4-(2-chloro/bromo/iodo)-2,5-dimethoxyPEA

[GrendelAvenger]

So I was thinking about 2C-EF (4-(2-flouroethyl)-2,5-dimethoxyphenethylamine and I was wondering about putting a chlorine, bromine, or iodine atom in place of the fluorine. Do you guys think that such compounds might be worth some study? No, I'm not talking about doing synthesis (and it's a bitch of a synthesis for 2C-EF as it is), but I was wondering if the same principle could be applied to the other halogens.

Also I was curious about 4-thio PEAs with a halogen stuck onto the sulphur. Stupid nonsense? Or not?

Thanks in advance if anybody takes up the thread with some ideas or answers.

Cheers

 

[Astavats]

Haloalkanes may pose an issue of reacting with the biological environmental, with the exception of fluorine. I believe a halogenated sulfur would pose a similar risk though, perhaps greater. No idea about "R-S-F", "(R)3-S-F" or "(R)5-S-F" or how enzymes would deal with them. I give the idea a thumbs down* unless someone corrects the listed faults.

Also a thread exists already for such discussions.

 

[reformer]

RSF + RNuH --> Death and Dismemberment?

I was curious about 4-thio PEAs with a halogen stuck onto the sulphur.

"R-S-F", "(R)3-S-F" or "(R)5-S-F"

Oh man o' man. A halogenated thiol compound would be a wicked electrophile targeting biological nucleophiles with likely devastating results.

The reaction would be (for a DNA amine or protein lysyl group, for example):

RNH2 + R'SF --> RN(H)SR' + HF (the HF dissociating at physiological pH).

Likely though, the dominant reaction would be to consume all your glutathione (GSH) in the following fashion:

GSH + R'SF --> GSSR' + HF

An analogous reaction to the glutathione adduction shown immediately above occurs with sulfenic acids in vivo, so the potent nature of the flourine as a leaving group would certainly make the thienylhalides you mention exceptionally reactive.

Sulfenic acid reaction: RSOH + GSH --> RSSG + H2O

tl;dr = Hell F'ing No Way.

My bet is that you couldn't even synthesize these! They wouldn't make it through the concentration steps, and would hydrolyze to RSOH and HF upon contact with water.

 

[Epsilon Alpha]

So much win in the post above
But, thio substituted PEA's tend to inhibit MAO-A and cause unfortunate side effects like death.

 

[Morninggloryseed]

there is the known active called DOMCL (4-chloromethyl-2,5-DMA) but those who know said humans would not want to eat it as the metabolites could represent a danger. Chlorine hold on for dear life when attached to a benzene ring, that is not true of chlorine when attached to a single carbon atom...or that is what i remember. If you search back many years ago I made a thread on DOMCL and DOMOM (4-methoxymethyl-2,5-DMA) and there is some interesting info. Not halogenated DOET, but close.

But, thio substituted PEA's tend to inhibit MAO-A and cause unfortunate side effects like death.

You thinking of that German paper? I thought it was confirmed that the paper does not say this...MAO inhibition is only seen in the ALEPH series.

 

[ebola?]

This paper (again, with Nichols as a coauthor) should elucidate things:

http://pubs.acs.org/doi/abs/10.1021/jm0493109

I now lack access to academic journals though. Can someone read the full text and report the findings to us?


MGS:

While your overall summary of the trend is correct, we have to begin talking about level of MAO inhibition. This can range from very low, as with amphetamine (which acts as a competitive inhibitor of MAO by virtue of being a substrate for it) to very high, as with harmala alkaloids. Some 4-x-thio substituted phenethylamines (eg, 2ct7) show MAO inhibition significant enough to prove unsafe in combination with monoamine releasers and in high dosages. 4-x-thio substituted amphetamines show much higher levels of MAO inhibition though.

ebola

 

[Astavats]

http://pubs.acs.org/doi/abs/10.1021/jm0493109

http://www.mediafire.com/?deqdedhduh79bl9

*If this violates the rules let me know and it won't happen again.

 

[tryp2fun]

There seems to be a lot of misinformation going around about MAO inhibition by phenethylamines. All the 2Cs are not inhibitors, they are substrates, as you can see here:

Biochem Pharmacol. 2007 Jan 15;73(2):287-97. Epub 2006 Sep 24.
Identification of monoamine oxidase and cytochrome P450 isoenzymes involved in the deamination of phenethylamine-derived designer drugs (2C-series).
Theobald DS, Maurer HH.

Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, D-66421 Homburg (Saar), Germany.
Abstract

In recent years, several compounds of the phenethylamine-type (2C-series) have entered the illicit drug market as designer drugs. In former studies, the qualitative metabolism of frequently abused 2Cs (2C-B, 2C-I, 2C-D, 2C-E, 2C-T-2, 2C-T-7) was studied using a rat model. Major phase I metabolic steps were deamination and O-demethylation. Deamination to the corresponding aldehyde was the reaction, which was observed for all studied compounds. Such reactions could in principal be catalyzed by two enzyme systems: monoamine oxidase (MAO) and cytochrome P450 (CYP). The aim of this study was to determine the human MAO and CYP isoenzymes involved in this major metabolic step and to measure the Michaelis-Menten kinetics of the deamination reactions. For these studies, cDNA-expressed CYPs and MAOs were used. The formation of the aldehyde metabolite was measured using GC-MS after extraction. For all compounds studied, MAO-A and MAO-B were the major enzymes involved in the deamination. For 2C-D, 2C-E, 2C-T-2 and 2C-T-7, CYP2D6 was also involved, but only to a very small extent. Because of the isoenzymes involved, the 2Cs are likely to be susceptible for drug-drug interactions with MAO inhibitors.

Granted, competing substrates can result in inhibition, but it will be weak and transient. The corresponding amphetamines are much better inhibitors because they are much slower substrates but still bind well. IIRC, the most potent of the amphetamines as an MAO inhibitor is the ethylthio (Aleph-2), not the propylthio (Aleph-7). The reason for the deaths resulting from 2C-T7 ingestion has never been established as resulting from MAO inhibition by the compound, it is just speculation. In contrast, as can be seen from the abstract, MAO inhibition in combination with 2C-Xs is potentially dangerous. IIRC, the deaths involved combinations of 2C-T7 with other things.

 

[fastandbulbous]

Biological targets of MAO are dopamine, noradrenaline etc - catecholamines with an oxygen atom on the 4 position on the ring. Compounds like 2,4,5-trimethoxyPEA are inactive because they are susceptable to metabolism by MAO, whereas 2C-T is identical to 2,4,5 trimethoxyPEA except for having a sulphur atom instead of an oxygen atom at the 4 position; 2C-T is active orally. The only way I could account for this is that 2C-T occupies the active site od MAO, but prevents it taling up the active conformation of the enzyme (probably because of it's greater size). I believe this occurs because sulphur is directly below oxygen in the periodic table and as such has the same electronic configuration. As such, that would imply that all 4-substituted PEAs with a sulphur atom replacing the oxygen would be competetive inhibitors of MAO