Trimethyltrienolone Explained

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.[1]

Side effects

Due to its close relation to metribolone (methyltrienolone), it is thought that TMT may produce hepatotoxicity.

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. The drug is a derivative of the extremely potent androgen/anabolic steroid metribolone (R-1881; 17α-methyltrenbolone),[2] [3] and has been reported to possess only about 4-fold lower affinity for the AR in comparison.[4] 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.[5] The AR weak partial agonistic activity of TMT is comparable to that of cyproterone acetate.[6]

Relative affinities (%) of TMT and related steroids
Compound
1–3, 1–5 100 <1 <1, 1–5 <1
<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
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the, testosterone for the, for the, for the, and aldosterone for the . Sources: [7] [8] [9] [10]

Chemistry

See also: Steroidal antiandrogen and List of steroidal antiandrogens.

TMT, also known as 2α,2β,17α-trimethyltrienolone[11] or as δ9,11-2α,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.[12] 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.

History

TMT was developed by Roussel Uclaf in France and was first known as early as 1969.[13] [14] It was one of the earliest antiandrogens to be discovered and developed, along with others such as benorterone, BOMT, cyproterone, and cyproterone acetate.[15] [16] [17] [18] [19] 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.[20] Roussel Uclaf subsequently developed and introduced nilutamide for medical use.[21]

Notes and References

  1. Book: Negwer M, Scharnow HG . Organic-chemical drugs and their synonyms: (an international survey). 2001. Wiley-VCH. 978-3-527-30247-5. 2158. 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.
  2. Book: James VH, Pasqualini JR . Proceedings of the Fourth International Congress on Hormonal Steroids: Mexico City, September 1974. 22 October 2013. Elsevier Science. 978-1-4831-4566-2. 618, 620. 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..
  3. Ostgaard K, Wibe E, Eik-Nes KB . Steroid responsiveness of the human cell line NHIK 3025 . Acta Endocrinologica . 97 . 4 . 551–558 . August 1981 . 7270009 . 10.1530/acta.0.0970551 .
  4. Book: Harms AF . Innovative Approaches in Drug Research: Proceedings of the Third Noordwijkerhout Symposium on Medicinal Chemistry, Held in the Netherlands, September 3-6, 1985. 1 January 1986. Elsevier. 978-0-444-42606-2. 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..
  5. Eil C, Douglass EC, Rosenburg SM, Kano-Sueoka T . Receptor characteristics of the rat mammary carcinoma cell line 64-24 . Cancer Research . 41 . 1 . 42–48 . January 1981 . 6256064 .
  6. Raynaud JP, Ojasoo T . The design and use of sex-steroid antagonists . Journal of Steroid Biochemistry . 25 . 5B . 811–833 . November 1986 . 3543501 . 10.1016/0022-4731(86)90313-4 .
  7. Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP . 6 . Steroid hormone receptors and pharmacology . Journal of Steroid Biochemistry . 12 . 143–157 . January 1980 . 7421203 . 10.1016/0022-4731(80)90264-2 .
  8. Ojasoo T, Raynaud JP . Unique steroid congeners for receptor studies . Cancer Research . 38 . 11 Pt 2 . 4186–4198 . November 1978 . 359134 .
  9. Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP . Towards the mapping of the progesterone and androgen receptors . Journal of Steroid Biochemistry . 27 . 1–3 . 255–269 . 1987 . 3695484 . 10.1016/0022-4731(87)90317-7 .
  10. Book: Raynaud JP, Ojasoo T, Bouton MM, Philibert D . Receptor Binding as a Tool in the Development of New Bioactive Steroids . Ariens EJ . Drug Design . 1979. 169–214. New York, Academic Press . 10.1016/B978-0-12-060308-4.50010-X. https://books.google.com/books?id=bhAlBQAAQBAJ&pg=PA169. 9780120603084.
  11. Book: Kohtz AS, Frye CA . Psychiatric Disorders . Dissociating behavioral, autonomic, and neuroendocrine effects of androgen steroids in animal models . 829 . 397–431 . 2012 . 22231829 . 10.1007/978-1-61779-458-2_26 . 978-1-61779-457-5 . Methods in Molecular Biology . 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). .
  12. Book: Brandes D . Male Accessory Sex Organs: Structure and Function in Mammals. 2 December 2012. Elsevier. 978-0-323-14666-1. 323–.
  13. Book: Hughes A, Hasan SH, Oertel GW. Voss HE,Bahner F, Neumann F, Steinbeck H, Gräf KJ, Brotherton J, Horn HJ, Wagner RK. Androgens II and Antiandrogens / Androgene II und Antiandrogene. 27 November 2013. Springer Science & Business Media. 978-3-642-80859-3. 1–.
  14. Baulieu EE, Jung I . A prostatic cytosol receptor . Biochemical and Biophysical Research Communications . 38 . 4 . 599–606 . February 1970 . 5443703 . 10.1016/0006-291X(70)90623-6 .
  15. Azadian-Boulanger G, Bonne C, Secchi J, Raynaud JP . [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 de Pharmacologie . 5 . 4 . 509–520 . 1974 . fr . 12 August 2016 . 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..
  16. Bonne C, Raynaud J . 1974 . Anti-androgenic Activity of R 2956 (17beta-hydroxy-2,2,17alpha-trimethyl-estra-4,9,11-trien-3-one). 2. Mechanism Of Action . Journal de Pharmacologie . 5 . 4. 521–532 .
  17. Book: Inaba M, Inaba Y . Androgenetic Alopecia: Modern Concepts of Pathogenesis and Treatment. 14 March 2013. Springer Science & Business Media. 978-4-431-67038-4. 531–.
  18. Bratoeff E, Ramírez E, Murillo E, Flores G, Cabeza M . Steroidal antiandrogens and 5alpha-reductase inhibitors . Current Medicinal Chemistry . 6 . 12 . 1107–23 . December 1999 . 10519917 . 10.2174/0929867306666220401180500. 248057720 . 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". .
  19. Book: Horsky J, Presl J . Ovarian Function and its Disorders: Diagnosis and Therapy. 6 December 2012. Springer Science & Business Media. 978-94-009-8195-9. 112–.
  20. Raynaud JP, Bonne C, Moguilewsky M, Lefebvre FA, Bélanger A, Labrie F . The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review . The Prostate . 5 . 3 . 299–311 . 1984 . 6374639 . 10.1002/pros.2990050307 . [...] 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. . 85417869 .
  21. Book: William Andrew Publishing. Pharmaceutical Manufacturing Encyclopedia . 3rd . 22 October 2013. Elsevier. 978-0-8155-1856-3. 2935–.

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