Trimethyltrienolone

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

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]

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

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. 1 2 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. 1 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. 1 2 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. 1 2 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. 1 2 3 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. 1 2 3 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. 1 2 3 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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