why 2C-TFM is so potent?

[King Kong]

Simple question, why is 2C-TFM so potent?

For what I have understant, the molecule is more powerfull if the 4-substituent is more lipophilic (and if it's not too big, for steric reason). Right?
So, i quote the wiki:
"The trifluomethyl group has a significant electronegativity that is often described as being intermediate between the electronegativities of fluorine and chlorine"

So, the polarity of trifluoromethyl is bigger than chlorine! So, 2C-TFM is less lipophilic than 2c-c! It must be less potent... But it's not the case! WHY?!

Is something special with 2C-TFM to cross the BBB?
Or the molecule bind to the receptor in a different way?
Maybe, the characteristics of a trifuloromethyl is different in a benzene ring?

Thank you for your answer!
Sorry for my english, hope you understant me!
And, sorry if the question is stupid... I make a search but don't find an answer...

Good day!

 

[MurphyClox]

Murphys mom: "There are no stupid questions, just stupid answers!"...

Potency is not a sole function of polarity. Of course, a more lipophilic substance will cross the BBB easier. Then again are aryl chlorides and trifluoromethyl aryls IMO in the same league concerning lipophilicity.

One possible explanation could be the size of CF3 vs Cl. What fits better should be a more efficient ligand, too. Speaking in general terms.

Peace! Murphy

 

[MurphyClox]

In Journal of Medicinal Chemistry 1994, 37(25), p.4346 (that's the Nichols-paper desribing 2C-TFM) , they give some values:

Electronegativity of CF3 = 3.5, compared to Cl = 3.16 (both Pauling scale), compared to F = 3.98. So, I agree, it's between Cl and F. (Note: Combined data from the article and Wikipedia)

The sizes given (effective van-der-Waals-radius) are:
CF3 = 2.20 Å
I = 1.97 Å (which showed similar ability to displace ketanserin-labeled 5HT2A/2C-receptors; of course this is no functional assay and tells only half of the story)
Br = 1.86
Cl = 1.75 (Wiki)

So, we encounter a significant difference in sizes, comparing CF3 vs. Cl. This could be, as said before, the explanation for higher efficacy at the receptors.

Hydrophobicity values (As measured by the relative partition coefficients of meta-substituted 3-phenoxyacetic acids between octanol and water):
Br = 0.94
I = 1.15
CF3 = 1.07
So, trifluoromethyl is between Br and I and significantly more hydrophobic than chlorine. Actually, I didn't find values for Cl but the trend from I to Br to Cl continues. Therefore, the hydrophobicity for chlorine must be smaller than 0.94.


Peace! Murphy

 

[Vanadium]

Salut king kong tu vas bien ???


By looking at the attached image, you can know why the 2c-family has the perfect structure to binds at the 5-HT2A receptors. There are many way to transform a molecule to a more potent analogue.

1) adding an alpha methyl protect form enzymatic destruction. i.e. 2c-I/DOI

2) Allowing the oxigen lone pair electron to create an intermolecular O-H bond. i.e. 2c-B/2C-B-FLY

3) Replacing the 4-substitued group with a more lipophilic one. trifluoromethyl is extremely electronegative and lipophilic. this is the case of 2c-TFM. Other groups such as pentafluoroethyl or pentafluorosulfanyl are more lipophilic than TFM. So it is logical to think that they are more potent than 2C-TFM...

Ma knowledge in pharmacology is very limited (just like my english...). Correct me if I'm wrong... thank you.

Bye !

 

[MurphyClox]

No correction but an addition:
Adding an alpha-methyl doesn't only protect from enzymatic degradation but increases the intrinsic activity, too! While affinities for compounds with and without an alpha-methyl are in a similar range, effective activation isn't (measured by 5HT2A-mediated activation of PLC).

Ref.: J Neurochem 2005, 95, p.1575

 

[fastandbulbous]

Vanadium, is thast diagram the original from hte Nichols paper or the modified version I used in my 'Acid, dragonflies & the 5HT2a receptor' thread?

As regards activity as well, the CF3 group is metabolically fairly indestructible unlike thre analogous methyl group


The above does raise the question as to why 4-fluoro-2,5-dimethoxyphenethylamine isn't the most potent of the lot? (I think it's because the 4-fluoro group doesn't prevent MAO from attaining it's active conformation once the PEA has attached to the active site, unlike larger halogens and alkylthio groups which lead to competetive inhibition to some degree)

 

[Hammilton]

It's worth mentioning again: just because something has a higher affinity it doesn't mean it's a more potent psychedelic/hallucinogen (mind vs. eye). IIRC, both pathways need to be activated, not just PLC, right?

 

[mad_scientist]

I'd say the reason for the low potency of 2CF is just that the fluorine atom is too small, despite being the most electronegative it just doesn't fill the binding pocket properly. 2CEF with a beta-fluoroethyl substituent is highly potent again. Agreed that the pentafluoroethyl and pentafluorosulfonyl compounds would be very interesting to see tested.

 

[King Kong]

First! A big thanks for all your answers!

3) Replacing the 4-substitued group with a more lipophilic one. trifluoromethyl is extremely electronegative and lipophilic. this is the case of 2c-TFM.

Coucou Vanadium!

Normally electronegative substituents create a strong dipole. In the most cases, a lipophilic molecule is almost non-polar... So why trifluoromethyl is so lipophilic? Her big size no?

In a larger subject. Branched alkanes is lipophilic, maybe good size... It must be a good "4-" substituents! Someone try to put a isopropyl or tertbutyl? I have find no data...

To stay in the topic...

As regards activity as well, the CF3 group is metabolically fairly indestructible unlike thre analogous methyl group

A hardly metabolised molecule dosen't implies very long effect?
But the duration of 2C-TFM is "only" for 6 to 8 hours! That's not so long... So, my theory must be false?!


Sorry, I am like a little boy asking a lot of questions... But I want to understant this topic quiet good! Thanks!
Good day!

 

[MurphyClox]

A hardly metabolised molecule dosen't implies very long effect?
But the duration of 2C-TFM is "only" for 6 to 8 hours! That's not so long... So, my theory must be false?!

Well, the most probable sites of metabolic degradation are supposed to be the amino-function (...MAO), the methoxys (maybe COMT or other methyl transferases) and the CF3. Then again does our body not posess the ability (i.e. the necessary enzymes) to degradade any organic fluorine compound (IIRC). Therefore, metabolism is "reduced" from 3 possibilities (like with 2C-B or alike) vs. just 2 possibilites with 2C-TFM.

So, your "theory" and FnB's statement are not mutually exclusive IMO.

Peace! Murphy

 

[Morninggloryseed]

In a larger subject. Branched alkanes is lipophilic, maybe good size... It must be a good "4-" substituents! Someone try to put a isopropyl or tertbutyl? I have find no data...

3 is the magic number (although strangely the amphetamine and probably the phenethylamines with an 4-isopropyl isnt very active) with regards to butyl and higher. It's true in reference to the potency of the 4-position in magic phenethylamiens, the alkyl chain in phenethylamines/amphetamines, as well as the N-alkylated tryptamines....potency keeps rising with each additional carbon atom until you get to three...

2C-E < 2C-P
PEA < AMP
DET<DPT

once you get to butyl all is futile ( to paraphrase Shulgin).

 

[egore]

Maybe someday I will again reunite with 2c-cf3, someday...

 

[dread]

What about a trifluoroethenyl-group?

I even thought a jazzy name for it: 2C-TFV as in trifluorovinyl...

 

[fastandbulbous]

A hardly metabolised molecule dosen't implies very long effect?

No some unmetabolized compounds are still pissed out fairly quickly (can't recall one at the moment, but give me a minute!)

 

[MurphyClox]

No some unmetabolized compounds are still pissed out fairly quickly (can't recall one at the moment, but give me a minute!)

maybe diethyl ether? dunno if it's cleared renally but it gets cleared fast and unmetabolized

 

[fastandbulbous]

It's mainly got rid of via the lungs (in breath) rather than pissed out, but thanks that is an example

 

[Vanadium]

Vanadium, is thast diagram the original from hte Nichols paper or the modified version I used in my 'Acid, dragonflies & the 5HT2a receptor' thread?

Yes I took it form that Nichlos paper http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=6484

What about a trifluoroethenyl-group?

I even thought a jazzy name for it: 2C-TFV as in trifluorovinyl...

I'd like to see what the vinyl group attached to the 4 position can do ! The trifluorovinyl can be interesting as the monohalogenated chlorovinyl or bromovinyl !

 

[vecktor]

Yes I took it form that Nichlos paper http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=6484

I'd like to see what the vinyl group attached to the 4 position can do ! The trifluorovinyl can be interesting as the monohalogenated chlorovinyl or bromovinyl !

The betachloro and beta bromo styrenes halovinyls are going to be horrible irritants, ask anyone who has ever come into contact with betanitrostyrene or betachlorostyrene, as well as being irritant as solids, both have vapours which potently irritate the skin on the face.

I wondered that it may be that highly withdrawing groups in the four position make the ring-oxygen bonds in the methoxy groups more polar, allowing them to interact more effectively with the hydrogen bond donors in the receptor, certainly a combination of lipophilic and electron withdrawing seems to give the greatest potencies.

someone needs to make the 4- trifluoromethoxy 2,5-dimethoxy PEA, but the chemistry is a bitch, and they are illegal in some countries.

are people sure that the duration of 2-ctfm is 8 hours? I have heard it is longer. The amph DOTFM is stupid potent and very long lasting.

 

[hugo24]

In my book its 8-10 hours,maybe a bit longer with higher doses.Not aware the human data of DOTFM is known at all,Nichols found alarming disuptions in rat behaviour if I remember that correctly.

 

[vecktor]

^ I have heard rumours that the shulgin group have tasted it DOTFM, and found it to have an extreme duration. some of the 2-ctfm that was around a while back (2yrs or so ago)was not 2-ctfm rather it was mostly 2-CI due to a botched synthesis.
if it has 8-10hr duration it is interesting, though not in the UK.