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Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay

McRobb, Lucinda; Handelsman, David J; Kazlauskas, Rymantas; Wilkinson, Shane M; McLeod, Malcolm; Heather, Alison K

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The recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of gestrinone has raised concerns about the risks of developing designer androgens from numerous marketed progestins. We therefore have used yeast-based in vitro androgen and progesterone bioassays to conduct a structure-activity study assessing...[Show more]

dc.contributor.authorMcRobb, Lucinda
dc.contributor.authorHandelsman, David J
dc.contributor.authorKazlauskas, Rymantas
dc.contributor.authorWilkinson, Shane M
dc.contributor.authorMcLeod, Malcolm
dc.contributor.authorHeather, Alison K
dc.date.accessioned2015-12-10T22:18:42Z
dc.identifier.issn0960-0760
dc.identifier.urihttp://hdl.handle.net/1885/51524
dc.description.abstractThe recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of gestrinone has raised concerns about the risks of developing designer androgens from numerous marketed progestins. We therefore have used yeast-based in vitro androgen and progesterone bioassays to conduct a structure-activity study assessing the intrinsic androgenic potential of commercially available progestins and their derivatives, to identify those compounds or structures with the highest risk of forming a basis for such misapplication. Progestins had a wide range of androgenic bioactivity that was not reliably predicted for individual steroids by their progestin bioactivity. 17α-Hydroxyprogesterone and 19-norprogesterone derivatives with their bulky 17β-substituents were strong progestins but generally weak androgens. 17α-Ethynylated derivatives of testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone such as gestrinone, ethisterone, norethisterone and norgestrel had the most significant intrinsic androgenicity of all the commercially marketed progestins. Facile chemical modification of the 17α-ethynyl group of each of these progestins produces 17α-methyl, ethyl and allyl derivatives, including THG and norbolethone, which further enhanced androgenic bioactivity. Thus by using the rapid and sensitive yeast bioassay we have screened a comprehensive set of progestins and associated structures and identified the ethynylated testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone derivatives as possessing the highest risk for abuse and potential for conversion to still more potent androgens. By contrast, modern progestins such as progesterone, 17α-hydroxyprogesterone and 19-norprogesterone derivatives had minimal androgenic bioactivity and pose low risk.
dc.publisherPergamon Press
dc.sourceJournal of Steroid Biochemistry and Molecular Biology
dc.subjectKeywords: 18 methyl 19 nortestosterone; 19 norprogesterone derivative; altrenogest; androgen receptor; chlormadinone; cyproterone; cyproterone acetate; delmadinone acetate; ethisterone; ethylestrenol; gestagen; gestrinone; hydroxyflutamide; hydroxyprogesterone; met Androgen; Androgen receptor; Hormone; Progesterone receptor; Progestin; Sports doping; Steroid
dc.titleStructure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume110
dc.date.issued2008
local.identifier.absfor030503 - Organic Chemical Synthesis
local.identifier.absfor030104 - Immunological and Bioassay Methods
local.identifier.ariespublicationu4005981xPUB226
local.type.statusPublished Version
local.contributor.affiliationMcRobb, Lucinda, Heart Research Institute
local.contributor.affiliationHandelsman, David J, ANZAC Research Institute
local.contributor.affiliationKazlauskas, Rymantas, National Measurement Institute
local.contributor.affiliationWilkinson, Shane M, University of Sydney
local.contributor.affiliationMcLeod, Malcolm, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationHeather, Alison K, Heart Research Institute
local.description.embargo2037-12-31
local.bibliographicCitation.issue1-2
local.bibliographicCitation.startpage39
local.bibliographicCitation.lastpage47
local.identifier.doi10.1016/j.jsbmb.2007.10.008
dc.date.updated2015-12-09T08:37:46Z
local.identifier.scopusID2-s2.0-44349161271
local.identifier.thomsonID000257409000005
CollectionsANU Research Publications

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