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Acid, dragonflies and the 5HT2A receptor

fastandbulbous

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Factors that influence the structure-activity relationship (SAR) of psychedelic drugs with respect to their agonist activity and binding at the 5HT2A receptor site - a possible new series of high potency 5HT2A agonists

The 5HT2A receptor is possibly the most important when it comes to investigating the actions of psychedelic drugs. These drugs belong almost exclusively to the phenethylamine, tryptamine and ergoline groups of compounds. The other sites that are believed to be important in how they exert their activity are the 5HT1A and 5HT2C receptors (the arrangement of the sites important for binding of compounds to the 5HT2C site are remarkably similar to those of the 5HT2A receptor).

In binding studies using cloned 5HT2A receptor, the drug(s) used in assays using radiolabelled markers are DOB and DOI (4-bromo-2,5-dimethoxyamphetamine and 4-iodo-2,5-dimethoxyamphetamine, respectively). SAR studies carried out by A Shulgin, and documented in the book PIHKAL have shown the following to be needed for maximum activity:

A ring substitution pattern that has methoxy groups at positions 2 and 5 on the benzene ring. Any variation, by either substitution of ethoxy groups for one or both methoxy groups, or substitution into the benzene ring in a pattern other than at position 2 and 5, leads to a reduction of activity; in most cases, this produces a marked fall in activity.

Substitution into the benzene ring at the 4 position with a hydrophobic group. Compounds formed by the use of any of the following groups have shown activity at doses under 100mg in man: alkoxy; alkyl; halogeno or thioalkyl. In order of the potency of the compound formed, they show the following pattern

Most potent… halogeno > alkyl > thioalkyl > alkoxy …least potent.

Within those groups, the more hydrophobic the group, the higher the activity. This is only limited by stearic considerations when the groups become very large. So for each group, the ordering is as follows:

Halogens Iodo > bromo > chloro >> fluoro

Alkyl Propyl > ethyl > methyl >> butyl >> pentyl(amyl)

Thioalkyl Propylthio > ethylthio > methylthio

With the alkoxy substituents, the nature of the intoxication seems to change qualitatively as the group gets bigger.

On the side chain, bearing the ethylamine function, an alpha methyl group (amphetamines) gives greatest activity, followed by the unsubstituted chain (phenethylamines). Substitution into the alpha position by a group larger than methyl abolishes any psychedelic activity.

Alpha substitution activity… methyl > hydrogen >>> ethyl.

Using the above data from PIHKAL, the most potent compound is either DOI or DOB, as both were fully active at about 2.5mg. Fig 1 shows how the relevant substitution pattern interacts with the 5HT2A receptor (diagram modified from original present in a paper by D Nichols)


figure_001.jpg



Further developing the SAR theme started by Shulgin, Nichols produced some conformationally restricted analogues of DOB (they’ve been nicknamed the “dragonfly” compounds, most probably because of their structural resemblance to said winged insects). Fig 2 shows the structure of a couple of the “dragonfly” compounds, and DOB for comparison. Also given are receptor binding data for the three compounds.


figure_002.jpg




As can be seen from the binding data, both of the dragonflies are more active than DOB, the three ringed, fully aromatic compound being the most potent (the dihydrofuran derivative is fully active in man at a dosage of 800-1000ug (0.8-1.0mg), and the fully aromatic furan derivative should be active at an even smaller dosage in man). The lone pairs of electrons on the oxygen atoms of the methoxy groups have been prevented from rotation by incorporation into a furan ring system fused with the benzene ring. The fully aromatic compound shows even more activity, and this is thought to be because all of the atoms of the three rings lie on the same plane. This is thought to be needed for maximum activity (with tryptamines, the indolic nitrogen is in the same space as the oxygen of the 5-methoxy group. Only difference is that nitrogen has only 1 lone pair electrons. The 2-methoxy group corresponds to the 5-hydroxy group of serotonin)

Fig 3 shows how the fully aromatic dragonfly compound would interact with the 5HT2A receptor, and its structure is compared with LSD (the aromatic dragonfly compound’s structure has been overlaid that of LSD for easier comparison. Also, the structure of 5HT/serotonin has also been overlaid that of LSD).


59655fig_3.JPG



It can be speculated that one of the reasons that LSD shows such high potency as a psychedelic agent in man is because all of the atoms of the indole nucleus, and that of the ring directly attached to it (rings a, b and c – see fig 5), all lie in the same plain, hence presenting a flat face to the receptor. Reduction of the double bond of the other ring (the d ring, that contains the tertiary amine function), abolishes the activity of LSD. Reduction of this bond also removes the conformational restraint that holds the a, b and c ring in the same plane, and the carbon atom at position 4 in LSD is forced either above or below the plane of the indole nucleus. This pushes it into the region of stearic occlusion, which in turn abolishes any activity. It is this area of stearic occlusion that is responsible for the loss of activity when an alpha methyl group is replaced by an alpha ethyl group in the phenethylamine hallucinogens (and why the 2-aminotetralin derivatives are devoid of activity – the saturated ring would not be flat, but would take a modified version of the boat/chair form that cyclohexane exhibits)..

Fig 4 shows a comparison of activity of the 2,5-dimethoxy-4-methylamphetamine (DOM) that occurs with different substitution patterns into the sidechain ethylamine function. As expected, there is a loss of activity that comes with the loss of the alpha-methyl group to give the compound 2C-D. Movement of the methyl group from the alpha position to the beta position causes activity to drop off dramatically (beta-methyl 2C-D). Replacement of the beta-methyl group with a beta-methoxy group (to give BOD), shows a twofold increase in activity over 2C-D. This being the case, the lack of activity of beta-methyl 2C-D cannot be explained as being due to stearic hindrance, as the methoxy group is quite a bit larger than the methyl group. Other than the size of the groups, the other main difference is that the oxygen atom of the methoxy group has two lone pairs of electrons, whereas the methyl group has none.


figure_004.jpg



At this point, it is advantageous to look at the comparison of two tryptamine hallucinogens, in order to shed some light on the activities of the DOM/2C-D derivatives. Comparing N,N-dimethyltryptamine (DMT), with its 4-hydroxy derivative (psilocin), one would expect to see a reduction in activity in psilocin, as the polar OH group would reduce the ability to cross the blood brain barrier: What in fact is seen is a 5 fold increase in activity.


figure_005.jpg



Fig 5 shows the structural configuration of psilocin and BOD superimposed over that of LSD. The thing that they have in common is that the oxygen atom in each compound is in a position to donate lone pairs of electrons into the space that would be occupied by the delocalised pi electrons of the double bond in LSD. The lack of activity of beta-methyl 2C-D confirms that there needs to be negative charge in the area of the double bond. It comes from the delocalised pi electrons in the case of LSD, and lone pairs in the case of psilocin and BOD. Because beta-methyl 2C-D “sticks an atom” into that space, but without a concentration of negative charge to interact with the positive charge in the receptor protein, it binds much more weakly than either 2C-D (doesn’t try to push a methyl group in there) or BOD (oxygen atom puts negative charge – lone pair electrons – into that space) Fig 5a shows distribution of negative charge (pi electrons) around double bond in d ring.


figure_005a.jpg



As well as contributing the negative charge, the double bond holds all 4 carbon atoms in the same plane as the atoms of the benzene ring, which as mentioned earlier is very important for receptor binding. The proposed phenethylamine/amphetamine 5HT2A agonists in fig 6 have the whole phenethyl skeleton held in the same plane due to the conjugation of the pi electrons with the delocalised electrons of the benzene ring, as well as presenting the pi electrons in the correct position. They should be more potent than their corresponding amphetamine derivative, as they will bond more strongly to the receptor. This also removes any complications that might occur with any adrenergic receptor interaction (the beta-hydroxy 2C-D derivative, BOHD caused a large drop in blood pressure – in fact the drug methoxamine has the 2,5-dimethoxy configuration, and a beta-hydroxy group, and it is a potent pressor agent), as the beta-hydroxy oxygen atom is in the same position as the benzylic hydroxy group oxygen atom. The corresponding DOM derivative would be 3-amino-2-(2,5-dimethoxy-4-methylphenyl)butene, and the 2C-D derivative would be 3-amino-2-(2,5-dimethoxy-4-methylphenyl)propene.


figure_006.jpg



Also shown in fig 6 is a modification that retains the double bond, substituted into a tryptamine, but retaining the conjugated system of the aromatic nucleus (indole instead of benzene). This would produce a series of 4-vinyl-N, N-dialkyltryptamines, which again should be more potent than their corresponding 4-hydroxy-N,N-dialkyltryptamine, and as the group is far less polar, so should allow better penetration of the blood brain barrier


59655fig_6a.JPG




Fig 6a shows all these modifications taken to their logical conclusion in the double bond version of the fully aromatic dragonfly molecule. If in this molecule, there is an increase in potency of the same magnitude as would be expected when applied to DOB etc, then it could possibly be a phenethylamine derivative that is on a par with LSD in terms of binding, dose etc


Numbering system of phenethylamines, tryptamines and ergolines is outlined in the jpeg attachment



If anybody can be bothered to plough though all of that, please point if I’ve not seen some obvious flaw in my reasoning


Papers referenced

James J. Chambers, Deborah M. Kurrasch-Orbaugh, Matthew A. Parker, and David E. Nichols. Enantiospecific Synthesis and Pharmacological Evaluation of a Series of
Super-Potent, Conformationally Restricted 5-HT2A/2C Receptor Agonists. J. Med. Chem. 2001, 44, 1003-1010

Nicholas M. Barnes; Trevor Sharp. A review of central 5-HT receptors and their function. Neuropharmacology 38 (1999) 1083–1152

David E. Nichols, Ph.D. The Medicinal Chemistry of Phenethylamine Psychedelics. The Heffter Review of Psychedelic Research, Volume 1, 1998

F. A. B. Aldous, B. C. Barrass, K. Brewster, D. A. Buxton, D. M. Green, R. M. Pinder, P. Rich, M. Skeels, and K. J. Tutt. Structure-Activity Relationships in Psychotomimetic Phenylalkylamines. J.Med. Chem., 2974, Vol. 27, No. 20 1100 - 1111

Nichols D.E, LSD and Its Lysergamide Cousins. The Heffter Review of Psychedelic Research, Volume 2, 2001, 80-87

Shulgin Ann & Alexander T. PIHKAL (Phenethyamines I Have Known And Loved)

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The final bit was just theoretical pondering on what should happen, but it’ll really need somebody to synthesize it and carry out trials with it to definitely confirm or deny the activity
 

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Excellent post fastandbulbous. I've considered each of these areas of 5-HT2a ligand binding, and have read Nichols papers describing the dragonfly moiety. But I've never laid these out as you have done.

I think your reasoning is basically sound, although I'm a bit unsure about the conformational comparisons -SAR wise- of a double bond compared to lone pair restrictions you mention. I also wonder if the terminal alkene would survive metabolic attack long enough to cross the BBB.

All in all a concise and easy to read post. Thanks very much
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Close enough for jazz!

Thanks, it’s something I’ve had forming in my mind for quite a while now, so I did worry about that a bit; I’ve stuck my ideas about it underneath

In all the receptor agonist interaction diagrams I’ve seen, where the 3D model of the receptor protein shows the hydrogen bonds etc with the drug, they’ve always looked like the match between charges just has to about in the same position, that being why you can get drugs with different molecular structures that still act as agonists. The example here being that the oxygens of the 2,5-dimethoxy - phenethylamine confiuration only approximates to the oxygen and indolic nitrogen of 5-methoxy-N,N-dialkyltryptamines (and 5HT), in that they are carriers of lone pairs. In the same way, either the pi electrons of the double bond, or the lone pair of an oxygen have to be about in the same position – that’s all they really have in common – an area of negative charge. The corresponding area of the receptor proteins will an area of some sort of positive charge, like an NH3+ from an amino acid.

I don’t think that it’ll be subject to much sort of metabolic fate through the alkene group though, as it’s part of the extended circle of delocalised pi electrons from the benzene ring, so it won’t behave like a normal double bond (same way benzene ring doesn’t act much like an unconjugated alkene with three double bonds). The body had chance to metaboize it the way it does the 2,5-dimethoxy-4-whatever-phenethylamines and amphetamines. Same thing with the 4-vinyldialkyltryptamines; unsubstituted dialkylamines are metabolised by 6-hydroxylation, or more importantly, by deamination (attacking aromatic systems normally takes a while, but by then it would have been removed from the body, even if it’s only pissed out unmetabolized).

Somewhere near the end, I had an idea; if anybody had done any studies on 4-cyano-dialkyltryptamines, the multiple C-N bond should wave a negative charge ‘round about the right place, and it might have binding data, or even animal trials data. Sadly, I tried a few search engines without success, but if you know of any, I’d be grateful for a shove in the right direction.

Even without anybody getting round to making the butenes, say something like alpha-methyl BOB (4-bromo-2,5,beta-trimethoxyamphetamine) should be of a greater potency than DOB itself (if what the beta-methoxy group did to the potencies of 2C-B/BOB and 2C-D/BOD hold, it could be twice the potency of DOB). Applied to Nichol’s dragonfly molecules, it would (if x2) reduce the dose to the 400-500ug range; with the aromatic dragonfly, you can only start guessing!

If you’re interested, I’ve PM’d you with a bit extra that’s not the sort of thing I could put here
 
Good job. Pity I dont feel qualified at this point in time. This is the same as what hest was working on across the pond? This is the first I have heard of this methine or vinyl extension in the theory though.
 
It's (the double bond on the beta-carbon) something that occurred to me as I was looking through lots of old papers on the SAR of phenethylamines. I was looking at all the Nichols data, and while it was fresh in my mind, I came across and old paper about the effects of side chain modification by those nice people at Porton Down, and then I had a eureka moment. I can't find any reference to ant PEA's/amphetamines with that modification in any papers by Nichols or anybody else, but on reflection, it seems so obvious that I can't think why it hasn't been looked at.

Hopefully, somebody will have a look at it in the near future (but not me, I left research to become a biology teacher 15 years ago)
 
You correctly pointed out that the double bond is conjugated with the aromatic ring. Would it be unreactive enough to not undergo acid catalyzed equilibration to the more stable Zaitsev position? A further driving force for this would be extra resonance stabilization from the nitrogen lone pair.

Presumably one would synthesize these compounds from methylone style precursors. You could do a Wittig reaction, or a Peterson olefination. Obviously Grignard + dehydration gives predominantly the unwanted internal alkene.

My feelings on this is that is worth looking into. I dont know for sure if the compound would survive stomach acid but that still leaves sublingual or IV administration.

Do you think this is something that works only on PEA hallucinogens, or could methcathionine be used to make a nice little novelty?

How certain even are you of the SAR between DOB and LSD? Obviously comparisons can be drawn amongst the tryptamines but DOB seems to be in a completely different kettle of fish. What gets me is how methyl-dob is considerably weaker, but this does not make nor-LSD stronger :|
 
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nice article but weren't these compounds actually called the butterfly series (not dragonfly) ?
 
It's definitly dragonfly - I've tried to attach the Nichols paper about the SAR but it's 8kb too big


What gets me is how methyl-dob is considerably weaker, but this does not make nor-LSD stronger

Methyl DOB - by that you mean N-methyl DOB? It's got something to do with the pKa of primary, secondary and teriary amines, but beyond that, your guess is as good as mine! I was just using the primary amine as the example, because it's the only one that works for phenethylamines and amphetamines.

Don't think I'd like to risk taking a 2,5-dimethoxycathinone derivative, as it's too close to the benzylic hydroxy group (just needs reducing) situation, with all the pressor concerns (the pressor methoxyamine has a 2,5-dimethoxy ring substitution pattern, as well as a benzylic hydroxy group and an alpha methyl carbon). On this, I'm more than willing to take Shulgin's warning/opinion about the dangers of that particular structure.

Why the potent cardiovascular effect seen by this compound? There are a couple of points that might argue for some adrenolytic toxicity. This material is a beta-ethanolamine and, with maybe one or two exceptions, clinically used beta-receptor blockers are beta-ethanolamines. In fact, a few of these so-called beta-blockers actually have two methoxy groups on the aromatic rings, also a property of BOHD. The antidiabetic drug Butaxamine (BW 64-9 in the code of Burroughs Wellcome) is identical to BOHD except that the 4-methyl group is on the alpha-carbon instead, and there is a tertiary butyl group on the nitrogen atom. Another point involves the proximity of the beta-hydroxy group and the methoxyl oxygen atom in the 2-position of the ring. There is going to be a strong hydrogen-bonding with this orientation, with the formation of a stable six-membered ring. This might help obscure the hydrophilic nature of the free hydroxyl group and allow the compound to pass into the brain easily. If this group is masked by an easily removed group such as an acetate ester, one gets the compound beta-acetoxy-3,4-dimethoxy-4-methylphenethylamine (BOAD) which is similar to BOHD as a hypotensive.
 
Right, I finally got a chance to read that....

-I'm confused, You've got the hydrogen bond pocket that the 5-methoxy group would fit into (the top one)... but what fits into that in LSD?

And then you've got DOI and DOB which have been regullarly reported to have a higher affinity that LSD for the 5-HT2A receptor, and they have no "beta-electrons" to donate, do they?

And re: DOI and DOB having a higher affinity- they don't have higher behavioural potency... so just have a high affinity isn't any good... we need to traffic the receptor in the right way

and finally dragonflies are active in man? Who where when?
 
I'm confused, You've got the hydrogen bond pocket that the 5-methoxy group would fit into (the top one)... but what fits into that in LSD

Nothing (I have thought that a methoxy group para to the indolic nitrogen on LSD would increase affinity - it's just that it would require a total synth to produce the appropriate lysergic acid derivative, and no-one's done that yet. Also, having a molecule that presents a "flat" molecule to the recptor is very important to activity - one of the reasons that 9,10-dihydro LSD doesn't work - the conformation is all wrong (it's bent out of shape!). Think of the difference between DMT/5-MeO-DMT, DiPT/5-MeO-DiPT or AMT/5-MeO-AMT

And then you've got DOI and DOB which have been regullarly reported to have a higher affinity that LSD for the 5-HT2A receptor, and they have no "beta-electrons" to donate, do they?

No, but neither does 2C-B, but adding a beta-methoxy group doubles the potency. That area only becomes a problem if something bigger than a hydrogen atom is attached, but doesn't carry some sort of electronegative charge.
Actually, after I'd posted the above, I found a paper where they'd produced beta-methoxy DOB and found it was more potent.

Richard A. Glennon,* Mikhail L. Bondarev, Nantaka Khorana, and Richard Young: beta-Oxygenated Analogues of the 5-HT2A Serotonin Receptor Agonist 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane: J. Med Chem - PDF doc doesn't give any further ref details other than to say it was received 13 April 2004.


And re: DOI and DOB having a higher affinity- they don't have higher behavioural potency... so just have a high affinity isn't any good... we need to traffic the receptor in the right way

From what I've read, the 5HT1A receptor acts as a sort of "multiplier" of 5HT2A activity (I know that's a crap analogy), LSD also has a high affinity for the 5HT1A receptor, whereas DOB/DOI doesn't, the LSD having a lower effective dose because of that. In the absence of 5HT1A affinity, the next best thing to reduce the effective dose would be to produce a drug with a higher 5HT2A affinity - hence the higher potency of the dragonfly derivative.

And on that issue, I'll PM you
 
From what I've read, the 5HT1A receptor acts as a sort of "multiplier" of 5HT2A activity (I know that's a crap analogy), LSD also has a high affinity for the 5HT1A receptor, whereas DOB/DOI doesn't, the LSD having a lower effective dose because of that. In the absence of 5HT1A affinity, the next best thing to reduce the effective dose would be to produce a drug with a higher 5HT2A affinity - hence the higher potency of the dragonfly derivative.
I don't buy that one little bit, if anything 5-HT1A receptor action will be a subtraction...

Oh, and I've even got a nice reference.. where pindolol (a 5-HT1A antagonist) markedly potentiated doses of DMT in HUMANS (Strassman, 1996)... and of course, my electrophysiological spin is that when it boils down to it, 5-Ht2A receptors are excitatory, while 5-HT1A receptors are inhibitory.
 
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I think it was one of Nichols papers that I picked that up from (I'll try and find the ref). Nonetheless, the dragonflies higher affinity for the 5HT2A doesn't have a linear correlation with its effective dose in humans, as according to Nichols binding data, the effective dose (for the non-aromatic dragonfly) should be around the 400ug dose, which would be 2.5x the potency seen.


Do you have a take on why LSD requires a much smaller dose, despite it' lower affinity (than DOB etc)? I took this table from one of Nichols reviews

Table 1. Affinities (in nanomolar) for LSD at various recombinant serotonin receptor

5HT2A - 3.5 (DOI) 11 (ket)

5HT2C - 5.5 (DOI) 23 (mes)

5HT1A - 1.1

5HT1E - 93

5HT5A - 7

5HT6 - 6

5HT7 - 6


DOI - DOI as radioligand
ket - ketanserin as radioligand
mes - mesulergine as radioligand
 
Well as I said, receptor agonist-directed trafficking... i.e. whether the drug causes stimulation of PLC, PLA2 or PLD (potentially). I used to have a theory that the PLA2 stimulated EPSCs in cortical pyramidal cells, and PLC inhibited them... and that the drugs with a higher ration of PLA2/PLC would be the most potent... Infact, drugs with a higher PLA2/PLC potency are the least potent. See page two of this. R2=0.962.... When one trys to account for partial agonist activity R2=0.989!

And I just realised that in any Descrimination vs Affinity correlation, one never takes into account pharmacokinetic parameters... So yeah... Have I explained anything?
 
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Still think 5HT1A is involved

where pindolol (a 5-HT1A antagonist) markedly potentiated doses of DMT in HUMANS (Strassman, 1996)...


Don't think you can use pindolol as an example of an antagonist, since it also has partial agonist activity at the 5HT1A receptor (1; 2). That being the case, it may well be the partial agonist activity that potentiated the DMT (which is, in a round about way, what I'm thinking might be the same effect LSD has on the 5HT1A receptor, therefore "potentiating itself")


1/
Clifford, E., Gartside, S.E., Umbers, V., et al., 1998. Electrophysiological
and neurochemical evidence that pindolol has agonist properties
at the 5-HT1A autoreceptor in vivo. Br. J. Pharmacol. 124,
206–212.

2/
Sanchez, C., Arnt, J., Moltzen, E., 1996. Assessment of relative
eficacies of 5-HT1A receptor ligands by means of in vivo animal
models. Eur. J. Pharmacol. 315, 245–254.
 
Well there are various papers out there that show that 5-HT2A mediated behaviour is reduced by 5-HT1A agonists, headtwitch being blocked by 8-OH-DPAT. (Though I suppose you could argue that head-twitch isn't correlative with hallucinations)

How could pindolol potentiate DMT by partial agonist activity, when DMT is a full agonist at 5-HT1A with a very similar affinity as to 5-HT2A?

Also, why would psilocin be about half as potent as DOM in man, even though their 5-HT2A affinities are very similar, when psilocin is a good 5-HT1A agonist, and DOM has no activity there? (I suppose one could argue pharmacokinetics?)

And finally, Lisuride: 5-HT1A and 5-HT2A agonist, but it has an affinity about 10-20 times higher at 5-HT1A than 2A. And its completely lacking in hallucinogenic activity in humans. How does that fit in with your theory?
 
Well if pindolol is a partial agonist, then it'll be effectivly a competetive antagonist in action (same mechanism as partial mu agonists, effectivly act as an antagonist in opiate dependant people), as it will deny full agonist DMT binding to some receptors.

I'm not sure what role the 5HT1A receptor plays in the genesis of the psychedelic state, just putting forward ideas in an attempt to understand the percived facts.


If I'm honest, I'm a lot happier with the chemistry side of neurochemistry


Oh, the psilocin/DOM dosage. Psilocin may have a higher affinity, but less will cross the blood brain barrier due to the polar OH (phenolic) group at the 4 position of the indole nucleus, DOM not having any phenolic OH groups, therefore more lipid soluble. DMT is much less polar, but the dose of DMT if severalfold higher as the 4-OH group is able to contribute 2 lone pairs, the increased electronegativity from them binding in the same way as the negative charge from the electrons of the double bond. All a balance between lipid solubility (well actually water/1-octanol partition coefficient) and having polar groups that have the ability to interact with opposite charges on the receptor protein.
 
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Well from my stand point, there are too many unknowns to get into in completely, but I highly doubt 5-HT1A has any additive/multiplier effects.. I tend to believe that is blocks hallucinogenic effects (which could be mediated by cortical excitation) by hyperpolarizing cells. Though I'm not adverse to the idea that one of the receptors that LSD hits has some additive effects (5-HT4/5/7?)
 
Trial and error

Do you reckon it would be as simple as administering LSD after pre treatment with a specific antagonist for each (5HT4/5HT5/5HT7) in turn, to rats trained to discriminate LSD from saline (might show that an antagonist for one of the 3 receptors mentioned requires a dose several times that with no antagonist present (if highly specific antagonists for those receptors exist at the moment).

Alternatively, are there any other hallucinogens where the dose required does not match the receptor affinity data (eg LSD having a lower affinity for 5HT2A than DOB, yet the dose required for full effects is less than that of DOB), but do show agonism at one of those 5HT receptors (and can't be accounted for using 1-octanol/water partition coefficient)?

In the absence of that sort of data, I suppose the best conclusion you can draw is that for the phenethylamines/amphetamines (mainly 5HT2A/2C agonists), a higher affinity corresponds to a lower dose for full effects, even if it's not a linear correlation.

There are times that pharmacology seems more like a dark art than a science!
 
Drug descrimination experiments always make me uneasy. I can accept the data from simple EC50 for responding, style potency evaluation... but ones where they start chucking in antagonists... I mean, those receptors are active regularly, blocking them is going to produce its own-interoceptive cues..

..Also, I don't like drug descrimination experiments where LSD is the training stimulus... It should be a clean 5-HT2A agonist..

And still, with pharmacokintic parameters not taken into account its all a bit silly... Rabin and Winter need to bring back there ICV administartion and do some ACTUAL discrimination experiements (instead of their silly time course ones).

And as I say, simple correlations with affinity don't work, when you've got agonists with different levels of efficacy and differeing abilitys to traffic the receptor to PLC or to PLA2...
 
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