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Acid, dragonflies and the 5HT2A receptor

http://www.heffter.org/review/Review2/chap6.pdf

That's a paper on receptor binding affinities for various lysergic acid derivatives (p. 84). Interestingly, none of those compounds has the activity of LSD in man. One can speculate that if binding affinities for these derivatives can vary so greatly, there is a significant difference between LSD and LSA as well.
 
timely16 said:
Hmm, I searched the literature and the net and I can't find anything on that. Obviously, if the theory presented here is correct, then LSA should have about the same affinity as LSD (which, btw, isn't all that high) for the 2A receptor. If it turns out not to, then we have to reexamine fastandbulbous's case.
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Nor really, I never went anywhere near the effects that different groups on the amide nitrogen have (there's a paper by Nichols that describes the importance of the conformation of the groups attached to the amide nitrogen atom). My above scribblings were purely concerned with the binding to the 5HT2a w.r.t. the aromatic (indolic) nucleus and associated stereochemistry of the C & D rings, especially concerning the importance of a fully conjugated backbone, replacement of the indolic nitrogen with other atoms that contain lone pairs and how the 4 & 5 substitution pattern fit into the receptor binding scheme.

I'm still looking at papers about why the diethylamide configuration is optimal to the binding of lysergic acid derivatives to the 5HT2a receptor. The above theory has absolutely no baring on the role of amide substituents on binding. As I said, I left that area alone because I have no definite model at this time for that region of the LSD molecule (if you note, the above meanderings is concerned with phenethylamines & simple tryptamines, none of which have any structure that impinges on that area of the receptor).


BilZ0r said:
How come ergine/LSA isn't potent?
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The Nichols paper about the amide substituents seems to imply that the groups have to be of a certain size and be able to adapt a specific conformation to interact with that part of the receptor. Not having big enough groups (eg lysergamide & N,N-dimethyl lysergamide) seems to be as big a detriment to affinity as too large (N,N-dipropyl) or too rigid (morpholamide). Bit of a Goldilocks situation (not too small, not too big, but just right) when it comes to those groups and I'm still pondering why...
 
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fastandbulbous said:
I'm still looking at papers about why the diethylamide configuration is optimal to the binding of lysergic acid derivatives to the 5HT2a receptor. The above theory has absolutely no baring on the role of amide substituents on binding. As I said, I left that area alone because I have no definite model at this time for that region of the LSD molecule (if you note, the above meanderings is concerned with phenethylamines & simple tryptamines, none of which have any structure that impinges on that area of the receptor).

So what do you think about my suggestion of a 4-bromo-dragonfly with a methylene at the beta carbon and a N,N-diethylpropionamide tacked on the nitorgen, which takes into account not only the planar requirements of the molecule, the double bond at positions 9-10 in the LSD molecule, and whatever seems to be going on with the diethylamide moiety (as suggested by experiment and the 3D-QSAR study you cite)? What you would have done, in effect, is almost recreated the LSD molecule, but without completely closing the C and D rings, and the addition of a furan. The benefits of this molecule over LSD would be the rigidity of the electron donor at the 2 position and the hydrophic species at the 4 position. If electron donors at both the furan oxygen and the amide oxygen are overkill, then a N,N-diethylpropionamine might be suitable.
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fastandbulbous said:
I'm still looking at papers about why the diethylamide configuration is optimal to the binding of lysergic acid derivatives to the 5HT2a receptor. The above theory has absolutely no baring on the role of amide substituents on binding. As I said, I left that area alone because I have no definite model at this time for that region of the LSD molecule (if you note, the above meanderings is concerned with phenethylamines & simple tryptamines, none of which have any structure that impinges on that area of the receptor).

So what do you think about my suggestion of a 4-bromo-dragonfly with a methylene at the beta carbon and a N,N-diethylpropionamide tacked on the nitorgen, which takes into account not only the planar requirements of the molecule, the double bond at positions 9-10 in the LSD molecule, and whatever seems to be going on with the diethylamide moiety (as suggested by experiment and the 3D-QSAR study you cite)? What you would have done, in effect, is almost recreated the LSD molecule, but without completely closing the C and D rings, and the addition of a furan. The benefits of this molecule over LSD would be the rigidity of the electron donor at the 2 position and the hydrophic species at the 4 position. The 3,4 position furan might be overkill, but who knows.
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I'm exploring why ergine (lysergic acid
amide) is so much less psychoactive than LSD. It turns out that ergine can
exhibit hydrogen bonding between the amide hydrogen(s) to the ring
6-position nitrogen, but only when the D-ring is is the less-stable boat
form.
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Does that make any sense to anyone.
 
BilZ0r said:
Does that make any sense to anyone.
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I THINK THIS QUOTE IS SAYING (without endorsing the idea): "But, ergine has 2 hydrogens on the amide group that can undergo H bonding (while LSD has none). So, these are H-bonding to the cyclohexene-ish ringymabob's nitrogen when there's enough energy to get the ring to bend into it's boat (boat vs chair vs twisty versions of each) conformer."

Where's this from anyways? And can't we put the "typical" comformers to bed anyways when we're dealing with steric interaction w/ complex G-protein coupled receptors. Or at least, isn't that bringing SAR way above it's predictive value?
 
Its from some guy who's emailing me.
and can't we put the "typical" comformers to bed anyways when we're dealing with steric interaction w/ complex G-protein coupled receptors. Or at least, isn't that bringing SAR way above it's predictive value?
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... I don't mean to sound stupid, but, Huh? What do you mean.

You mean, compounds with relatively different structures should be able to bind with high affinities to the same receptor, because receptors should be able to make a large number of structurally quite different active conformations?
 
journals...

Thought with all the discussion over here and the journals needed, i'd just drop in that you can get them 'on the fly' by using - www.bugmenot.com . You simply type in the url of the site and it'll give you a user name and password (if its got one). They dont always work, but many do. enjoy.
 
I THINK THIS QUOTE IS SAYING (without endorsing the idea): "But, ergine has 2 hydrogens on the amide group that can undergo H bonding (while LSD has none). So, these are H-bonding to the cyclohexene-ish ringymabob's nitrogen when there's enough energy to get the ring to bend into it's boat (boat vs chair vs twisty versions of each) conformer."
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Thing is, you don't get classic boat/chair conformations with the D ring of LSD/LSA because of the constraints of the conjugated system etc thast prevent the whole molecule from doing much in the way of 'flexing' at all. It's the planar nature of all four rings that contributes so much to the affinity of LSD (and other ergolines) for the receptor, and why the more flexible compounds have a much lower affinity. Besides which, the oxygen of the carboxylic acid group is involved with hydrogen boinding to one of the serine residues of the receptor protein (see one of my previous posts on the subject). Without the rigid, conjugated backbone & the hydrogen bond to the serine residue, ergine (LSA) would be way less potent a compound
 
BilZ0r said:
Its from some guy who's emailing me.
... I don't mean to sound stupid, but, Huh? What do you mean.

You mean, compounds with relatively different structures should be able to bind with high affinities to the same receptor, because receptors should be able to make a large number of structurally quite different active conformations?
Click to expand...

Yes i do think so, but no thats not what I was trying to say. As for what you describe above, of course there are certain electronic interactions which seem very ideal for agonism and affinity (probably most key: amine w/ aspartate on helix 3... and then H bonds on helix 5, and a bunch of aromaticity and lipophilicity. But, theres more than one way to pull that off, and though we haven't dissected this yet, YES it does matter how you pull it off. Think of how many novel agonists of the mu opioids receptor have been described. Their variable activity isn't described completely by classical pharmacology (which of course is great for half-life, absorption, etc... but starts to fail off with potency, activation of secondary messengers, and so on).

The receptor is not the level where pharmacologically important data is going to be coming from if your looking for some sort of selectivity before whacking up rats. Secondary messenger cascades, which are DIFFERENTIALLY activated depending on the agonist in question (described by the rather odd term "agonist directed trafficking"), implies that there must be some mechanism for this to be. Using rhodopsin G-protein models for everything REALLY limits the relevance of experimental observations. This variability in activation is (IMO) a function of HOW the receptor is being agonized. This is a consequence for the most part of localization using proteomic "scaffolding" (blah blah .... PDZ domains and so forth...).

Can you make many (relatively different) compounds w/ a high affinity? Absolutely if you satisfy the general conditions for binding. But this is where what I was trying to say comes in. The molecule is subject to the formation of a range of conformers with energies low enough to form a complex (which is why restricting it's ability to do rotate increases the stability of the ligand-protein complex). But, you get extensive discussion of the conformational change in the receptor as "ideal" or "not ideal". If a receptor was a lightswitch, that'd be all fine and dandy, since all we'd be concerned with is activation. But the receptors a switchboard, and if you push in the right way (for example) Ca2+'ll be released, but only near nNOS.

I think I kind of approached what you said too fastandbulbous...
 
It'd be neat to synth the least potent chemical. I wonder if you can come
above 1 gram to reach threshold.
 
I fully appriciate the idea of agonist-directed trafficking... however, I have seen first hand how signalling in even -primary- cell culture is fucked... How much evidence for agonist directed trafficking is there in naitive tissue?

Also, am I just being retarded, but I can't find a reference to LSAs affinity anywhere... anyone actually got a reference?
 
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I think I kind of approached what you said too fastandbulbous...
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Yeah, it's just I had the urge to put my two pennethworth in and explain why to the nth degree. Sort of happens from a combination of being stuck in the house, my wife not being in from having to be on call this weekend and amphetamine (big contribution from the latter)!
 
Substitution into the benzene ring at the 4 position with a hydrophobic group...have shown activity at doses under 100mg in man: alkoxy; alkyl; halogeno or thioalkyl...Most potent… halogeno > alkyl > thioalkyl > alkoxy …least potent.
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Beyond TMPEA and the nearly unexplored 2C-O-4, is there any real-world data to support this statement, as far as the 2,5-dimethoxyphenylethanamines are concerned? It seems that a para-isopropyl-something group in a 2,5-DMPEA makes for a compound of reduced potency (DOIP), or a compound with an erratic nature nature (2C-T-4.) Heck, even in the tryptamine world, isopropyl groups are strange. Just look at DiPT.

Personally, I think it was premature to dismiss the entire 2C-O series with only 2C-O-4 as an active representative to show for. With the remarkable nature of MEM, I'm surprised 2C-MEM (or 2C-O-2) was never tried. If I had the nessessary skills to produce it, I'd be quick to want to work with this one. I'd also wager that the 4-(2,2,2-trifluoromethyl)oxy analogue is an interesting compound as well.
 
Beyond TMPEA and the nearly unexplored 2C-O-4, is there any real-world data to support this statement
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Comparison of the 4-substituted amphetamines. The 4-alkoxy compounds are the least potent of all the 2,5-dimethoxy-4-X-amphetamines, both in terms of acxtive dosage and receptor affinity. MEM dosage range in humans is 20-50mg and MPM is >30mg. The 4-halo,alkyl or alkylthio compounds all have active doses that are anything from half to a fraction of that of MEM/MPM.

As for 2,4,5-TMPEA & 2C-O-4, compounds with an oxygen atom attached in the 3&4 position are similar to natural neurotransmitters; they fit nicely into the active site of MAO (lone pair binding of both oxygen atoms). With the 4-halo, 4-alkyl and 4-thioalkyl compounds, they do not have an atom with lone pairs to bind in the active site of MAO, or are just too big to fit neatly into the active site (hence their escaping deactivation by MAO). The 4-alkoxy configuration seems to be the most important for metabolism by MAO - hence the lack of activity of 4-methoxyPEA, 3,4-DMPEA and 3,4-methylenedioxyPEA.

The 3,4,5-trimethoxy configuration is most probably resistant to degredation by MAO because of simple steric hinderance (the methoxy groups being bunched too close together for say mescaline to fit into the active site of MAO). That most probably also explains the increase in activity seen with escaline, proscaline and the 4-allyloxy compound.
 
Yeah, but what is to say that 4-ethyloxy-2,5-DMPEA or 4-allyloxy-2,5-DMPEA will not be active psychedelics? Obviously, your guess is as good as mine but I think it is a shame the good doctor did not invesitgate any other 2C-O members. There have been enough surprises in the past with other things, that I think a few of the 2C-Os are worth looking into. Certainly the erratic action of the isopropyl group in other molecules points to the fact that this is not the best substitution for which to base/summerize an entire series.
 
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just posting here so I remember to read it later.
looks like a very good read for when I have some time to soak it all in
 
morninggloryseed said:
Yeah, but what is to say that 4-ethyloxy-2,5-DMPEA or 4-allyloxy-2,5-DMPEA will not be active psychedelics? Obviously, your guess is as good as mine but I think it is a shame the good doctor did not invesitgate any other 2C-O members. There have been enough surprises in the past with other things, that I think a few of the 2C-Os are worth looking into. Certainly the erratic action of the isopropyl group in other molecules points to the fact that this is not the best substitution for which to base/summerize an entire series.
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Escaline been made and explored in PIHKAL. I'd be more interested in the allyl-thio analog but then the tendancy is to just forget about the unsaturation and hit it with a linear alkyl group. After the bromo-dragon-fly saga I find the idea of unsaturated groups quite sickly unless one is dedicated to puncturing their skin with a needle. Just allyl-amphetamine on its own might be good for this purpose, and is also unlikely to be as damaging to the mucous membranes as the 4-fluoro analog.

Edit: I meant vinyl analog, but such compounds may or may not be carcinogenic.
 
Yeah, but what is to say that 4-ethyloxy-2,5-DMPEA or 4-allyloxy-2,5-DMPEA will not be active psychedelics?
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3D studies of the active binding site of MAO enzymes. If an isopropyl group isn't big enough to prevent degradation by the enzyme, you can be pretty certain that an ethyl or allyl group isn't going to be big enough either. 2C-O-4 should have had some sort of activity if it escaped enzymatic degredation. if 60mg+ did next to nothing (as was the case of 300mg of 2,4,5-TMPEA when tried by Shulgin). The 2,4,5-TMPEA reduced the dose of mescaline needed by Shulgin to achive an effect as the TMPEA effectively 'kept the MAO busy' leaving more of the mescaline to do its stuff.

The only way that they got any activity with 2,4,5-TMPEA is when it was injected (sound similar to DMT?). It worked because it was able to bypass the gut MAO (but even then it seemed to get chewed up pretty easily by MAO in tissues etc). Possibly the fly analogue of 2,4,5-TMPEA might escape metabolism by MAO because of steric considerations (as might apply to the whole 2C-O-x series)
 
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