|Synonyms||TMT; 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|
|Chemical and physical data|
|Molar mass||312.453 g/mol g·mol−1|
|3D model (JSmol)|
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.
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), and has been reported to possess only about 4-fold lower affinity for the AR in comparison. 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. The AR weak partial agonistic activity of TMT is comparable to that of cyproterone acetate.
|Testosterone||1–3, 1–5||100||<1||<1, 1–5||<1|
|Metribolone (RU-1881)||200–300, 250–600||200–300, 250–600||<1||25–50||15–25|
|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: |
|Notes: (1): Reference ligands (100%) were testosterone for the AR, progesterone for the PR, estradiol for the ER, dexamethasone for the GR, and aldosterone for the MR. (2): Tissues were rat prostate (AR), rabbit uterus (PR), mouse uterus (ER), rat thymus (GR), and rat kidney (MR). (3): Incubation times (0°C) were 24 hours (AR, a), 2 hours (PR, ER), 4 hours (GR), and 1 hour (MR). (4): Assay methods were different for bicalutamide for receptors besides the AR. Sources: See template.|
|Compound||AR RBA (%)||AR Ki (nM)|
|Notes: (1) Human skin fibroblasts used for assays. (2) Situation in vivo is different for flutamide and spironolactone due biotransformation. (3) Conflicting findings for spironolactone. Sources: See template.|
TMT, also known as 2α,2β,17α-trimethyltrienolone 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. 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.
TMT was developed by Roussel Uclaf in France and was first known as early as 1969. It was one of the earliest antiandrogens to be discovered and developed, along with others such as benorterone, BOMT, cyproterone, and cyproterone acetate. 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. Roussel Uclaf subsequently developed and introduced nilutamide for medical use.
- 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.
[...] flutamide but we soon abandoned the development of steroid derivatives such as RU 2956 because of inherent androgenicity , and focused on the nonsteroidal antiandrogens.
- 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
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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.
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R-2956 [41-43], a dimethyl derivative of an extremely potent androgen, R 1881 , is a powerful testosterone antagonist with very low androgenic activity.
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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.
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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).
- David Brandes (2 December 2012). Male Accessory Sex Organs: Structure and Function in Mammals. Elsevier. pp. 323–. ISBN 978-0-323-14666-1.
- 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.
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Several androstane derivatives have also demonstrated an antiandrogenic activity; 17a-methyl-B-nortestosterone 8 was prepared and tested in 1964 for antihormonal activity . 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".
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