Chemistry:Metribolone

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Short description: Chemical compound
Metribolone
Methyltrienolone.svg
Metribolone molecule ball.png
Clinical data
Other namesMethyltrienolone, 17α-Methyltrenbolone; R1881; R-1881; RU-1881; NSC-92858; 17α-Methyl-19-nor-Δ9,11-testosterone; 17α-Methylestra-4,9,11-trien-17β-ol-3-one
Routes of
administration		By mouth
Drug classAndrogen; Anabolic steroid; Progestogen
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H24O2
Molar mass284.399 g·mol−1
3D model (JSmol)
  (verify)

Metribolone (developmental code R1881, also known as methyltrienolone) is a synthetic and orally active anabolic–androgenic steroid (AAS) and a 17α-alkylated nandrolone (19-nortestosterone) derivative which was never marketed for medical use but has been widely used in scientific research as a hot ligand in androgen receptor (AR) ligand binding assays (LBAs) and as a photoaffinity label for the AR.[1][2][3] More precisely, metribolone is the 17α-methylated derivative of trenbolone. It was investigated briefly for the treatment of advanced breast cancer in women in the late 1960s and early 1970s, but was found to produce signs of severe hepatotoxicity at very low dosages, and its development was subsequently discontinued.[2][4]

Medical uses

Metribolone was never approved for medical use,[2] a situation unlikely to change given its liver toxicity even at low doses.[2] It was studied for the potential treatment of advanced breast cancer in women but development was abandoned.[2][4]

Side effects

Side effects of metribolone include virilization and hepatotoxicity among others.[2]

Pharmacology

Pharmacodynamics

Metribolone is an AAS, or an agonist of the AR, with both anabolic and androgenic activity.[2] It is one of the most potent AAS to have ever been synthesized, with 120 to 300 times the oral anabolic potency and 60 to 70 times the androgenic potency of the reference AAS methyltestosterone in castrated male rats, although the same level of potency has not been observed in studies in humans.[2][4] In addition to the AR, metribolone has high affinity for the progesterone receptor (PR), and binds to the glucocorticoid receptor (GR) as well.[5][6] The drug was also identified in 2007 as a potent antimineralocorticoid, with similar affinity for the mineralocorticoid receptor as aldosterone and spironolactone.[7] In addition, metribolone was identified in 2010 as a potent inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD) 1 and 2 (IC50 = 0.02 and 0.16 μM, respectively).[8] On the basis of this finding, it has been said that metribolone should be used very cautiously in scientific research, taking into account 3β-HSD inhibition to avoid erroneous interpretation.[8]

Metribolone has a high potential for hepatotoxicity, similarly to other 17α-alkylated AAS.[9] However, the hepatotoxic potential of metribolone appears to be exceptionally high, likely in relation to its very high potency and metabolic stability; in a study of treatment with the drug for advanced breast cancer, severe hepatic dysfunction was observed at very low dosages.[4]

Relative affinities (%) of metribolone and related steroids
Compound Chemical name PR AR ER GR MR
Testosterone T 1.0 100 <0.1 0.17 0.9
Nandrolone 19-NT 20 154 <0.1 0.5 1.6
Trenbolone ∆9,11-19-NT 74 197 <0.1 2.9 1.33
Trestolone 7α-Me-19-NT 50–75 100–125 ? <1 ?
Normethandrone 17α-Me-19-NT 100 146 <0.1 1.5 0.6
Metribolone ∆9,11-17α-Me-19-NT 208 204 <0.1 26 18
Mibolerone 7α,17α-DiMe-19-NT 214 108 <0.1 1.4 2.1
Dimethyltrienolone ∆9,11-7α,17α-DiMe-19-NT 306 180 0.1 22 52
v · d · e Relative affinities of nandrolone and related steroids at the androgen receptor
Compound rAR (%) hAR (%)
Testosterone 38 38
5α-Dihydrotestosterone 77 100
Nandrolone 75 92
5α-Dihydronandrolone 35 50
Ethylestrenol ND 2
Norethandrolone ND 22
5α-Dihydronorethandrolone ND 14
Metribolone 100 110
Sources: See template.

Pharmacokinetics

Metribolone has very low affinity for human serum sex hormone-binding globulin (SHBG), less than 5% of that of testosterone and less than 1% of that of dihydrotestosterone (DHT).[10]

Chemistry

Metribolone, also known as 17α-methyltrenbolone, as well as 17α-methyl-δ9,11-19-nortestosterone or 17α-methylestra-4,9,11-trien-17β-ol-3-one, is a synthetic estrane steroid and a 17α-alkylated derivative of nandrolone (19-nortestosterone).[1][2] It is the C17α methylated derivative of trenbolone (δ9,11-19-nortestosterone) and the C9- and C11-dehydrogenated (δ9,11) analogue of normethandrone (17α-methyl-19-nortestosterone).[1][2] Other close relatives and derivatives of metribolone include mibolerone (7α,17α-dimethyl-19-nortestosterone) and dimethyltrienolone (RU-2420; 7α,17α-dimethyl-δ9,11-19-nortestosterone).[1][2] In addition to AAS, trimethyltrienolone (R2956; 2α,2β,17α-trimethyl-δ9,11-19-nortestosterone), a highly potent antiandrogen, has been derived from metribolone.[11][12]

History

Metribolone was first described in the literature in 1965.[2] It was studied clinically in the late 1960s and early 1970s, most notably in the treatment of advanced breast cancer.[2] The drug was found to be effective and showed weak androgenicity, but also produced severe signs of hepatotoxicity, and was ultimately never marketed.[2][4] By the mid-1970s, metribolone was becoming an accepted standard as a ligand and agonist of the AR in scientific research.[2] It remains in wide use for this purpose today.[2] Aside from scientific research, metribolone has also been encountered as an AAS in non-medical contexts, for instance in doping in sports and bodybuilding.[2]

Society and culture

Generic names

Metribolone is the generic name of metribolone and its INN.[1] It is also known by the name methyltrienolone and its developmental code names R1881, R-1881, RU-1881, and RU1881, and is very commonly referred to by these other names rather than as metribolone in the scientific literature.[1]

Doping in sports

Prior to the 2008 Beijing Olympic Games, 11 members of the Greek national weightlifting team and 4 Greek track and field athletes tested positive for metribolone.[13]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 654–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA654. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 William Llewellyn's Anabolics. Molecular Nutrition LLC. 2011. pp. 546–. ISBN 978-0-9828280-1-4. https://books.google.com/books?id=afKLA-6wW0oC&pg=PT546. 
  3. ↑ "Characterization of androgen receptors after photoaffinity labelling with [3H]methyltrienolone (R1881)". Journal of Steroid Biochemistry 24 (1): 245–249. January 1986. doi:10.1016/0022-4731(86)90058-0. PMID 2422446. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Sex Hormones (Male): Analogs and Antagonists". Encyclopedia of Molecular Cell Biology and Molecular Medicine. 13 (2nd ed.). 2006. doi:10.1002/3527600906.mcb.200500066. ISBN 3527600906. 
  5. ↑ "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Current Medicinal Chemistry 7 (2): 211–247. February 2000. doi:10.2174/0929867003375371. PMID 10637363. 
  6. ↑ "Binding of methyltrienolone to glucocorticoid receptors in rat muscle cytosol". Endocrinology 109 (5): 1418–1423. November 1981. doi:10.1210/endo-109-5-1418. PMID 6975208. 
  7. ↑ "The synthetic androgen methyltrienolone (r1881) acts as a potent antagonist of the mineralocorticoid receptor". Molecular Pharmacology 71 (2): 473–482. February 2007. doi:10.1124/mol.106.031112. PMID 17105867. 
  8. ↑ 8.0 8.1 "Methyltrienolone (R1881) is a Potent Inhibitor of 3B-Hydroxysteroid Dehydrogenase (3B-HSD) Activity". Characterization of Enzymes Involved in the Metabolism of Dihydrotestosterone, the Most Potent Natural Androgen (thesis). 2010. pp. 91–103. 
  9. ↑ "Liver toxicity of a new anabolic agent: methyltrienolone (17-alpha-methyl-4,9,11-estratriene-17 beta-ol-3-one)". Steroids 8 (1): 13–24. July 1966. doi:10.1016/0039-128x(66)90114-0. PMID 5955468. 
  10. ↑ "Relative binding affinity of anabolic-androgenic steroids: comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin". Endocrinology 114 (6): 2100–2106. June 1984. doi:10.1210/endo-114-6-2100. PMID 6539197. 
  11. ↑ "Structure-Activity Relationships in Steroid Anaesthetics". Proceedings of the Fourth International Congress on Hormonal Steroids: Mexico City, September 1974. Elsevier Science. 22 October 2013. pp. 618. ISBN 978-1-4831-4566-2. https://books.google.com/books?id=Iq0aAwAAQBAJ&pg=PA608. "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." 
  12. ↑ Innovative Approaches in Drug Research: Proceedings of the Third Noordwijkerhout Symposium on Medicinal Chemistry, Held in the Netherlands, September 3-6, 1985. Elsevier. 1 January 1986. ISBN 978-0-444-42606-2. https://books.google.com/books?id=PwhtAAAAMAAJ. "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." 
  13. ↑ "Eleven Greek weightlifters test positive; coach suspended". Associated Press / USATODAY.com. 2008-04-04. https://www.usatoday.com/sports/olympics/2008-04-04-greek-weightlifters_N.htm. 

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