Methoxygonadiene

Structure:
methoxygonadiene
Nomenclature:
18-methyl-3-methoxy-estra-2,5(10)-dien-17-one or
13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one

Synonyms:
Methoxygonadiene, methoxydienone, Max-LMG, M-LMG

History:
This compound first appears in patents dating to the 1960s filed by researchers Gordon Alan Hughes and Herchel Smith at Wyeth Laboratories, in which they synthesized a number of 13-alkylated 19-nor compounds, including some that would become the first synthetic contraceptives. [1][2] These patents would prove so profitable that after retiring from Wyeth, Smith was able to donate hundreds of millions of dollars to universities in the UK and US. [3]

Methoxygonadiene is a chemical intermediate in the synthesis of steroids such as Norbolethone, 18-methyl-nortestosterone, and Norgestrel/Levonorgestrel. [1]

Preparation of Norbolethone from Methoxydienone

Preparation of Norbolethone from Methoxydienone. [1]

Grignard methylation and acid-catalyzed hydrolysis of methoxygonadiene yields the steroid Norbolethone. Norbolethone was originally developed by Wyeth, and later made famous by its use as a then-undetectable doping agent in the ‘BALCO’ scandal.

This ready availability as a chemical intermediate, and its association with the BALCO scandal, are likely to be how it found its way into the “designer steroid” supplement market in 2005, when it was released by ALRI as Max-LMG (LMG stands for “Lean Mass Generator”).
alri-max-lmg__Anabolic and Androgenic Activity:
Methoxygonadiene is believed to act as a ‘prodrug’, deriving pharmacological activity by being metabolised to an active compound. Methoxygonadiene is unlikely to have any ‘intrinsic’ anabolic activity due to the lack of a 17b-hydroxyl function.

methoxygonadiene proposed metabolism

Proposed scheme of metabolism of methoxygonadiene

The diagram above illustrates the commonly suggested metabolic route. According to the scheme proposed, after ingestion methoxydienone’s enol ether group (methoxy) will undergo hydrolysis to the 3-ketone and the remaining 5(10) double bond should isomerize readily under acidic conditions in the body to produce a 4-en-3-one conjugation. It will then further convert to the biologically active 17b-hydroxyl steroid, 18-methyl-19-nortestosterone.

18-methyl-19-nortestosterone is a potent anabolic by injection, holding an A:A ratio of approximately 54:27 (LA:VP vs. testosterone propionate). [4] and 90:625 (LA:VP vs. 19-nortestosterone). [5] No data is available on the oral activity of either methoxygonadiene or 18-methyl-19-nortestosterone.

Structure and Function:
Methoxydienone belongs to a class of steroids called gonanes. The most basic gonane is a steroid devoid of the C-10 and C-13 methyl groups and is generally referred to as the ‘steroid nucleus’.

gonane

Structure of the steroid nucleus; the simplest gonane.

Herchel Smith and Richard Edgren originally described hormones such as methoxygonadiene and norbolethone as “13-substituted bisnortestosterones”, though they soon switched to the gonane nomenclature system to avoid confusion.

“We initially started calling them 13-substituted, bisnor testosterones… However this became very cumbrous from a nomenclature standpoint and to get some consistency in our work, at least internally, we followed the IUPAC recommendations, starting from the gonane nucleus and building from there.” – Richard Edgren [5]

Since by the strictest definition all steroids can be considered gonanes, Edgren has expressed a preference for the term “carbon 18-homologated 19-nortestosterones”, or alternatively “levonorgestrel family of progestins” for 18-methyl hormones such as methoxygonadiene. [6]

When this was released as a dietary supplement in 2005, the accompanying advertising copy declared:

“Max LMG is structurally related to the so-called abortion pill RU-486…”

In fact it’s almost entirely unrelated, structurally, to the “abortion pill” RU-486 (Mifepristone), as can be seen by even a cursory glance at the molecular structures.

methoxygonadiene, mifepristone, and norgestrel

Left to right: methoxygonadiene, mifepristone (RU-486), and norgestrel.

It’s possible that the confusion may have arisen because Wyeth’s oral contraceptive Nordette (which contained ethinyl estradiol and levonorgestrel) was marked “Wyeth” on one side, and “486” on the other. Since levonorgestrel can be made from methoxygonadiene, a comparison with that compound would have been much more appropriate.

nordette

“…being a 5-alpha-reduced analog prevents conversion to DHT. It is important to remember that being 5-alpha-reduced also means it is related to DHT.”

Methoxygonadiene is not 5-alpha-reduced, or even remotely related to DHT. It has a double bond from C5-C10, which it’s believed may isomerise in vivo to the more thermodynamically stable C4-C5 position.

“Naturally the lack of estrogenic activity translates into low water retention and solid gains.”

Contrary to the assertion above, this compound is noted by users for a high degree of water retention – and is certain to aromatise. Ironically, both of the compounds sold by ALRI under the name “LMG” (Lean Mass Generator) were renowned for doing the opposite: Ergomax LMG (desoxymethyltestosterone; “Pheraplex”) was also usually characterized as a “wet bulker” that caused significant water retention.

References:
[1] US Patent US3959322: Synthesis of 13-alkyl-gon-4-ones. Smith, Herchel
[2] US Patent US3547909: Hughes GA. Synthesis of Gona-2,5(10)-Dienes. 1970.
[3] Herchel Smith Biography – University of Cambridge
[4] Buzby GC, Walk CR, Smith H. Totally Synthetic Steroid Hormones. X. Some (±)-13β-Ethyl-7α-methylgonane Derivatives. J. Med. Chem. 1966 Sep 1;9(5):782–4.
[5] Biological effects of synthetic gonanes. Edgren RA, Peterson DL, Jones RC, Nagra CL, Smith H, Hughes GA. Recent Prog Horm Res. 1966;22:305-49.
[6] Nomenclature of the gonane progestins. Edgren RA, Stanczyk FZ. Contraception. 1999 Dec;60(6):313

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