I feel that this crystallographic study may shed some light on as to why the potency of the MDMA stereoisomers is the reverse of MDA and analogs...Ecstasy: 3,4-Methylenedioxymethamphetamine (MDMA)Acta Crystallographica C54, 229-231 (1998)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/mdma.crystal.structure.pdf)
There are several structure-activity relationships which clearly differentiate MDMA from other hallucinogenic amphetamines, such as DOB (2,5-dimethoxy-4-bromoamphetamine) or DOM (2,5-dimethoxy-4- methylamphetamine). N-Methylation of hallucinogenic amphetamines attenuates activity three- to tenfold and the R(-) configuration is more potent. For MDMA, N-methylation has very little effect on activity and the S(+) configuration is more potent. The structure-activity relationship of MDMA is different even when compared with MDA (3,4-methylenedioxyamphetamine), which lacks N-methylation. For MDA, the R(-) isomer has the greatest potency in an in vivo rabbit model for classical hallucinogenic activity, whereas the S(+) isomer, at the same dose as the R(-) isomer, has a greater effect on emotion and empathy.
The structure of MDMA is illustrated in Fig. 1. The methylenedioxy ring is essentially coplanar [0.7°] with the phenyl ring.
One interesting structural feature of MDMA is the orientation of the isopropylamine group. In MDMA, the torsion angle which describes the relationship of the
![](https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000437649-file_lwwo.gif)
-methyl group (C10) and the phenyl ring is -66.4°. This is unlike other hallucinogenic amphetamines, such as DOET (2,5-dimethoxy-4-ethyl-amphetamine), where the
![](https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000437649-file_lwwo.gif)
-methyl group is antiplanar with a torsion angle of 178°, and TMA (2,4,5-trimethoxyamphetamine), where the angle formed by the
![](https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000437649-file_lwwo.gif)
-methyl group is 170°.
The relative position of the amino N atom is also different for MDMA when compared with DOET or TMA. For MDMA, N-methylation results in a rotation about the C8---C9 bond, giving rise to a torsion angle between the
![](https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000437649-file_lwwo.gif)
-methyl (C10) and N-methyl (C11) groups of 170.0°.
When comparing the structure of MDMA with DOET or TMA, it appears that the relative position of the
-methyl group (C10) and the amino N atom (N1) are transposed.![](https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000437649-file_jlam.gif)