Inhibition of ABCC5-mediated cGMP transport by progesterone, testosterone and their analogues. Issue 213 (October 2021)

• Record Type: Journal Article
• Authors: Odland, Sondre Ulstein; Ravna, Aina Westrheim; Smaglyukova, Natalia; Dietrichs, Erik Sveberg; Sager, Georg
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 213(2021)
• Publication Date: 2021-10
• Subjects: Progesterone -- Testosterone -- Analogues -- Cyclic GMP -- ABCC5 -- MRP5 -- Transport modulation -- Cellular efflux; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2021.105951
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Progesterone and testosterone were potent inhibitors of ABCC5. Nineteen putative analogues to progesterone and testosterone were identified by virtual ligand screening ( in silico ). Eleven substances were screened in vitro . Six analogues were thoroughly characterized with concentration inhibition studies. Two analogues of each hormone, were more potent than the hormone itself. Abstract: The biodynamics and biokinetics of sex hormones are complex. In addition to the classical steroid receptors (nuclear receptors), these hormones act through several non-genomic mechanisms. Modulation of ABC-transporters by progesterone represents a non-genomic mechanism. In the present study, we employed inside out vesicles from human erythrocytes to characterize high affinity cGMP transport by ABCC5 (member 5 of the ATP-Binding Cassette subfamily C). Progesterone and testosterone inhibited the transport with respective Ki of 1.2 ± 0.3 and 2.0 ± 0.6 μmol/L. We used virtual ligand screening (VLS) to identify analogues to progesterone and testosterone. A large number of substances were screened in silico and the 19 most promising candidates were screened in vitro . Each substance was tested for a concentration of 10 μmol/L. The range of cGMP transport reduction was 21.5% to 86.2% for progesterone analogues and 8.6% to 93.8 % for testosterone analogues. Three of the most potent test compounds (TC) of each analogue class, in addition to progesterone and testosterone, were characterized for concentrations from 1 nanomol/L to 1 mmol/L. The progesterone analogues showed following Ki -values (μmol/L): TC-08: 0.61, TC-16: 0.66 and TC-15: 9.3. The Ki -values (μmol/L) for the testosterone analogues were: TC-18: 0.10, TC-07: 0.67 andTC-05: 2.0. The present study shows that VLS may be a versatile tool in the development of membrane transport modulating agents (MTMAs).