Trimethyltrienolone

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]

Trimethyltrienolone
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 classSteroidal antiandrogen
ATC code
  • None
Identifiers
IUPAC name
  • (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
FormulaC21H28O2
Molar mass312.453 g·mol−1
3D model (JSmol)
SMILES
  • CC1(CC2=C3C=CC4(C(C3CCC2=CC1=O)CCC4(C)O)C)C
InChI
  • 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

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
CompoundPRARERGRMR
Testosterone1–3, 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
See also: Steroidal antiandrogen and List of steroidal antiandrogens

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]

References
  1. Raynaud, J. P.; Bonne, C.; Moguilewsky, M.; Lefebvre, F. A.; 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. ISSN 0270-4137. 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. Martin Negwer; Hans-Georg Scharnow (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
  3. Hughes A, Hasan SH, Oertel GW (27 November 2013). Voss HE, Bahner F, Neumann F, Steinbeck H, Gräf KJ, Brotherton J, Horn HJ, Wagner RK (eds.). Androgens II and Antiandrogens / Androgene II und Antiandrogene. Springer Science & Business Media. pp. 1–. ISBN 978-3-642-80859-3.
  4. Raynaud JP, Ojasoo T (November 1986). "The design and use of sex-steroid antagonists". J. Steroid Biochem. 25 (5B): 811–33. doi:10.1016/0022-4731(86)90313-4. PMID 3543501.
  5. Azadian-Boulanger G, Bonne C, Secchi J, Raynaud JP (1974). "[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 (in French). 5 (4): 509–520. Retrieved 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.
  6. V. H. T. James; J. R. Pasqualini (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, K. B. (1981). "Steroid responsiveness of the human cell line NHIK 3025". European Journal of Endocrinology. 97 (4): 551–558. doi:10.1530/acta.0.0970551. ISSN 0804-4643. PMID 7270009.
  8. A. F. Harms (1 January 1986). Innovative Approaches in Drug Research: Proceedings of the Third Noordwijkerhout Symposium on Medicinal Chemistry, Held in the Netherlands, September 3-6, 1985. Elsevier. ISBN 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.
  9. Eil C, Douglass EC, Rosenburg SM, Kano-Sueoka T (1981). "Receptor characteristics of the rat mammary carcinoma cell line 64-24". Cancer Res. 41 (1): 42–8. PMID 6256064.
  10. Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP (January 1980). "Steroid hormone receptors and pharmacology". Journal of Steroid Biochemistry. 12: 143–57. 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): 4186–98. PMID 359134.
  12. Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP (1987). "Towards the mapping of the progesterone and androgen receptors". J. Steroid Biochem. 27 (1–3): 255–69. doi:10.1016/0022-4731(87)90317-7. PMID 3695484.
  13. Raynaud, J.P.; Ojasoo, T.; Bouton, M.M.; Philibert, D. (1979). "Receptor Binding as a Tool in the Development of New Bioactive Steroids". Drug Design. pp. 169–214. doi:10.1016/B978-0-12-060308-4.50010-X. ISBN 9780120603084.
  14. Kohtz, Amy S.; Frye, Cheryl A. (2012). "Dissociating Behavioral, Autonomic, and Neuroendocrine Effects of Androgen Steroids in Animal Models". Psychiatric Disorders. Methods in Molecular Biology. Vol. 829. pp. 397–431. doi:10.1007/978-1-61779-458-2_26. ISBN 978-1-61779-457-5. ISSN 1064-3745. 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. David Brandes (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". Biochem. Biophys. Res. Commun. 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. Masumi Inaba; Yoshitaka Inaba (14 March 2013). Androgenetic Alopecia: Modern Concepts of Pathogenesis and Treatment. Springer Science & Business Media. pp. 531–. ISBN 978-4-431-67038-4.
  19. Bentham Science Publishers (December 1999). Current Medicinal Chemistry. Bentham Science Publishers. pp. 1000–1111. 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. J. Horsky; J. Presl (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 Edition. Elsevier. pp. 2935–. ISBN 978-0-8155-1856-3.
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