3,4-Methylenedioxyamphetamine activity

One of the structural features of MDMA that is somewhat unusual is the fact that it is 3,4-disubstituted. Both 3,4-methylenedioxyamphetamine (MDA) (figure 2) and MDMA possess the 3,4-methylenedioxy function, and there apparently are no other active compounds known that fall within the... 

EXTENSIONS AND COMMENTARY This is pretty sparse information upon which to build a picture of biological activity. First, the synthesis was done by someone else and, as I have not been able to find where the notes are, this will be the one recipe in the footnote without explicit directions incorporated. The procedure used was exactly the same as that described for DMMDA, except that the starting material was dillapiole rather than apiole. The dillapiole was obtained by the careful fractionation of Oil of Dill (as opposed to the isolation of apiole from the careful fractionation of Oil of Parsley). Isomerization to isodillapiole, nitration with tetra-nitromethane to give 1 -(2,3-dimethoxy-4,5-methylenedioxyphenyl)-2-nitropropene, and its reduction with LAH in ether to give 2,3-dimethoxy-4,5-methylenedioxyamphetamine hydrochloride (DMMDA-2) proceeded in a precisely analogous manner to the preparation of DMMDA. 

Anyway, MADAM-6 is not active. And the equally intriguing positional isomer, the easily made MADAM-2, will certainly contribute to these speculations. A quiz for the reader Will 2,N-dimethyl-3,4-methylenedioxyamphetamine (MADAM-2) be (1) Of much reduced activity, akin to MADAM-6, or (2) Of potency and action similar to that of MDMA, or (3) Something unexpected and unanticipated I know only one way of finding out. Make the Schiffs base between piperonal and cyclohexylamine, treat this with butyl lithium in hexane with some TMEDA present, add someN-methylformanilide, convert theformed benzaldehyde toanitrostyrenewith nitroethane, reduce this with elemental iron to thephenylacetone, reduce this in the presence of methylamine with sodium cyanoborohydride, then taste the result. 

Amphetamine and methamphetamine possess an essentially pure psychostimulant effect however, substituted derivatives in position 3 and 4 on benzene ring are defined as entactogene [14], This class of substances includes methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA), methylenedioxyethyl-amphetamine (MDEA), and others such as the /V-melhyl-l-(3-4-methylenedioxyphenyl)-2-butanamine (MBDB), methoxymethylenedioxyam-phetamine (MMDA) (Fig. 4). All of these substances are more active in the d form. There are also amphetamine-like substances which combine sympathomimetic (euphoric) and hallucinogen effects they are primary amines, trisubstituted on the benzene ring, that produce effects similar to mescaline. Among these the 2,5-dime-thoxy-4-methylamphetamine (DOM) is the most important. 

Active Constituents Dillapiole (non-amine precursor of 2,3-dimethoxy-4,5-methylenedioxyamphetamine [DMMDA-2]). 

Active Constituents Apiole (non-amine precursor of 2,5-dimethoxy-3,4-methylenedioxyamphetamine [DMMDA]) and other unidentified olefinic substance with an allyl side chain which is the non-amine precursor of 2,3,4,5-tetramethoxyamphetamine (Tetra MA). 

Active Constituents Safrole (non-amine precursor of MDA [3,4-methylenedioxyamphetamine]). 

Ricaurte and colleagues (1985) demonstrated that an analog of amphetamine, 3,4-methylenedioxyamphetamine (MDA), is neurotoxic to monoamine systems. They observed that neostriatal and hippocampal 5-HT and 5-HIAA contents were depressed after MDA administration and that hippocampal norepinephrine (NE) content was also compromised. In comparing the effects of methylenedioxymethamphetamine (MDMA) and methamphetamine, it was observed (Stone et al. 1986, 1987) that while methamphetamine decreased both TH and TPH activity, MDMA depressed only TPH activity without altering the DA-synthesizing enzyme. Although MDMA releases DA (Yamamoto and Spanos... 

Oberlender R, Nichols DE. ( + )-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative stimulus in studies of 3,4-methylenedioxyamphetamine-like behavioral activity. J Pharmacol Exp Ther 1990 255 1098-1106. 

Several people have asked me what I thought about the potential activity of a compound with a methyl group added to DMMDA. One of these possibilities would be the N-methylated derivative, 2,5-dimethoxy-N-methyl-3,4-methylenedioxyamphetamine, or METHYL-DMMDA (or... 

---