Rhodium
(Chief Bee)
06-04-03 01:10
No 437649
      Interesting crystallographic study of MDMA HCl
(Rated as: excellent)
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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) (../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 -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 -methyl group is antiplanar with a torsion angle of 178, and TMA (2,4,5-trimethoxyamphetamine), where the angle formed by the -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 -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.

 
 
 
 
    Lilienthal
(Moderator)
06-04-03 11:50
No 437747
      The crystal structure of the hydrochlorides of  Bookmark   

The crystal structure of the hydrochlorides of such simple molecules has nothing to do with the receptor bound conformation.

The difference between R and S stereoisomers has most probably to do with the different molecular targets (5-HT receptor vs. 5-HT transporter). smile
 
 
 
 
    Rhodium
(Chief Bee)
06-05-03 00:31
No 437830
      lowest energy conformer receptor fitting  Bookmark   

Yes, but why do MDA and MDMA have different molecular targets despite the small difference in structure? smile

I checked the conformation of MDA vs. MDMA after doing an energy minimization of the structures in ChemOffice 3D, and it gave approximately the same results as the crystallographic study above - the molecule wants to be in its lowest energy conformation both in solution and in a crystal (even though it may differ between the two) - therefore (S)-MDA and (R)-MDMA are more alike in the solution phase, and the 5-HT transporter wants to have the side chain bent in that fashion, therefore these two isomers are the most 5-HT releasing ones...
 
 
 
 
    Aurelius
(Hive Addict)
06-05-03 21:52
No 438055
      Rating  Bookmark   

This should be an "excellent" thread.  (I want to be able to find it under the positive rating threads.  Not to mention it simply deserves that rating.)