Trimethyltrienolone

Last updated
Trimethyltrienolone
R-2956.svg
Clinical data
Other namesTMT; R-2956; RU-2956; 2α,2β,17α-Trimethyltrienolone; 2α,2β,17α-Trimethyltrenbolone; 2α,2β-Dimethylmetribolone; δ9,11-2α,2β,17α-trimethyl-19-nortestosterone; 2α,2β,17α-Trimethylestra-4,9,11-trien-17β-ol-3-one; 17β-Hydroxy-2α,2β,17α-trimethylestra-4,9,11-trien-3-one
Drug class Steroidal antiandrogen
ATC code
  • None
Identifiers
  • (8R,13S,14S,17R)-17-hydroxy-2,2,13,17-tetramethyl-6,7,8,14,15,16-hexahydro-1H-cyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H28O2
Molar mass 312.453 g·mol−1
3D model (JSmol)
  • CC1(CC2=C3C=CC4(C(C3CCC2=CC1=O)CCC4(C)O)C)C
  • InChI=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
  • Key: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. [1] [2] [3]

Contents

Side effects

Due to its close relation to metribolone (methyltrienolone), it is thought that TMT may produce hepatotoxicity. [4]

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. [5] [6] The drug is a derivative of the extremely potent androgen/anabolic steroid metribolone (R-1881; 17α-methyltrenbolone), [6] [7] and has been reported to possess only about 4-fold lower affinity for the AR in comparison. [8] 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. [9] The AR weak partial agonistic activity of TMT is comparable to that of cyproterone acetate. [4]

Relative affinities (%) of TMT and related steroids
Compound PR AR ER GR MR
Testosterone 1–3, 1–5100<1<1, 1–5<1
5α-Dihydrotestosterone <1, 1–3100–125<1<1<1
Metribolone (RU-1881)200–300, 250–600200–300, 250–600<125–5015–25
Trimethyltrienolone (RU-2956)≤114<1<1<1
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PR, testosterone for the AR, E2 for the ER, DEXA for the GR, and aldosterone for the MR. Sources: [10] [11] [12] [13] [6]

Chemistry

TMT, also known as 2α,2β,17α-trimethyltrienolone [14] 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. [5] [15] [2] 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. [15]

History

TMT was developed by Roussel Uclaf in France and was first known as early as 1969. [3] [16] [15] It was one of the earliest antiandrogens to be discovered and developed, along with others such as benorterone, BOMT, cyproterone, and cyproterone acetate. [5] [17] [18] [19] [20] 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. [1] Roussel Uclaf subsequently developed and introduced nilutamide for medical use. [21]

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References

  1. 1 2 Raynaud JP, Bonne C, Moguilewsky M, Lefebvre FA, Bélanger A, Labrie F (1984). "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. doi:10.1002/pros.2990050307. PMID   6374639. S2CID   85417869. [...] 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.
  2. 1 2 Negwer M, Scharnow HG (2001). Organic-chemical drugs and their synonyms: (an international survey). Wiley-VCH. p. 2158. ISBN   978-3-527-30247-5. 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
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  6. 1 2 3 James VH, Pasqualini JR (22 October 2013). Proceedings of the Fourth International Congress on Hormonal Steroids: Mexico City, September 1974. Elsevier Science. pp. 618, 620. ISBN   978-1-4831-4566-2. 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.
  7. ↑ Ostgaard K, Wibe E, Eik-Nes KB (August 1981). "Steroid responsiveness of the human cell line NHIK 3025". Acta Endocrinologica. 97 (4): 551–558. doi:10.1530/acta.0.0970551. PMID   7270009.
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  9. ↑ Eil C, Douglass EC, Rosenburg SM, Kano-Sueoka T (January 1981). "Receptor characteristics of the rat mammary carcinoma cell line 64-24". Cancer Research. 41 (1): 42–48. PMID   6256064.
  10. ↑ Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, et al. (January 1980). "Steroid hormone receptors and pharmacology". Journal of Steroid Biochemistry. 12: 143–157. doi:10.1016/0022-4731(80)90264-2. PMID   7421203.
  11. ↑ Ojasoo T, Raynaud JP (November 1978). "Unique steroid congeners for receptor studies". Cancer Research. 38 (11 Pt 2): 4186–4198. PMID   359134.
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  13. ↑ Raynaud JP, Ojasoo T, Bouton MM, Philibert D (1979). "Receptor Binding as a Tool in the Development of New Bioactive Steroids". In Ariens EJ (ed.). Drug Design. pp.  169–214. doi:10.1016/B978-0-12-060308-4.50010-X. ISBN   9780120603084.
  14. ↑ Kohtz AS, Frye CA (2012). "Dissociating behavioral, autonomic, and neuroendocrine effects of androgen steroids in animal models". Methods in Molecular Biology. Methods in Molecular Biology. 829: 397–431. doi:10.1007/978-1-61779-458-2_26. ISBN   978-1-61779-457-5. PMID   22231829. 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).
  15. 1 2 3 Brandes D (2 December 2012). Male Accessory Sex Organs: Structure and Function in Mammals. Elsevier. pp. 323–. ISBN   978-0-323-14666-1.
  16. ↑ Baulieu EE, Jung I (February 1970). "A prostatic cytosol receptor". Biochemical and Biophysical Research Communications. 38 (4): 599–606. doi:10.1016/0006-291X(70)90623-6. PMID   5443703.
  17. ↑ 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.
  18. ↑ Inaba M, Inaba Y (14 March 2013). Androgenetic Alopecia: Modern Concepts of Pathogenesis and Treatment. Springer Science & Business Media. pp. 531–. ISBN   978-4-431-67038-4.
  19. ↑ Bratoeff E, Ramírez E, Murillo E, Flores G, Cabeza M (December 1999). "Steroidal antiandrogens and 5alpha-reductase inhibitors". Current Medicinal Chemistry. 6 (12): 1107–23. PMID   10519917. 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".
  20. ↑ Horsky J, Presl J (6 December 2012). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 112–. ISBN   978-94-009-8195-9.
  21. ↑ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Elsevier. pp. 2935–. ISBN   978-0-8155-1856-3.
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