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Metribolone

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Metribolone
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
  • (8S,13S,14S,17S)-17-Hydroxy-13,17-dimethyl-1,2,6,7,8,14,15,16-octahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChemCID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.190.113Edit this at Wikidata
Chemical and physical data
FormulaC19H24O2
Molar mass284.399g·mol−1
3D model (JSmol)
  • C[C@@]1(CC[C@@H]2[C@@]1(C=CC3=C4CCC(=O)C=C4CC[C@@H]23)C)O
  • InChI=1S/C19H24O2/c1-18-9-7-15-14-6-4-13(20)11-12(14)3-5-16(15)17(18)8-10-19(18,2)21/h7,9,11,16-17,21H,3-6,8,10H2,1-2H3/t16-,17+,18+,19+/m1/s1☒N
  • Key:CCCIJQPRIXGQOE-XWSJACJDSA-N☒N
(verify)

Metribolone(developmental codeR1881,also known asmethyltrienolone) is asyntheticandorally activeanabolic–androgenic steroid(AAS) and a17α-alkylatednandrolone(19-nortestosterone)derivativewhich was never marketed formedical usebut has been widely used inscientific researchas ahot ligandinandrogen receptor(AR)ligand binding assays(LBAs) and as aphotoaffinity labelfor the AR.[1][2][3]More precisely, metribolone is the 17α-methylated derivative oftrenbolone.It was investigated briefly for the treatment ofadvanced breast cancerin women in the late 1960s and early 1970s, but was found to produce signs of severehepatotoxicityat very low dosages, and its development was subsequently discontinued.[2][4]

Medical uses

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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 ofadvanced breast cancerin women but development was abandoned.[2][4]

Side effects

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See also:Anabolic steroid § Adverse effects

Side effectsof metribolone includevirilizationandhepatotoxicityamong others.[2]

Pharmacology

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Pharmacodynamics

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Metribolone is an AAS, or anagonistof the AR, with bothanabolicandandrogenicactivity.[2]It is one of the mostpotentAAS 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 AASmethyltestosteronein 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 highaffinityfor theprogesterone receptor(PR), and binds to theglucocorticoid receptor(GR) as well.[5][6]The drug was also identified in 2007 as a potentantimineralocorticoid,with similar affinity for themineralocorticoid receptorasaldosteroneandspironolactone.[7]In addition, metribolone was identified in 2010 as a potent inhibitor of3β-hydroxysteroid dehydrogenase(3β-HSD)1and2(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 forhepatotoxicity,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 andmetabolic stability;in a study of treatment with the drug foradvanced breast cancer,severe hepatic dysfunction was observed at very low dosages.[4]

Relative affinities (%) of metribolone and related steroids
Compound Chemical name PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor
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
Notes:Values are percentages (%). Referenceligands(100%) wereprogesteronefor thePRTooltip progesterone receptor,testosteronefor theARTooltip androgen receptor,estradiolfor theERTooltip estrogen receptor,DEXATooltip dexamethasonefor theGRTooltip glucocorticoid receptor,andaldosteronefor theMRTooltip mineralocorticoid receptor.Sources:[10][11]
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

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Metribolone has very lowaffinityfor human serumsex hormone-binding globulin(SHBG), less than 5% of that oftestosteroneand less than 1% of that ofdihydrotestosterone(DHT).[12]

Chemistry

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See also:List of androgens/anabolic steroids

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 asyntheticestranesteroidand a17α-alkylatedderivativeofnandrolone(19-nortestosterone).[1][2]It is the C17αmethylatedderivative of trenbolone (δ9,11-19-nortestosterone) and the C9- and C11-dehydrogenated(δ9,11)analogueofnormethandrone(17α-methyl-19-nortestosterone).[1][2]Other close relatives and derivatives of metribolone includemibolerone(7α,17α-dimethyl-19-nortestosterone) anddimethyltrienolone(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 potentantiandrogen,has been derived from metribolone.[13][14]

History

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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 advancedbreast 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 indoping in sportsandbodybuilding.[2]

Society and culture

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Generic names

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Metriboloneis thegeneric nameof metribolone and itsINNTooltip International Nonproprietary Name.[1]It is also known by the namemethyltrienoloneand its developmental code namesR1881,R-1881,RU-1881,andRU1881,and is very commonly referred to by these other names rather than asmetribolonein the scientific literature.[1]

Doping in sports

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Prior to the2008 Beijing Olympic Games,11 members of the Greek national weightlifting team and 4 Greek track and field athletes tested positive for metribolone.[15]

References

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  1. ^abcdefElks J (14 November 2014).The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies.Springer. pp. 654–.ISBN978-1-4757-2085-3.
  2. ^abcdefghijklmnopqWilliam Llewellyn's Anabolics.Molecular Nutrition LLC. 2011. pp. 546–.ISBN978-0-9828280-1-4.
  3. ^Brinkmann AO, Kuiper GG, de Boer W, Mulder E, Bolt J, van Steenbrugge GJ, van der Molen HJ (January 1986). "Characterization of androgen receptors after photoaffinity labelling with [3H]methyltrienolone (R1881)".Journal of Steroid Biochemistry.24(1): 245–249.doi:10.1016/0022-4731(86)90058-0.PMID2422446.
  4. ^abcdeBrueggemeier RW (2006). "Sex Hormones (Male): Analogs and Antagonists". In Meyers RA (ed.).Encyclopedia of Molecular Cell Biology and Molecular Medicine.Vol. 13 (2nd ed.).doi:10.1002/3527600906.mcb.200500066.ISBN3527600906.
  5. ^Singh SM, Gauthier S, Labrie F (February 2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships".Current Medicinal Chemistry.7(2): 211–247.doi:10.2174/0929867003375371.PMID10637363.
  6. ^Ho-Kim MA, Tremblay RR, Dubé JY (November 1981). "Binding of methyltrienolone to glucocorticoid receptors in rat muscle cytosol".Endocrinology.109(5): 1418–1423.doi:10.1210/endo-109-5-1418.PMID6975208.
  7. ^Takeda AN, Pinon GM, Bens M, Fagart J, Rafestin-Oblin ME, Vandewalle A (February 2007). "The synthetic androgen methyltrienolone (r1881) acts as a potent antagonist of the mineralocorticoid receptor".Molecular Pharmacology.71(2): 473–482.doi:10.1124/mol.106.031112.PMID17105867.S2CID28647372.
  8. ^abZheng F (2010). "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). pp. 91–103.CiteSeerX10.1.1.428.3729.
  9. ^Krüskemper HL, Noell G (July 1966). "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.doi:10.1016/0039-128x(66)90114-0.PMID5955468.
  10. ^Delettré J, Mornon JP, Lepicard G, Ojasoo T, Raynaud JP (January 1980). "Steroid flexibility and receptor specificity".Journal of Steroid Biochemistry.13(1): 45–59.doi:10.1016/0022-4731(80)90112-0.PMID7382482.
  11. ^Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP (1987). "Towards the mapping of the progesterone and androgen receptors".Journal of Steroid Biochemistry.27(1–3): 255–269.doi:10.1016/0022-4731(87)90317-7.PMID3695484.
  12. ^Saartok T, Dahlberg E, Gustafsson JA (June 1984). "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.doi:10.1210/endo-114-6-2100.PMID6539197.
  13. ^Phillipps GH (22 October 2013)."Structure-Activity Relationships in Steroid Anaesthetics".In James VJ, Pasqualini JR (eds.).Proceedings of the Fourth International Congress on Hormonal Steroids: Mexico City, September 1974.Elsevier Science. p. 618.ISBN978-1-4831-4566-2.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.
  14. ^Harms AF (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.ISBN978-0-444-42606-2.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.
  15. ^"Eleven Greek weightlifters test positive; coach suspended".Associated Press / USATODAY. 2008-04-04.Retrieved2009-06-28.
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