membrane fractions isolated from rat testes and ovaries were evaluated in vitro using [α-32P]-adenosine triphosphate. Furthermore, the in vivo experiments investigated the effects of TP03 and Org43553 (two intraperitoneal doses, 10 and 20 mg/kg) on blood testosterone levels of male rats and blood progesterone levels of immature female rats previously stimulated with Follimag®, and the effects of co-administration of TP03 or Org43553 (10 mg/kg, intraperitoneal) with human chorionic gonadotropin (10 IU/rat, subcutaneous) on testosterone levels of male rats. Testosterone and progesterone levels were determined by enzyme immunoassay.

Results: TP03 proved comparable to Org43553 in its ability to stimulate adenylate cyclase in testicular and ovarian membranes of rats. When administered to male rats, TP03 demonstrated a dose-dependent stimulation of testosterone synthesis. Similarly, TP03 increased progesterone levels in immature female rats, showing comparable efficacy to Org43553. The co-administration of low doses of TP03 and human chorionic gonadotropin to male rats has been observed to produce an additive effect on testosterone levels, with this effect being more significant than that observed with a combination of Org43553 and human chorionic gonadotropin.

Conclusion: TP03, developed by the authors, has been shown to have a comparable ability to stimulate testicular and ovarian steroidogenesis as Org43553. Furthermore, it has been demonstrated to have an additive effect in combination with human chorionic gonadotropin, suggesting its potential for enhancing the effectiveness of gonadotropin therapy.

Обоснование. Препараты лютеинизирующего гормона и хорионического гонадотропина человека (ХГЧ) широко используются в медицине для коррекции репродуктивных расстройств, но характеризуются множеством побочных эффектов. В связи с этим осуществляется разработка низкомолекулярных аллостерических агонистов рецептора лютеинизирующего гормона, наиболее активными среди которых являются тиено[2,3-d]пиримидиновые производные.

Цель — изучить стимулирующие эффекты разработанного нами соединения TP03 на активность мембранной аденилатциклазы in vitro и на тестикулярный и овариальный стероидогенез in vivo в сравнении с таковыми Org43553, являющегося золотым стандартом низкомолекулярных агонистов рецептора лютеинизирующего гормона.

Материалы и методы. В условиях in vitro с применением [α-32P]-АТФ оценивали эффекты TP03 и Org43553 (10–8–10–3 М) на базовую и стимулированную ХГЧ (10–9 М) активность аденилатциклазы во фракциях мембран, выделенных из семенников и яичников крыс. В условиях in vivo оценивали эффекты TP03 и Org43553 (в двух дозах — 10 и 20 мг/кг, внутрибрюшинно) на уровень тестостерона в крови самцов крыс и на уровень прогестерона в крови неполовозрелых самок крыс, предварительно стимулированных препаратом Фоллимаг®, а также влияние совместного введения TP03 или Org43553 (10 мг/кг, внутрибрюшинно) с ХГЧ (10 МЕ/крыса, подкожно) на уровень тестостерона у самцов крыс. Уровни тестостерона и прогестерона определяли с помощью иммуноферментного анализа.

Результаты. Соединение TP03 было сопоставимым с Org43553 по способности стимулировать аденилатциклазу в тестикулярных и овариальных мембранах крыс. При введении самцам крыс оно дозозависимо стимулировало продукцию тестостерона, а при введении неполовозрелым самкам крыс повышало у них уровень прогестерона, не уступая по этим показателям Org43553. При совместном введении сравнительно низких доз TP03 и ХГЧ самцам крыс отмечали аддитивность их стимулирующих эффектов на уровень тестостерона, причем аддитивность была в большей степени выражена, чем в случае комбинации Org43553 и ХГЧ.

Заключение. Разработанное нами соединение TP03 по способности стимулировать тестикулярный и овариальный стероидогенез сопоставимо с соединением Org43553 и, наряду с этим, демонстрирует аддитивность при совместном применении с ХГЧ, что указывает на перспективы его использования для повышения эффективности гонадотропиновой терапии.

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