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dc.contributor.authorOdland, Sondre Ulstein
dc.contributor.authorRavna, Aina Westrheim
dc.contributor.authorSmaglyukova, Natalia
dc.contributor.authorDietrichs, Erik Sveberg
dc.contributor.authorSager, Georg
dc.date.accessioned2021-12-07T07:59:58Z
dc.date.available2021-12-07T07:59:58Z
dc.date.issued2021-07-13
dc.description.abstractThe 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 K<sub>i</sub> 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 K<sub>i</sub>-values (μmol/L): TC-08: 0.61, TC-16: 0.66 and TC-15: 9.3. The K<sub>i</sub>-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).en_US
dc.identifier.citationOdland, Ravna, Smaglyukova, Dietrichs, Sager. Inhibition of ABCC5-mediated cGMP transport by progesterone, testosterone and their analogues. Journal of Steroid Biochemistry and Molecular Biology. 2021;213:1-6en_US
dc.identifier.cristinIDFRIDAID 1926621
dc.identifier.doi10.1016/j.jsbmb.2021.105951
dc.identifier.issn0960-0760
dc.identifier.issn1879-1220
dc.identifier.urihttps://hdl.handle.net/10037/23293
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalJournal of Steroid Biochemistry and Molecular Biology
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2021 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700::Clinical medical disciplines: 750::Endocrinology: 774en_US
dc.subjectVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Endokrinologi: 774en_US
dc.titleInhibition of ABCC5-mediated cGMP transport by progesterone, testosterone and their analoguesen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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