more MDMA substitutes

[Acyl]

Yeah, I was talking about the NH-C(=O)CH3, im not so sure at the ease of which it can be removed in the body.. I suggested it because it seems to happen to tylenol and melatonin if I remember correctly. If a problem with de-acetylation arises it could always just be transformed into NH-C(=O)C[EWD] where EWD stands for an electron withdrawing group that allows for the structure to be cleaved into the PEA derivative and a benign carboxylic acid.

From a chemists stand point (ok well, student of chemistry) that NH-O- bond appears to be very susceptible to acid hydrolysis, mainly in the stomach.

Acyl: Well no what I was envisaging wouldn't really be satisfied by many existing compounds. More advanced materials are required.

Oh ok, I see where you're coming from now. Ideally, it could work.. But Ive got a feeling that its beyond our abilities. It would be like separating pain killing from the positively reinforcing feelings brought on by opiates. Many organic functions are just too biologically intertwined to be separated. If it did happen, I could see some sort of peptide doing the trick. But then again, I dont really know what Im talking about.. better see a professional about this, this is a pretty cool idea.






I just read a paper about oximes replacing regular amines with affinities to 5-HT receptors.

Turns out, the oxime wouldnt even act as a prodrug. It would complete its deed with its structure more or less intact. Its very possible that the oxime you suggested has similar properties to MDMA, I cant say.. but this paper im looking at didnt substitute the oxime in for an amine in the original structure. Its odd, they removed (theoretically) two carbon atoms, replaced one with an oxygen doubly bonded to a carbon that preceeds (R-C(=O)) it and the other with an alkoxyamine (R2-O-NH2) and formed the oxime by combining the two.

So they busted a part of the original drug molecule, R-CH2-R2 (where R,R2= primary alkyl) into R-C(=O) and H2N-O-R2 and recombined them to give R-C=N-O-R2 .


A major effect of this replacement was a complete loss of reactivity to alpha-andrenergic receptors while still retaining 5-HT1/2 affinities.

source:

itle: Synthesis and 5-HT2A, 5-HT1A and α1- binding affinities of 2-[2-hydroxy-3-(pyridin-3-yl-methyl)amino]-, 2-[2-hydroxy-3-(2-pyridin-2-yl-ethyl)amino]- and 2-[2-hydroxy-3-(4-N-methyl- piperazin-1-yl)-amino]propoxybenzaldehyde-O-(substituted) benzyl oximes
Source: Archiv der Pharmazie [0365-6233] Orlandini yr:2007 vol:340 iss:3 pg:135 -139

 

[MattPsy]

Well I just checked out the structures in Chem3D, the orientation of the nitrogen is all wrong, regardless of (E) or (Z) spatial arrangement, once you minimize the energy. Doesn't fit either the R or S isomers of MDA.
Who knows, maybe it would retain /some/ of the activity, and just lose affinity to some targets.

 

[Acyl]

The R MDA isomer and the cis (to aromatic ring) oxime look pretty good to me ? Im using spartan.

Is it not possible for a molecule to change an unstrained dihedral angle by a few degrees to fit in the receptor?

Can that oxygen even interact with the receptor?

 

[MattPsy]

I wouldn't know, it's beyond my level of ability .
That and my energy minimizing thing is behaving in odd ways with this structure and i'm not sure why! It's doing a good job of confusing me, spitting out a new 3d orientation as output each time, with identical output fed in .

On the plus side, it would appear that these could act as antidotes to nerve agents as well as maybe getting you high . Check out the wikipedia page on oximes, haha.

 

[Refluxer]

A direct prodrug would likely be an amide or diester.

Matt: Straight minimization of the energy is not very valuable in this case. The conformation in which a molecule binds to a receptor is dependent on a lot more than the ligand itself. Remember that it is not in vacuum when it binds to a receptor. It is however interesting to examine if a molecule can adopt a certain conformation without being too high in energy. In the end, it is the overall sum of energy change in a reaction (process) that will determine if it proceeds or not.

 

[hugo24]

-Acetyl Mescaline seems inactive.Altough the acetyl is said to be labile metabolically.
-O-acetyl hydroxylamines are known but not stable enough I guess,unless the amine is tertiary
-the ketoxime is (in my chemical opinion) too stable to be broken down and I suspect it to be inactive (I'm trying to hear the literature though),it hasn't the basicity for example.
-and,please leave the hydroxylamines aside,you'll run into serious toxicity troubles sooner or later
-you still have all possibilities with the imines as prodrugs

The bk's of the primary amines are possible btw,no problem if your last step is for example an acidic de-BOC-ylation you'll get the pure hydrochkloride of the compound.And its still acidic in your stomach.Later on,cyclisation might occur to some degree,probably dependable on the substitutionpattern on the aromatic ring.And whats the deal when the duration of DOM is reduced a bit?