Comparative analysis of steroidogenic effects of thienopyrimidine derivatives and partial agonists for luteinizing hormone receptor

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Abstract

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.

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About the authors

Kira V. Derkach

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: derkatch_k@list.ru
ORCID iD: 0000-0001-6555-9540
SPIN-code: 6925-1558

Cand. Sci. (Biology)

Russian Federation, Saint Petersburg

Viktor N. Sorokoumov

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences; Saint Petersburg State University

Email: sorokoumov@gmail.com
ORCID iD: 0000-0002-4917-2175
SPIN-code: 1042-8142

Cand. Sci. (Chemistry)

Russian Federation, Saint Petersburg; Saint Petersburg

Alexander O. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Author for correspondence.
Email: alex_shpakov@list.ru
ORCID iD: 0000-0002-4293-3162
SPIN-code: 6335-8311

Dr. Sci. (Biology)

Russian Federation, Saint Petersburg

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