Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay.
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 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. 17alpha-Hydroxyprogesterone and 19-norprogesterone derivatives with their bulky 17beta-substituents were strong progestins but generally weak androgens. 17alpha-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 17alpha-ethynyl group of each of these progestins produces 17alpha-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, 17alpha-hydroxyprogesterone and 19-norprogesterone derivatives had minimal androgenic bioactivity and pose low risk.
McRobb
L
L
Heart Research Institute, Sydney, NSW 2050, Australia.
Handelsman
D J
DJ
Kazlauskas
R
R
Wilkinson
S
S
McLeod
M D
MD
Heather
A K
AK
D000728:Androgens / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001681:Biological Assay / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005003:Ethisterone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005867:Gestrinone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D009640:Norethindrone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009644:Norgestrel / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009652:Norpregnenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009653:Norprogesterones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011372:Progestins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000187:drug effects / Q000378:metabolism*
D000728:Androgens; D009652:Norpregnenes; D009653:Norprogesterones; D011372:Progestins; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D005867:Gestrinone; C030703:19-norprogesterone; D009644:Norgestrel; D005003:Ethisterone; D009640:Norethindrone; C103408:norbolethone