Agonistic and Antagonistic Effects of Progesterone Derivatives on the Transcriptional Activity of Nuclear Progesterone Receptor B in Yeast Model System

• Published in: Biochemistry (Moscow) Vol. 83; no. 5; pp. 574 - 585
• Main Authors: Michurina, A. O., Polikarpova, A. V., Levina, I. S., Kulikova, L. E., Zavarzin, I. V., Guseva, A. A., Morozov, I. A., Rubtsov, P. M., Smirnova, O. V., Shchelkunova, T. A.
• Format: Journal Article
• Language: English
• Published: Moscow Pleiades Publishing 01.05.2018; Springer; Springer Nature B.V
• Subjects: Antagonists; Baking yeast; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Derivatives; Drug development; Galactosidase; Gene expression; Genes; Gynecology; Hormones; Isoforms; Life Sciences; Ligands; Microbiology; Models, Biological; Modulators; Observations; Physiological aspects; Progesterone; Progesterone - analogs & derivatives; Progesterone - chemistry; Progesterone - pharmacology; Progesterone receptors; Progestin; Receptors; Receptors, Progesterone - agonists; Receptors, Progesterone - antagonists & inhibitors; Receptors, Progesterone - genetics; Reporter gene; Saccharomyces cerevisiae; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Steroid hormones; Steroids; System identification; Transcription; Transcription (Genetics); Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; Uterus; Yeasts; β-Galactosidase; antagonists; reporter gene analysis; agonists; transcriptional activity; progesterone receptors; pentaranes; steroid
• ISSN: 0006-2979; 1608-3040
• DOI: 10.1134/S0006297918050103

Identification of progesterone selective agonists and antagonists that act through one of the nuclear progesterone receptor isoforms is of particular importance for the development of tissue-specific drugs in gynecology and anticancer therapy. Fourteen pregna-D′ 6 - and pregna-D′ 3 -pentarane progesterone derivatives with 16α,17α-cycloalkane groups and two progesterone 3-deoxyderivatives were examined for their ability to regulate transcriptional activity of human nuclear progesterone receptor isoform B (nPR-B) expressed in Saccharomyces cerevisiae yeast. Transcriptional activity of nPR-B was measured from the expression of the β-galactosidase reporter gene with a hormone-responsible element in the promoter. Among the compounds tested, two were full progesterone agonists, four were partial agonists, one compound possessed both agonistic and antagonistic activity, one compound displayed only partial antagonistic activity, and eight compounds did not show any activity. Modifications of the pentarane structure, precisely, introduction of an additional double bound in the A or B rings and/or modification at the 6th position of progesterone, lead to a switch from the complete agonistic activity to partial agonistic or mixed activities. These modifications enable progestins to act as selective modulators of progesterone receptor. Steroids with reduced A-ring and 3-ketogroups lose their ability to regulate PR-B activity. Both 3-deoxycompounds, being selective ligands of progesterone membrane receptors, do not affect PR-B activity.