Potent Serotonergic Phenthylamines (+ A Half Million Noob Questions)

[MrPorter]

Probably been suggested before but I was reading this post earlier (Must note, I didn't read many comments past first page, nor understand all) and they way I understand it, the reason DragonFLY is so potent is because of the aromatic rings from Oxygens 2 lone pairs and the pi bondings lone pair. This totals 3 lone pairs for each furan ring either side of the benzene, totalling 6 lone pairs. 2C-B only has 4, the same with 2CBFLY with 2CBFLY being only a little more potent - I assume by being locked into place by the non-aromatic ring. Would a MethyleneDioxy ring in place of the aromatic furan rings also increase the potency? I just assume this because each ring has 4 lone pairs in the aromatic ring, totalling 8.
I was going to suggest it wouldn't work because it was too bulky, but if butterflys are active still then this should be. But then there's also the difficulty of production or cost or millions of other factors.

I also couldn't find much other information on other halogens except TFM groups, any one know why this might be? Inactive? Iodine seems like it would be slightly more active but since it is bigger could it give some steric hinderance? I can't imagine it does vs things like like Propyl- etc
Also, same post again says a hydrophobic 4 substituent is required and says Halogen > alkyl > thioalkyl > alkoxy. What about Allyl/Vinyl? Halogenoalkyl groups or even halogenoalkoxy? Trouble with synthesis, not hydrophobic? I'm not 100% about bioisosteres but couldn't iodomethoxy or iodoxy (is this even possible?) be better?


The thread also mentions adding a Beta methoxy potentially being better 'because it adds lone pairs of electrons/negative charge into LSD's 9-10 double bond' and because BOHD (2CD analogue) and methoxamine lower blood pressure, battling adrenergic effects. Methoxy groups are also less polar than hydroxy and ketone (thinking bk-mdma etc.) so should be better at crossing the BBB.
It also mentions requiring methoxy at the 2 position, or rather an oxygen directly attached. Could it not be possible to place the furan ring going from 2-> Beta Carbon? Or possibly better a methylenedioxy to fulfill the 2 and Beta Oxygen situation? Thinking about it now I imagine adding substituents simultaneously aromatic and aliphatically would be difficult, I certaintly haven't came across any thing of the sort except a-ethyl joining to benzene to form I think it was mdai? But that's joining a chain to the ring, bit different unless you have a -o-ch2-o- kind of chain protuding at beta... Both would still give planar structures.
Oooh, completely new thought after loading a picture upside down, the 2->B,furan link is pretty much an upside down tryptamine with one less carbon and oxygen in place of nitrogen. Actually you could really fuck about and put a Nitrogen on the 2', complete the tryptamine and make it a tertiary nitrogen by adding half the MD ring on beta, I know tertiary amines are technically inactive but there is still a lone pair on that nitrogen adding to the aromaticity.

I must admit again, I'm just a college kid who struggles to get through a single scientific paper yets wants to be a chemist >.> This might not even make any sense...

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Now for the noob questions,

Springing from the above, 2-CB-FLY's wikipedia has a nice little image of multiple analogues possible. I see 2CBFLY has no alpha methyl group and no aromatic furan rings, BDragonFLY has an alpha methyl group and aromatic furan rings. What would the intermediates be called? (2CBFLY + aMethyl, and 2CBFLY with aromatic furans, no aMethyl) Wikipedia gives nothing but sources on the active dose range of the NBOME-2CBFLY and as far as i can tell they give no indication of potency comparison, nor an actual figure range, any ideas what it could be and if NBOMe-DFLY could work?

Caffeine is a drug without a benzene ring and I'm sure there are others (although most seems to require aromaticity, syaing that... ethanol). I'm not saying I want a huge dose of caffeine analogue but could there be a whole range of psychedelics/stimulants out there that don't require a benzene ring? Are we limiting ourselves? I know we've cracked into pyridine and i think pyramidines but what about furans, purines, thiophenes? I suppose 5 point rings with a Nitrogen in gives very little substituent positions and benzene is basically the boss with 6 possible places.

In say the benzofuran ring, the electrons are delocalised. How delocalised are they? Are they completely free flowing about the ring? Could Carbon-2's be passing C-6's? My chemistry teacher won't explain stuff like this to me, "ooh this isn't on this curriculum and you're wasting my time by asking such silly things"

Speaking about silly things, could a benzene hydrogen 'swing' through the middle or would it be repelled/not fit? What about cyclohexane? Or would it have to be bigger still and be like cyclooctane? Probably completely useless information, but I feel I just have to know.

That will probably do for now, hopefully some of you will be able to help question some of these!

 

[King Kong]

the reason DragonFLY is so potent is because of the aromatic rings from Oxygens 2 lone pairs and the pi bondings lone pair.

The pi bonding isn't a electron lone pair.

If bromo-dragonfly is more potent than DOB, it's not because of the number of "lone pairs". The bromo-dragonfly is locked in the right conformation, which reduce the entropy lost during the binding with the receptor.
The double bonds could also (I am not sure in this case) favor the binding with the receptor through pi-stacking (better enthalpy).

For the rest... I think you should read more about medicinal chemistry before doing some speculation. Here is a very good and free review: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905122/

Have a fun reading!

 

[Solipsis]

Yes the favorable energetic properties make it more easy or indeed less energy-intensive for the drug to bind with the receptor.

King Kong already said this: it is the conformation that makes it energetically favorable. With 2C-B the two methoxy groups are free and able to rotate like tentacles, this happens unimaginably quickly. Constraining is the term for redesigning the chemical structure so that this tentacle is partially locked into place by looping it back to the main ring. Not all manoevrability is eliminated this way but a part is.
Imagine that when 2C-B approaches a serotonin receptor there is a chance that methoxy tentacles are not positioned nicely to activate it, and a chance that they are. Because constraining these groups increases the chance that this part is positioned nicely to fit, this makes it more potent.

Methylenedioxy rings as replacement for FLY / DragonFLY / ButterFLY rings in these compounds are not favorable because there is not 1 but 2 oxygens in the ring. Therefore the electronegativity is resembled more by not 1 but 2 methoxy groups, bound together to loop as a ring, one ring on each side yields 4 methoxy groups total instead of 2.
This just doesn't fit well in the receptors, where a somewhat electronegative (δ-) pocket expects or tolerates an electropositive (δ+) moiety.

That is what was meant by the lone pairs: they are what make oxygen electronegative and carbon not so much.

It's not like the more the better, they work well in some places and not in others, depending on the shape of the receptor pocket.

Still figuring out the rest of your questions.

*You can't find more info on halogens, could you be more specific? You mean other dragonfly types besides bromo?

Apparently the difference between the 4-substitutions is not considered interesting enough for someone to randomly substitute it for something else, this is not restricted to the halogens or haloalkyls.

 

[sekio]

Would a MethyleneDioxy ring in place of the aromatic furan rings also increase the potency? I just assume this because each ring has 4 lone pairs in the aromatic ring, totalling 8.

Not neccesarily - lone pairs are not everything..

I also couldn't find much other information on other halogens except TFM groups, any one know why this might be? ... Halogen > alkyl > thioalkyl > alkoxy. What about Allyl/Vinyl? Halogenoalkyl groups or even halogenoalkoxy? Trouble with synthesis, not hydrophobic? I'm not 100% about bioisosteres but couldn't iodomethoxy or iodoxy (is this even possible?) be better?

I think people just assume that the FLYs will behave similarly to the DOx/2Cx series. That potency ranking sounds right to me. I don't think 4-vinyl/allyl substitiution is worthwhile cos of the possibility for metabolism to hings like the glycol and the ketone... (acetophenone type things). As for iodoxy compounds (hypervalent iodine), those are potent oxidisers/explosivews (c.f. IBX). alpha-halogenated alkoxy groups are also a no go because they are hydrolytically unstable i believe. iodomethoxy groups would likely decompose to methyl iodide & the parent phenol pretty quick.

The thread also mentions adding a Beta methoxy potentially being better

No, not really, see e.g. Shulgin & Shulgin PiHKAL entries for BOx. Generally psychedelics should not touch adrenergic receptors because it can cause serious blood pressure/vasoconstriction issues.

but could there be a whole range of psychedelics/stimulants out there that don't require a benzene ring?

Sure, but they all suck (that dumb straight chain alkylamie used in "bath salts"... name escapes me, and propylhexidrine, and methiopropamine (if you count a thiophene as a benzene replacement). Most drugs end up having phenyl rings because most neurotransmitters have phenyl rings and hey, they're just a handy scaffold.

really this boils down to: SAR is just guesswork based on observations and inferences. it's not a "hard" science like math where you can "prove" a drug will have activity or not just by thinking about it on paper. at least, not at today's level of technology. Shulgin got it right - most of the time pharmacology is a "make em and taste em" kind of business.

I see 2CBFLY has no alpha methyl group and no aromatic furan rings, BDragonFLY has an alpha methyl group and aromatic furan rings. What would the intermediates be called?

Don't think they have names, apart from the IUPAC ones. the whole FLY-naming scheme just invites disaster in my opinion.

In say the benzofuran ring, the electrons are delocalised. How delocalised are they?

The 2' carbon is more electronegative than the others in benzofuran. (A good way to figure this out empirically is look at how e.g. a Friedel-Crafts acylation goes on an aromatic system) I suppose you could ask Chem3d to calculate a map of electron density but that's overkill. Symmetrical systems like benzene have the pi electrons being equivalent, but charges that unbalance the symmetry (i.e. in nitrobenzene) will redistribute electrical charge. Quantum mechanics!

could a benzene hydrogen 'swing' through the middle or would it be repelled... how about cyclohexane? cyclooctane?

the sp2-carbons don't allow that kind of rotation, the benzene molecule stays planar. I am fairly sure the dimensions of the cyclohexane ring do not allow a hydrogen to sit "inside" the ring. perhaps in a cyclooctane ring... I think cyclooctanes are the first class of molecule that is 'loose' enough to allow rotation. see also: Cyclooctene)

 

[Solipsis]

Don't think they have names, apart from the IUPAC ones. the whole FLY-naming scheme just invites disaster in my opinion.

There are some naming conventions although there are inconsistencies like sekio is aiming at... or are they just apparent inconsistencies? (can be just as bad, being just as confusing)

2C-B-FLY - 'fly' corresponds with two dihydrofuranyl rings (no double bond), IMHO by default it is an amphetamine but the '2C' the name starts with shows us that there is in fact NO alpha-methyl. 'B' is of course for the 4-substitution, here bromo.
(DO)B-DFLY - 'dragonfly' corresponds with two furanyl rings (with double bond), no 2C in the name means an alpha-methyl. B is again for bromo.

Intermediates are strictly speaking compounds that are halfway between precursor and product. I think what you mean is crossover compound or hybrid or bridging analogue or something like that:

(DO)B-Fly - dihydrofuranyl rings, alpha carbon, bromo (should be taken as the basis for nomenclature, NOT 2C-B-Fly - check here http://isomerdesign.com/PiHKAL/explore.php?domain=pk&id=2023)
2C-B-DFLY - furanyl rings, no alpha carbon, bromo

IMO the apparent inconsistency comes from believing that with bromo-dragonfly there is no reason to assume it is an amphetamine, raising confusion.
The confusion may be real but I'm not sure if I find there to be a true inconsistency. Sekio?

Butterfly and hemifly compounds are named thus:

I'll put the image in a spoiler - the TS has already mentioned he saw it, in the OP:

NSFW:

http://upload.wikimedia.org/wikipedia/commons/thumb/f/f0/2C-B-FLY-SAR.png/540px-2C-B-FLY-SAR.png[/img
[/nsfw]

About caffeine: there is no fair argument because although caffeine doesn't have a benzene ring it also doesn't [I]directly[/I] affect neurotransmitters that have benzene-rings. It affects adenosine to which it bears striking resemblance. Then, indirectly it does affect monoamines.

Serotonergic drugs are modelled after serotonin which does have a benzene ring. There might be clever ways to create bioisosteres not without any benzene ring this becomes very hard. There are a number of special properties to benzene rings, derived by for example conjugation systems. If this is affected, it changes the electron distribution for a large part of the molecule - this yields compounds that may act or react quite differently.

 

[sekio]

I never drew the analogy from 2cb-fly to (DO)B-FLY. That makes more sense now.

 

[batmanboner]

That is what was meant by the lone pairs: they are what make oxygen electronegative and carbon not so much.

I thought it was the size of the atom the determined this?

 

[Solipsis]

I thought it was the size of the atom the determined this?

Hmmm, I wonder if I recall this correctly: ...

The size of the atom can be remotely involved with this but I wouldn't call it a cause as much as something epiphenomenal. Atoms are not solid balls of matter and their size corresponds to the radius of electron orbits. The size of the nucleus is negligible compared to that radius.
As atomic numbers go up throughout the PT periods so does the number of electrons to occupy a new shell. However throughout the groups in one period, size apparently often decreases.

Let's take fluorine for a moment: being the 7th compound (in the 2nd period), like other halogens the F- ion has 7 electrons in its outer shell. Let it be a bonded F atom in an organic molecule and 1 electron of the 7 is in the covalent bond, the other 6 are coupled into sets of two called the lone pairs according to the octet rule and they are just swarming around doing a whole bunch of nothing.
Those lone pairs make the F-atom an electron-dense portion, at least compared to the rest an average organic compound. What makes it δ- (ever so slightly negatively charged) is that this electron-dense region is benign to harboring any optional electrons, if only just a little bit for a very short time.

(Remember, with atoms, electron presence is just a probability distribution, the electrons are flying around so fast that it makes more sense to consider a place as being more or less likely to have an electron. When you bond atoms of difference electronegativity there forms an inequality in the electron distribution - I think this is what actual polarity or dipole is.)

Now take carbon: it is the 4th compound in that same period, and the 4 electrons in the outer shell can form 4 covalent bonds. There are no lone pairs left, all electrons are preoccupied in bonds and there is hardly a lower shell of electrons present (just the σ-orbit). There is no party of electrons going on, this lack of hospitality makes its partial charge a δ+.

There is some difference between similar atoms, for example between the halogens... the lower they are in the PT, the more occupied electron shells there are, although there is the same number on the outer orbit: namely 7.
Fluorine is the most electronegative, I'm not sure but I guess that this is because the phenomenon I just described is more significant or severe at the lower orbits, the inner shells of electrons, the smaller atoms. I don't know whether this may be due to other orbits interacting (I really don't think they can though) or simply because the radius and sheer surface/volume are larger...

 

[cannibalsnail]

Electronegativity is governed by orbital/shell ratio. Fluorine (using the bohr model) has a ratio of 2:9 hence has the highest possible ratio.

The trend is Electronegativity increases up the group and across the period.

 

[Spooky Snacks]

Drugs interactions are transmitted through increased or decreased chemical availability through the brain and synaptic responses.

This is the only response.