Trimethyltrienolone

{{Short description|Chemical compound}} {{Infobox drug | Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = (8''R'',13''S'',14''S'',17''R'')-17-hydroxy-2,2,13,17-tetramethyl-6,7,8,14,15,16-hexahydro-1''H''-cyclopenta[''a'']phenanthren-3-one | image = R-2956.svg | image_class = skin-invert-image | width = 225px

| C=21 | H=28 | O=2 | SMILES = CC1(CC2=C3C=CC4(C(C3CCC2=CC1=O)CCC4(C)O)C)C | StdInChI_Ref = | StdInChI = 1S/C21H28O2/c1-19(2)12-16-13(11-18(19)22)5-6-15-14(16)7-9-20(3)17(15)8-10-21(20,4)23/h7,9,11,15,17,23H,5-6,8,10,12H2,1-4H3/t15-,17-,20-,21+/m0/s1 | StdInChIKey_Ref = | StdInChIKey = VFKZTCQVCJGPGF-STRKUORWSA-N }}

'''Trimethyltrienolone''' ('''TMT'''), also known by its developmental code name '''R-2956''' or '''RU-2956''', is an antiandrogen medication which was never introduced for medical use but has been used in scientific research.<ref name="RaynaudBonne1984" /><ref name="NegwerScharnow2001">{{cite book| vauthors = Negwer M, Scharnow HG |title=Organic-chemical drugs and their synonyms: (an international survey)|url=https://books.google.com/books?id=zmpqAAAAMAAJ|year=2001|publisher=Wiley-VCH|isbn=978-3-527-30247-5|page=2158|quote=10635 (8596) C21H28O2 23983-19-9 17β-Hydroxy-2,2,17-trimethylestra-4,9,11-trien-3-one : (17β)-17-Hydroxy-2,2,17-trimethylestra-4,9,11-trien-3-one (•) S R 2956 U Anti-androgen}}</ref><ref name="HughesHasan2013" />

==Side effects== Due to its close relation to metribolone (methyltrienolone), it is thought that TMT may produce hepatotoxicity.<ref name="pmid3543501" />

==Pharmacology==

===Pharmacodynamics=== TMT is a selective and highly potent competitive antagonist of the androgen receptor (AR) with very low intrinsic/partial androgenic activity and no estrogenic, antiestrogenic, progestogenic, or antimineralocorticoid activity.<ref name="Azadian-BoulangerBonne1974" /><ref name="JamesPasqualini2013" /> The drug is a derivative of the extremely potent androgen/anabolic steroid metribolone (R-1881; 17α-methyltrenbolone),<ref name="JamesPasqualini2013">{{cite book| vauthors = James VH, Pasqualini JR |title=Proceedings of the Fourth International Congress on Hormonal Steroids: Mexico City, September 1974|url=https://books.google.com/books?id=Iq0aAwAAQBAJ&pg=PA620|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4831-4566-2|pages=618, 620|quote=R-2956 [41-43], a dimethyl derivative of an extremely potent androgen, R 1881 [44], is a powerful testosterone antagonist with very low androgenic activity.}}</ref><ref name="OstgaardWibe1981">{{cite journal | vauthors = Ostgaard K, Wibe E, Eik-Nes KB | title = Steroid responsiveness of the human cell line NHIK 3025 | journal = Acta Endocrinologica | volume = 97 | issue = 4 | pages = 551–558 | date = August 1981 | pmid = 7270009 | doi = 10.1530/acta.0.0970551 }}</ref> and has been reported to possess only about 4-fold lower affinity for the AR in comparison.<ref name="Harms1986">{{cite book| vauthors = Harms AF |title=Innovative Approaches in Drug Research: Proceedings of the Third Noordwijkerhout Symposium on Medicinal Chemistry, Held in the Netherlands, September 3-6, 1985|url=https://books.google.com/books?id=PwhtAAAAMAAJ|date=1 January 1986|publisher=Elsevier|isbn=978-0-444-42606-2|quote=At this stage, RU 2956 exerts a competitive effect about 4 times less marked than metribolone may be because the steric hindrance of the dimethyl group in position C-2 interferes with H-bond formation between the C-3 oxygen and the receptor protein, i.e., with the recognition step, and consequently, with the association rate.}}</ref> In accordance, it has relatively high affinity for the AR among steroidal antiandrogens, and almost completely inhibits dihydrotestosterone (DHT) binding to the AR ''in vitro'' at a mere 10-fold molar excess.<ref name="pmid6256064">{{cite journal | vauthors = Eil C, Douglass EC, Rosenburg SM, Kano-Sueoka T | title = Receptor characteristics of the rat mammary carcinoma cell line 64-24 | journal = Cancer Research | volume = 41 | issue = 1 | pages = 42–48 | date = January 1981 | pmid = 6256064 }}</ref> The AR weak partial agonistic activity of TMT is comparable to that of cyproterone acetate.<ref name="pmid3543501">{{cite journal | vauthors = Raynaud JP, Ojasoo T | title = The design and use of sex-steroid antagonists | journal = Journal of Steroid Biochemistry | volume = 25 | issue = 5B | pages = 811–833 | date = November 1986 | pmid = 3543501 | doi = 10.1016/0022-4731(86)90313-4 }}</ref>

{| class="wikitable mw-collapsible mw-collapsed" style="text-align:left; margin-left:auto; margin-right:auto; border:none;" |+ class="nowrap" | Relative affinities (%) of TMT and related steroids |- ! Compound || {{abbrlink|PR|Progesterone receptor}} || {{abbrlink|AR|Androgen receptor}} || {{abbrlink|ER|Estrogen receptor}} || {{abbrlink|GR|Glucocorticoid receptor}} || {{abbrlink|MR|Mineralocorticoid receptor}} |- | Testosterone || 1–3, 1–5 || 100 || <1 || <1, 1–5 || <1 |- | 5α-Dihydrotestosterone || <1, 1–3 || 100–125 || <1 || <1 || <1 |- | Metribolone (RU-1881) || 200–300, 250–600 || 200–300, 250–600 || <1 || 25–50 || 15–25 |- | Trimethyltrienolone (RU-2956) || ≤1 || 14 || <1 || <1 || <1 |- class="sortbottom" | colspan="6" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' Values are percentages (%). Reference ligands (100%) were progesterone for the {{abbrlink|PR|progesterone receptor}}, testosterone for the {{abbrlink|AR|androgen receptor}}, {{abbr|E2|estradiol}} for the {{abbrlink|ER|estrogen receptor}}, {{abbrlink|DEXA|dexamethasone}} for the {{abbrlink|GR|glucocorticoid receptor}}, and aldosterone for the {{abbrlink|MR|mineralocorticoid receptor}}. '''Sources:''' <ref name="pmid7421203">{{cite journal | vauthors = Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP | display-authors = 6 | title = Steroid hormone receptors and pharmacology | journal = Journal of Steroid Biochemistry | volume = 12 | pages = 143–157 | date = January 1980 | pmid = 7421203 | doi = 10.1016/0022-4731(80)90264-2 }}</ref><ref name="pmid359134">{{cite journal | vauthors = Ojasoo T, Raynaud JP | title = Unique steroid congeners for receptor studies | journal = Cancer Research | volume = 38 | issue = 11 Pt 2 | pages = 4186–4198 | date = November 1978 | pmid = 359134 | url = http://cancerres.aacrjournals.org/content/38/11_Part_2/4186.short }}</ref><ref name="pmid3695484">{{cite journal | vauthors = Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP | title = Towards the mapping of the progesterone and androgen receptors | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 1–3 | pages = 255–269 | date = 1987 | pmid = 3695484 | doi = 10.1016/0022-4731(87)90317-7 }}</ref><ref name="RaynaudOjasoo1979">{{cite book| vauthors = Raynaud JP, Ojasoo T, Bouton MM, Philibert D |chapter=Receptor Binding as a Tool in the Development of New Bioactive Steroids | veditors = Ariens EJ | title = Drug Design |year=1979|pages=[https://archive.org/details/drugdesign0004unse/page/169 169–214]|publisher=New York, Academic Press |doi=10.1016/B978-0-12-060308-4.50010-X|chapter-url=https://books.google.com/books?id=bhAlBQAAQBAJ&pg=PA169|isbn=9780120603084|url=https://archive.org/details/drugdesign0004unse/page/169}}</ref><ref name="JamesPasqualini2013" /> |}

==Chemistry== {{See also|Steroidal antiandrogen|List of steroidal antiandrogens}}

TMT, also known as 2α,2β,17α-trimethyltrienolone<ref name="KohtzFrye2012">{{cite book | vauthors = Kohtz AS, Frye CA | title = Psychiatric Disorders | chapter = Dissociating behavioral, autonomic, and neuroendocrine effects of androgen steroids in animal models | volume = 829 | pages = 397–431 | year = 2012 | pmid = 22231829 | doi = 10.1007/978-1-61779-458-2_26 | isbn = 978-1-61779-457-5 | series = Methods in Molecular Biology | quote = Administration of steroidal, blocking agents such as spironolactone, cyproterone acetate, or trimethyltrienolone, or nonsteroidal, such as flutamide, bicalutamide, blocking agents, can attain this result (169–171). }}</ref> or as δ<sup>9,11</sup>-2α,2β,17α-trimethyl-19-nortestosterone, as well as 2α,2β,17α-trimethylestra-4,9,11-trien-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone and 19-nortestosterone.<ref name="Azadian-BoulangerBonne1974" /><ref name="Brandes2012">{{cite book| vauthors = Brandes D |title=Male Accessory Sex Organs: Structure and Function in Mammals|url=https://books.google.com/books?id=TPfM6mwJozYC&pg=PA323|date=2 December 2012|publisher=Elsevier|isbn=978-0-323-14666-1|pages=323–}}</ref><ref name="NegwerScharnow2001" /> It is the 2α,2β,17α-trimethyl derivative of trenbolone (trienolone) and the 2α,2β-dimethyl derivative of metribolone (methyltrienolone), both of which are synthetic androgens/anabolic steroids.<ref name="Brandes2012" />

==History== TMT was developed by Roussel Uclaf in France and was first known as early as 1969.<ref name="HughesHasan2013">{{cite book|vauthors = Hughes A, Hasan SH, Oertel GW|veditors = Voss HE, Bahner F, Neumann F, Steinbeck H, Gräf KJ, Brotherton J, Horn HJ, Wagner RK|title=Androgens II and Antiandrogens / Androgene II und Antiandrogene|url=https://books.google.com/books?id=7JPsCAAAQBAJ&pg=PA1|date=27 November 2013|publisher=Springer Science & Business Media|isbn=978-3-642-80859-3|pages=1–}}</ref><ref name="pmid5443703">{{cite journal | vauthors = Baulieu EE, Jung I | title = A prostatic cytosol receptor | journal = Biochemical and Biophysical Research Communications | volume = 38 | issue = 4 | pages = 599–606 | date = February 1970 | pmid = 5443703 | doi = 10.1016/0006-291X(70)90623-6 | bibcode = 1970BBRC...38..599B }}</ref><ref name="Brandes2012" /> It was one of the earliest antiandrogens to be discovered and developed, along with others such as benorterone, BOMT, cyproterone, and cyproterone acetate.<ref name="Azadian-BoulangerBonne1974">{{cite journal | vauthors = Azadian-Boulanger G, Bonne C, Secchi J, Raynaud JP | title = [17beta-hydroxy-2,2,17-trimethyl-estra-4, 9,11-trien-3-one). 1. Profil endocrinien. (Antiandrogenic activity of R2956 (17beta-hydroxy-2,2,17-trimethyl-estra-4,9,11-trien-3-one). 1. Endocrine profile)] Activite anti-androgene du R 2956 | journal = Journal de Pharmacologie | volume = 5 | issue = 4 | pages = 509–520 | year = 1974 | language = fr | url = http://www.popline.org/node/494155 | access-date = 12 August 2016 | quote = R 2956 (17beta-hydroxy-2,2,17-trimethyl-estra-4,9,11-trien-3-one) was tested for antiandrogenic activity in rats (Dorfman test); in dogs; for androgenic activity in female rats (Hershberger); in male rats; for progestagenic activity in rabbits (Clauberg); for uterotrophic activity in mice (Rubin); and for antiestrogenic activity in mice (Dorfman). R 2956 significantly antagonized the hypertrophic effect of .05 mg testosterone propionate on rat seminal vesicles and ventral prostate in proportion to dose from .4-5 mg/day orally. In dogs R 2956 lowered prostate epithelial hyperplasia induced by androstanolone. R 2956 had no androgenic, estrogenic, progestational, or antiestrogenic activities and inhibited development of corpora lutea to an extent comparable with that of norethindrone.}}</ref><ref name="BonneRaynaud1974">{{cite journal | vauthors = Bonne C, Raynaud J | year = 1974 | title = Anti-androgenic Activity of R 2956 (17beta-hydroxy-2,2,17alpha-trimethyl-estra-4,9,11-trien-3-one). 2. Mechanism Of Action | journal = Journal de Pharmacologie | volume = 5 | issue = 4| pages = 521–532 }}</ref><ref name="InabaInaba2013">{{cite book| vauthors = Inaba M, Inaba Y |title=Androgenetic Alopecia: Modern Concepts of Pathogenesis and Treatment|url=https://books.google.com/books?id=RX7dBgAAQBAJ&pg=PT531|date=14 March 2013|publisher=Springer Science & Business Media|isbn=978-4-431-67038-4|pages=531–}}</ref><ref name="Bratoeff_1999">{{cite journal | vauthors = Bratoeff E, Ramírez E, Murillo E, Flores G, Cabeza M | title = Steroidal antiandrogens and 5alpha-reductase inhibitors | journal = Current Medicinal Chemistry | volume = 6 | issue = 12 | pages = 1107–23 | date = December 1999 | pmid = 10519917 | doi = 10.2174/0929867306666220401180500| s2cid = 248057720 |quote=Several androstane derivatives have also demonstrated an antiandrogenic activity; 17a-methyl-B-nortestosterone 8 was prepared and tested in 1964 for antihormonal activity [43]. Within the next decade, several other androstane analogs were prepared and found to possess antiandrogenic activity [43, 44, 45, 46] including BOMT 9 "figure 2", R2956 10, SC9420 11, and oxendolone 12 "figure 3". }}</ref><ref name="HorskyPresl2012">{{cite book| vauthors = Horsky J, Presl J |title=Ovarian Function and its Disorders: Diagnosis and Therapy|url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA112|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9|pages=112–}}</ref> The drug was under investigation by Roussel Uclaf for potential medical use, but was abandoned in favor of nonsteroidal antiandrogens like flutamide and nilutamide due to their comparative advantage of a complete lack of androgenicity.<ref name="RaynaudBonne1984">{{cite journal | vauthors = Raynaud JP, Bonne C, Moguilewsky M, Lefebvre FA, Bélanger A, Labrie F | title = The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review | journal = The Prostate | volume = 5 | issue = 3 | pages = 299–311 | year = 1984 | pmid = 6374639 | doi = 10.1002/pros.2990050307 | quote = [...] flutamide but we soon abandoned the development of steroid derivatives such as RU 2956 because of inherent androgenicity [17], and focused on the nonsteroidal antiandrogens. | s2cid = 85417869 }}</ref> Roussel Uclaf subsequently developed and introduced nilutamide for medical use.<ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia | edition = 3rd |url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA2935-IA22|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=2935–}}</ref>

== References == {{Reflist}}

Category:Abandoned drugs Category:Tertiary alcohols Category:Estranes Category:Hepatotoxins Category:Ketones Category:Steroidal antiandrogens