Shulgin listed thedosage of DMMDA inPiHKAL as 30 to 75mg and theduration as 6 to 8hours.[1] He reported DMMDA as producingLSD-like subjective effects:images,mydriasis,ataxia, andtime dilation.[1] DMMDA is not mentioned much in literature outsidePiHKAL.[1]
Themechanism behind the subjective effects of DMMDA has not been specifically established. InPiHKAL, Shulgin asserts that the subjective effects of 75mg of DMMDA are equivalent to those of 75 to 100μg ofLSD.[1] LSD is a well-knownpartial agonist of theserotonin5-HT2A receptor. This may suggest that DMMDA is also anagonist or partial agonist of the 5-HT2A receptor.[citation needed]
DMMDA is equivalent to 12 "mescaline units" in terms ofpotency. DMMDA's isomer DMMDA-2 is equivalent to 5 "mescaline units" in terms of potency.[2]
Repeated administration ofmescaline (3,4,5-trimethoxyphenethylamine), a somewhat similar compound to DMMDA, has shown to slowly createtolerance. This may suggest that the same applies to DMMDA.[3]
Computationally predicted toxicology and metabolism
Computational prediction with ProTox-3.0 predicts that DMMDA has the following toxicological properties from most probable to least probable: respiratorically toxic (P=0.76),nephrotoxic (P=0.58),ecotoxic (P=0.54), andcarcinogenic (P=0.51). DMMDA is also predicted to cross theblood–brain barrier (BBB) (P=0.80).[4]
ProTox-3.0's predictions about DMMDA's toxicological properties.
DMMDA is predicted to bemetabolized via cytochromeCYP3A4 (P=0.60).[4] DMMDA is somewhat similar to3,4-methylenedioxy-1-N,α-dimethylphenylethylamine which is primarily metabolized into 3,4-dihydroxy-1-N,α-dimethylphenylethylamine. This may suggest that DMMDA can be metabolized into 3,4-dihydroxy-2,5-dimethoxy-1-α-methylphenylethylamine. The metabolism of3,4,5-trimethoxyphenylethylamine results in the demethylation of its methoxy groups, which may suggest that metabolism of DMMDA may also result in the demethylation of its methoxy groups.[5][3]
Precursors in the synthesis of DMMDA and its regioisomers.
Shulgin explains in his book that DMMDA has 6 isomers similar toTMA.[1]DMMDA-2 is the only other isomer that has been synthesized as of yet. DMMDA-3 could be made fromexalatacin (1-allyl-2,6-dimethoxy-3,4-methylenedioxybenzene). Exalatacin can be found in theessential oil of bothCrowea exalata andCrowea angustifolia var. angustifolia.[6] In other words, exalatacin is an isomer of bothapiole anddillapiole, which can be used to make DMMDA and DMMDA-2 respectively. Additionally, yet another isomer of DMMDA could be made from pseudodillapiole or 4,5-dimethoxy-2,3-methylenedioxyallylbenzene.[7] The last two isomers of DMMDA are 5,6-dimethoxy-2,3-methylenedioxy-1-α-methylphenylethylamine and 4,6-dimethoxy-2,3-methylenedioxy-1-α-methylphenylethylamine.
Like all other α-methylphenylethylamine derivative compounds, DMMDA and itsregioisomer have twoenantiomers due to the methyl group being in the alpha position of the ethyl group in position number 1 on the benzene ring.[8] There is no information regarding the differences in the pharmacological effects of (S)-DMMDA and (R)-DMMDA.
Shulgin describes the synthesis of DMMDA fromapiole in hisPiHKAL.[1] Apiole is subjected to anisomerization reaction to yieldisoapiole by adding to solution of ethanolicpotassium hydroxide and holding the solution at a steam bath.[1] Isoapiole is thennitrated to 2-nitro-isoapiole or 1-(2,3-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene by adding it to a stirred solution ofacetone andpyridine at ice-bath temperatures and treating the solution withtetranitromethane. Thepyridine acts as a catalyst in this reaction.[1] 2,5-dimethoxy-3,4-methylenedioxybenzaldehyde can also be used as precursors in this step of the synthesis. The 2-nitro-isoapiole is finallyreduced tofreebase DMMDA by adding it to a well-stirred andrefluxing suspension ofdiethylether andlithium aluminium hydride under an inert atmosphere.[1] The reduction can also be achieved with pressurized hydrogen. Finally, the freebase DMMDA converted into itshydrochloride salt.[1]
Shulgin's synthesis of DMMDA can reasonably be considered unsafe, at least by modern standards, since it usestetranitromethane for its nitration reaction, which is toxic, carcinogenic and prone to detonating.[9] DMMDA can be made from apiole via other safer methods. Among other methods, DMMDA can be synthesized from apiole via the intermediate chemical 2,5-dimethoxy-3,4-methylenedioxyphenylpropan-2-one or DMMDP2P in the same manner asMDA is made fromsafrole.
DMMDP2P can be made from apiole via aWacker oxidation withbenzoquinone. DMMDP2P can be alternatively made by subjecting apiole to anisomerisation reaction to yield the thermodynamically stabler internal alkene, isoapiole, followed by a peroxyacidoxidation, with for example peracetic acid, and finally ahydrolyticdehydration.[10] Peroxyacids can be made by combining hydrogen peroxide with an acid like formic acid or acetic acid to create performic acid or peracetic acid. It has been suggested that peroxynitric acid could also be used in this synthesis.[11] The oxidation first creates an epoxide in the alkene of isoapiole and then isopaiole glycol's monoformate ester if peracetic acid is used.[12] The hydrolysis is usually acid-catalyzed with a strong acid, such as sulphuric acid or hydrochloric acid, because the strong acid will also result in the intermediary isoapiole monoformyl glycol being dehydrated to DMMDP2P via a pinacol rearrangement. A small amount of the epoxide can form a carboxycation, which can rearrange itself to DMMDP2P, or react with water to form isoapiole glycol. Thus only one reagent, sulphuric acid, is needed for both the hydrolysis and dehydration and both reactions can be done in the same reaction vessel. Then the DMMDP2P can then be subjected to areductive amination with a source ofnitrogen, such asammonium chloride orammonium nitrate, and a reducing agent, such assodium cyanoborohydride, anamalgam ofmercury andaluminium or pressurized hydrogen, to yield freebase DMMDA.[13][14][15][16][17]
Sodium borohydride usually is not used as a reducing agent due to it being much stronger than sodium cyanoborohydride; this usually results in side products in addition to DMMDA. Reductive aminations are exothermic reactions. Thus it is necessary to employ different methods of cooling the reaction mixture to prevent overheating; this can be accomplished by using a large amount of solvent or an ice bath, for example. The use of a mercury amalgam is unsafe due to mercury's well-known toxic effects on the central nervous system. In addition toperacetic acid, otherperoxy acids can be used for the peroxy acid oxidation of isoapiole and other analogues of isoallylbenzene in general. For example, combining nitric acid with hydrogen peroxide would result in the same reaction.[14][15][16][17]
^Brophy JJ, Goldsack RJ, Punruckvong A, Forster PI, Fookes CJ (July 1997). "Essential oils of the genus Crowea (Rutaceae)".Journal of Essential Oil Research.9 (4):401–409.doi:10.1080/10412905.1997.9700740.
^US patent 4,876,277, Burke BA, Nair MG, "Antimicrobial/antifungal compositions", issued 1989-10-24, assigned to Plant Cell Research Institute, Inc., Dublin, Calif.
^Cox M, Klass G, Morey S, Pigou P (July 2008). "Chemical markers from the peracid oxidation of isosafrole".Forensic Science International.179 (1):44–53.doi:10.1016/j.forsciint.2008.04.009.PMID18508215.
^Waumans D, Hermans B, Bruneel N, Tytgat J (July 2004). "A neolignan-type impurity arising from the peracid oxidation reaction of anethole in the surreptitious synthesis of 4-methoxyamphetamine (PMA)".Forensic Science International.143 (2–3):133–9.doi:10.1016/j.forsciint.2004.02.033.PMID15240033.
^Braun U, Shulgin AT, Braun G (February 1980). "Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine)".Journal of Pharmaceutical Sciences.69 (2):192–195.doi:10.1002/jps.2600690220.PMID6102141.
^abClayden J, Greeves N, Warren S (2012).Organic Chemistry. Oxford University Press. pp. 234–235.ISBN978-0-19-927029-3.
^abCarey FA, Sundberg RJ (2007).Organic Chemistry B: Reactions and Synthesis. Springer. pp. 403–404.ISBN978-0-387-68350-8.
^abSmith MB, March J (2007).March's Advanced Organic Chemistry. John Wiley & Sons. pp. 1288–1290.ISBN978-0-471-72091-1.
^abTurcotte MG, Hayes KS (2001).Amines, Lower Aliphatic Amines, Kirk-Othmer Encyclopedia of Chemical Technology. New York: John Wiley & Sons.
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