5-HT2B SAR and speculation

[kazure]

Hello everyone, please keep in mind that I'm a noob in the field, so forgive any mistake I may make.

I had a question regarding 5-HT2B receptor structure-activity relationships in molecules. The reason I was wondering what kind of characteristics a molecule needs to have in order to act as an agonist on 5-HT2B receptors is speculation about a particular research chemical, 2-FMA. I'll get to this soon enough.

As you know, 5-HT2B agonism is associated with cardiac problems. I was looking at the Wikipedia page for the 5-HT2B receptor and it provides a list for its known agonists. Now, a thing I have noticed is that if the agonist has an amphetamine-like structure, then it basically always has to have something bound to the 3 or 4 position in the benzene ring, in order to show 5-HT2B agonistic activity.

For example:

6-APB

MDMA

Norfenfluramine

Fenfluramine

Chlorophentermine

And the list goes on and on. As you can see, we basically always have something bound to the 3rd or 4th position in the benzene ring. Could this be required in order to display 5-HT2B agonism? And in that case, is it possible that 2-FMA (molecule shown below) wouldn't manifest it (fluorine bound to the 2nd position)?

 

[Hodor]

Based on my understanding, 2-FMA should show very little - if any - 5HT2B agonism.

In general, substances capable of activating 5HT2B also tend to exhibit entactogenic (as 5HT2B agonism seems to affect the release of serotonin) and/or psychedelic properties (due to the close structural relationship between 5HT2B and 5HT2A).

As you already noted, the "ideal" location for a single substituent on an amphetamine in order to activate 5HT2B seems to be in the 3- or 4-position; also, N-alkylation apparently decreases the level of 5HT2x agonism (fenfluramine is significantly less active as a 5HT2B agonist than its metabolite, norfenfluramine).
Furthermore, fluorine is pretty much the smallest substituent you can attach. The trifluoromethyl group on fenfluramine is significantly bigger than the chlorine on chlorphentermine, which is in turn significantly bigger than a single fluorine; this is also reflected in 3-FA and 3-FEA being considered mostly stimulating and only mildly entactogenic (i.e. very close to their non-ring-substituted counterparts), whereas fenfluramine was so selective for serotonin over dopamine/noradrenaline that it was never regarded as being anywhere near as recreational as other amphetamines.

 

[kazure]

Based on my understanding, 2-FMA should show very little - if any - 5HT2B agonism.

Yes, that's what I figured too from available data.

In general, substances capable of activating 5HT2B also tend to exhibit entactogenic (as 5HT2B agonism seems to affect the release of serotonin) and/or psychedelic properties (due to the close structural relationship between 5HT2B and 5HT2A).

Indeed, and there's evidence that even at high dosages (100+ mg) 2-FMA doesn't present entactogenic effects.

Furthermore, fluorine is pretty much the smallest substituent you can attach. The trifluoromethyl group on fenfluramine is significantly bigger than the chlorine on chlorphentermine, which is in turn significantly bigger than a single fluorine; this is also reflected in 3-FA and 3-FEA being considered mostly stimulating and only mildly entactogenic (i.e. very close to their non-ring-substituted counterparts), whereas fenfluramine was so selective for serotonin over dopamine/noradrenaline that it was never regarded as being anywhere near as recreational as other amphetamines.

This is very interesting and I wasn't aware of it at all. So, this means that the bigger the substituent is, the greater the effect on 5-HT2B is? Vey cool.

At this point I wish we had some mass spectrometer analysis to determine 2-FMA metabolites, it is speculated that the metabolic pathway is the same as methamphetamine, i.e.:

The difference being that the fluorine atom should block para-hydroxylation and thus avoid the 4-hydroxy meth metabolite, effectively yielding 2-FA by itself (and possibly 2-fluoro-phenylacetone?). Then dunno about 2-FA metabolism, could give 2-fluoro-phenylacetone as well...

Would really love to know the exact details, and most importantly, if any of these metabolites are toxic in any way.

 

[Cotcha Yankinov]

Indeed, and there's evidence that even at high dosages (100+ mg) 2-FMA doesn't present entactogenic effects.

Just to play devil's advocate, a substance could still be active at 5-HT2B and not produce entactogenic effects as long as its not also a substrate for SERT, and it appears 2-FMA is indeed more of a DA/NE releasing agent rather than a triple monoamine releaser

There is some correlation between a molecule having activity at SERT and also having activity at 5-HT2B but I'm sure that there are exceptions

One thing to consider is that some molecules have affinity for 5-HT2B but are very poor at activating 5-HT2B - e.g. partial agonists/weak agonists. The full agonism is what people are usually concerned about, and for that you would need a functional assay to test how potently 2-FMA actually activates fibroblast's 5-HT2B

 

[Hodor]

This is very interesting and I wasn't aware of it at all. So, this means that the bigger the substituent is, the greater the effect on 5-HT2B is? Vey cool.

I wouldn't generalize it like that... it may very well be that iodine could be inferior to bromine because it is *too* large, or not electronegative enough. Fluorine is strongly electronegative, but it is also pretty tiny. If we look at the 2C-X series of phenylethylamines, 2C-I and 2C-B are considered to be of similar potency, 2C-C is significantly weaker and 2C-F is barely active at all. Not saying you can directly extrapolate from this SAR since the 2C-X are fairly selective for 5HT2a/2c over 2b, just pointing out that sometimes size does matter (no pun intended).

A trifluoromethyl tends to act as a "pseudohalogen" that is bigger than chlorine (although somewhat irregularly shaped) and strongly electronegative, so there are various situations where it can be superior to either a plain methyl or any of the true halogens. Looking at the 2C's again, 2C-TFM is apparently significantly more powerful than 2C-B or 2C-I (Daniel Trachsel reports it to be an active psychedelic at 3-5mg).

However, for the reasons Cotcha Yankinov posted, take this all with a chunk of salt. While 2-FMA can be reasonably assumed to possess relatively little cardiotoxicity/neurotoxicity compared to other substituted amphetamines, it is certainly never a good idea to go overboard with almost completely unexplored chems.

 

[Limpet_Chicken]

Electronegativity seems to play a strong role in terms of activity in phenethylamines/amphetamines etc. at the 4 position, as psychedelic. But size also, it seems like there is a minimum size, rather than solely metabolic effects (contrast DOH to DOF, the fluorinated version is similarly inactive or poorly active seeming, with that tiny fluorine, but which can't just be lopped off metabolically. But 2C-TFM and DOTFM are both known to be highly potent.

Anyone know what the general trend is for electronegative, reasonably sized 3,4,5-trisubstituted phen or phet substituents, (in this case, it is to be a bromine atom, specifically, and the 5 position is methoxy, whilst the 4' phenyl carbon is a difluoromethoxy substituent.

(I.e the 3-bromo analog of difluoromescaline)

 

[Hodor]

Anyone know what the general trend is for electronegative, reasonably sized 3,4,5-trisubstituted phen or phet substituents, (in this case, it is to be a bromine atom, specifically, and the 5 position is methoxy, whilst the 4' phenyl carbon is a difluoromethoxy substituent.

(I.e the 3-bromo analog of difluoromescaline)

According to Shulgin, 3,5-Dimethoxy-4-Bromoamphetamine causes a suppression of pain, but no noticleable psychedelic effects at doses of up to 10mg.

Meta-DOB (2,4-Dimethoxy-5-Bromoamphetamine) is significantly weaker than DOB - according to secondhand reports mentioned in PIHKAL, doses greater than 50mg seem to produce anxiety and paranoia that may be interpreted as a psychedelic effect, although they are overshadowed by a very unpleasant body load.

So bromine doesn't seem like it would be all that effective in combination with a 3,4,5-substitution pattern, nor at the 5-position in a 2,4,5-substituted DOx; I would also expect this to be a bitch to synth, especially in relation to the low expected potency.