5HT2a ligands and RC Tryptamines

[ubermensch]

Oh, I have always wondered about the differential activation across seretonin receptor subtypes of the RC tryptamines, in an effort to understand their action upon my mind.

I found this great website from the minnesota uni team
http://www2.umt.edu/medchem/ttt/pdf/oof2.PDF
that does a whole battery of tests on most of them, including such rareities as 4-HO DBT!

In my quest to find out whether 4-HO tryptamine can cross the BBB, I also found this great page on 5ht2a and tryptamines for further reading:
http://webdoc.sub.gwdg.de/diss/2004/jensen/jensen.pdf

PS Does anyone know whether 4-HO tryptamine can cross the BBB if ingested orally?

 

[specialspack]

Umm, yes of course 4 HO tryptamines can cross the BBB - at least some of them. Like psilocin, 4-HO-DMT.

EDIT - Sorry, I misread you...

 

[ubermensch]

whether 4-HO tryptamine in particular can cross the BBB - thru the stomach

it does name an actual discrete molecule you know

 

[fastandbulbous]

Doubt it'll get that far - it'll be subject to metabolism by MAO (no alpha-methyl, or N-alkyl substituents - MAO will chew it up before it gets out of the gut)

 

[C6H6]

^Not necessarily. DMT is orally inactive, 4-OH-DMT is orally active. The 4-OH seems to have a very stabilizing effect. One theory is that it's acidic and forms an inner salt or strong hydrogen bond with the basic amine.

 

[fastandbulbous]

^ I suppose that is a possibility. A primary amine isn't going to form anywhere near as strong a hydrogen bond to the oxygen of the 4-OH group as a tertiary amine though.

The only other problem I'd forsee with that is that such an internal hydrogen bond requires the amine group to be in the wrong position to form a hydrogen bond with the COO- residue of the transmembrane protein that makes up part of the 5HT2a receptor.

It does give a bloody good theory as to why 4-OH tryptamines are not subject to degradation by gut MAO though.

Tricky business the molecular modelling lark!

 

[Smyth]

^Not necessarily. DMT is orally inactive, 4-OH-DMT is orally active. The 4-OH seems to have a very stabilizing effect. One theory is that it's acidic and forms an inner salt or strong hydrogen bond with the basic amine.

This is a substantially interesting theory. Nothing of this was ever discussed in Tihkal. That is a good 16 page pdf by the way. I am gonna read all of it.

 

[BilZ0r]

Some of the things in that table 2 are quite interesting. Like what looks like 4-OH-DiBT is relatively selective for 5-HT2A over 5-HT1A... I'd always kinda made the assumption that tryptamines were always gonna be highly active at 5-HT1A

 

[Dondante]

This is a great thread. I almost posted this in the Big and Dandy 4-ACO-DMT thread but it's better off here in ADD. From the B&D thread ...

... 2.5 to 3h to peak but WHAT an AMAZING peak it is. Insuffilation is SWIM's prefered method of injestion as this provides an initial "rush" effect followed by a slow and insanely mild come up followed by a pleasant and extended comedown when compared to P.Cubensis.

SWIM has tried I.V. dose of 10mg and would have rather snorted it as SWIM found out the initial rush was INTENSE AS ALL CRAP but the peak was less "Magical" and much shorter in duration. SWIM thinks that the acetyl bond provides this molecule with the ability to pass directly through the blood brain barrier as it does with di-acetyl-morphine. SWIM believes that once inside the blood brain barrier it is converted into 4-ho-dmt.

The long climb to the peak with intranasal administration makes me even more confident that the 4-aco-dmt has at least some trouble passing the BBB. If it could pass easily, you would peak earlier. I bet if you insufflated 4-ho-dmt, you'd peak pretty damned fast. Anyway, thanks for the report MadShroomer.

Actually, SWIM DID experience an initial RUSH and this is believed to be the result of the 4-acetyl bond, wich is the same bond that turns Morhpine into Heroine (makes it more effective/addictive BECAUSE the acetyl bond enables it to pass VERY quickly through the blood/brain barrier). But don't take my word for it...check it

According to Alexander Shulgin, "In the case of psilocybin to psilocin, this saponification is essential for activity, as the phosphate ester is far too polar to get across the blood-brain barrier. But this problem need not exist with the acetate ester. I have explored the 4-hydroxy-DET but I am more familiar with the 4-hydroxy-DIPT. It is of a rather rapid onset implying possible absorption directly from the stomach. However, in a group study with the corresponding ester 4-AcO-DIPT, we felt that it had an even faster onset and perhaps a increased potency. This would suggest that it might be considered an active drug in its own right rather than simply a precursor to the active drug 4-HO-DIPT."

This quote came from here:
http://www.erowid.org/chemicals/4_ac...article1.shtml

So the initial "RUSH" is the molecule entering the central kingdom, then the body does what ever and turns it into a much more potent tryptamine (this would be 4-ho-dmt but might be oxidized to a very quinonic product that is unknown).

Read the above link to the article its FACINATING!

The problem with this theory is that it seems that nearly everyone other than Shulgin thinks that the 4-ACOs have a slower onset and a weaker peak than the 4-HOs at the same dosage (even after accounting for MW). If someone agrees with Shulgin and has tried both versions of a particular tryptamine, by all means, let me know.

At first glance, it seems that the hydroxy should be more polar than the acetoxy, so it should have more trouble crossing the BBB. This is obviously why Shulgin decided to put a methoxy on the tryptamine ring, since the methoxy has very little polarity and can cross more easily. But this doesn't seem to be how it is, unless you think that Shulgin is right w/ respect to the potency and onset time.

I love C6H6's hypothesis ... that the 4-HO-DMT can form an internal salt, with the positive nitrogen wraped up close to the negative oxygen. This hides its polarity and protects it from MAO enzymes. And F&B ... perhaps this conformation is in equilibrium with another that is responsible for the receptor binding?

So my humble theory is that the 4-ACO-DMT either (A) can't make the internal salt as well because of the bulky acetoxy substituient and gets eaten up by MAO enzymes more easily or (B) is more polar in the internal salt conformation because of the carbonyl group still sticking out. I'm leaning toward (B).

(A) would explain the weaker effect, but not the slower onset. (B) would solve the problem by either making the 4-ACO-DMT have more trouble crossing the BBB, or by not allowing it to cross and forcing it to be converted to 4-HO-DMT first.

Any comments would be appreciated.

 

[MadShroomer]

This is a great thread. I almost posted this in the Big and Dandy 4-ACO-DMT thread but it's better off here in ADD. From the B&D thread ...

So my humble theory is that the 4-ACO-DMT either (A) can't make the internal salt as well because of the bulky acetoxy substituient and gets eaten up by MAO enzymes more easily or (B) is more polar in the internal salt conformation because of the carbonyl group still sticking out. I'm leaning toward (B).

(A) would explain the weaker effect, but not the slower onset. (B) would solve the problem by either making the 4-ACO-DMT have more trouble crossing the BBB, or by not allowing it to cross and forcing it to be converted to 4-HO-DMT first.

Any comments would be appreciated.

Wait a sec. How could an Acetyl bond make it harder to cross the BBB? It would make it harder to bind to certain receptors in the brain but the body takes care of that by processing it.
If the Acetyl bond made it HARDER to pass the BBB then Heroin (Diacetyl-morhpine) would be LESS potent than morphine and that just isn't so.
With the Heroin molecule the Acetyl bond enables it to "Pass directly through the blood brain barrier" meaning that this bond should do the same on tryptamines. SWIM believes that what ever the molecule is doing BEHIND the BBB is envolved with the "PEAK" effects. Take a look at some of these crazy molecules and read this article....
http://www.erowid.org/chemicals/4_acetoxy_det/4_acetoxy_det_article1.shtml

 

[Smyth]

How do u know that with heroin the acetoxy groups are immediately hydrolyzed?

Nobody has ever pointed to any recent scientific in-vitro studies that can unequivocally prove that heroin is not active in its own right and only serves as a prodrug for morphine.

If this were the case, it might be that 4-AcO-DMT crosses the BBB a piece of cake only once across it has to hang around long enough for the AcO to be hydrolyzed. And that this is the reason for the time delay. At least that would be my primeval guess although I must stress that im not a biochemist.

I have a really far-out pdf on BBB penetration in drug design if anybody is interested but it is not particularly helpful although it is indepth and extensive.

Also there is the fact that esterase enzymes in the body effect this hydrolysis (sometimes enantioselectivity although not of any relevence here), and this is quoted to occur in the pores that lie in the BBB.

 

[Dondante]

Well, heroin is nothing like 4-HO-DMT for one thing. Yes, the acetyl groups do make the molecule less polar and allow it faster access to the brain ... and yes, that is what is expected.

What I'm saying is that there is something else going on with the tryptamines that actually makes the opposite true. The 4-HOs get though just fine, and the 4-ACOs have more trouble. It's about conformations of the molecules rather than just reducing polarity in a single conformation.

Edit: And Smyth, that hypothesis seems just as valid (the 4-ACO-DMT has immediate access, but cannot stimulate the receptor as effectively until it undergoes hydrolysis. Hmm ... I'll have to think about this for a while.

Edit 2 (moved from B&D thread again, sorry):

So the initial "RUSH" is the molecule entering the central kingdom, then the body does what ever and turns it into a much more potent tryptamine (this would be 4-ho-dmt but might be oxidized to a very quinonic product that is unknown).

MadShroomer, do you even know what a quinone is?

The quinone idea (I think) is very similar to C6H6's internal salt idea, although I have no idea how that product Shulgin is describing would be classified as a quinone. I think he's talking about a delocalized pi electron bond between the quinonic oxygen and the nitrogen that would occur after oxidation (maybe?) I don't really have much of a chem background so I'm not in familiar territory here.

I like the internal salt hypothesis, because it does not require oxidation like Shulgin's hypothesis. Also, I think there's a general consensus that a quinonic product would not be active ... so that would require reduction, which I don't see happening (just seems like too much work). The internal salt would possibly allow for a natural equilibrium between two conformations (one to get past the BBB and one to activate the receptor). Who knows? There are many possibilities. If someone could clear up what exactly this cross-conjugated product looks like I'd appreciate it.

 

[Dondante]

If I am making any sense at all, could someone with chemdraw help me out here?

 

[MattPsy]

The increased abillity of the hydroxyl ring-substituted tryptamines in regards to permeation of the BBB may be the result of a conformation where the amine end of a tryptamine is attracted to the hydroxyl present in the ring, making it non-polar.
This would explain why AcO-T's have more trouble than would be otherwise reasonably expected - because the ester blocks the amine from being attracted.

 

[Dondante]

^^And ...

Did you just not read my post, or did you just feel like summarizing?

 

[MadShroomer]

How do u know that with heroin the acetoxy groups are immediately hydrolyzed?

Nobody has ever pointed to any recent scientific in-vitro studies that can unequivocally prove that heroin is not active in its own right and only serves as a prodrug for morphine.

If this were the case, it might be that 4-AcO-DMT crosses the BBB a piece of cake only once across it has to hang around long enough for the AcO to be hydrolyzed. And that this is the reason for the time delay. At least that would be my primeval guess although I must stress that im not a biochemist.

I have a really far-out pdf on BBB penetration in drug design if anybody is interested but it is not particularly helpful although it is indepth and extensive.

Also there is the fact that esterase enzymes in the body effect this hydrolysis (sometimes enantioselectivity although not of any relevence here), and this is quoted to occur in the pores that lie in the BBB.

OK! SWIM wasn't saying that it "hangs around" to be hydrolisized (although this is the leading theary, but what SWIM Was saying is that HEROIN (Di-ACETYL-morphine) is more potent and quicker acting becuase of the ACETYL bond wich enables it easier passage.

[edit:deleted stupid drunk babble, sorry folks]

How do u know that with heroin the acetoxy groups are immediately hydrolyzed?

SWIM didn't say that.... did SWIM? SWIM simply stated that this organic bond enabled the compount to directly pass through a certain barrier to the inner workins of the mind (THE BBB )

Nobody has ever pointed to any recent scientific in-vitro studies that can unequivocally prove that heroin is not active in its own right and only serves as a prodrug for morphine.

THIS IS TRUE...although...di-acetyl-morhpine IS converted at least PARTIALLY to morphine and VISA VI ---- Codeine and so on as to the components that are detectable via drug testing..... SWIM believes that di-acetyl-morphine IS extremely active IN-VITRO and eventually breaks down to a less potent analog that doesn't have the ability to bypass the BBB...

If this were the case, it might be that 4-AcO-DMT crosses the BBB a piece of cake only once across it has to hang around long enough for the AcO to be hydrolyzed. And that this is the reason for the time delay. At least that would be my primeval guess although I must stress that im not a biochemist.

ok, PSILACETIN DOES cross the BBB AS WELL AS OR NOT BETTER THAN di-acetyl morphine (SWIM does not meen to suggest that 4-aco-dmt is not able too do so better than the TWO bonded pairs [twice the ability?].)

there is the fact that esterase enzymes in the body effect this hydrolysis (sometimes enantioselectivity although not of any relevence here), and this is quoted to occur in the pores that lie in the BBB.

This would point to the evidence with 4-aco-det and 4-aco-dipt that was elaborated in the previous article posted (via erowid).

The point is SWIM thinks that similar breakdowns in molecular bonding that was evident in the 4-aco-det and 4-aco-dipt experiments (tests, scientific process stuff ).
SWIM believes that because of 4-ho-dmt's ease of breakdown in the body would be avoided if this molecule was MADE inside the BBB by MAOI's or other breakdown stuff.....
SWIM belives that at least SIMILAR molecular compounds ARE produced once inside the BBB and safe from the HARMFUL processes of other parts of the body (the blood stream DOES go through everything but the BBB does PROTECT the brain from certain stuff)

SWIM has typed enough and will await reply's to SWIM's beliefs in chemistry/biology...
Atlest SWIM believes Shulgin would consider SWIM's ideas....

 

[MadShroomer]

Well, heroin is nothing like 4-HO-DMT for one thing. Yes, the acetyl groups do make the molecule less polar and allow it faster access to the brain ... and yes, that is what is expected.

What I'm saying is that there is something else going on with the tryptamines that actually makes the opposite true. The 4-HOs get though just fine, and the 4-ACOs have more trouble. It's about conformations of the molecules rather than just reducing polarity in a single conformation.

SWIM isn't saying that 4-ho-dmt is anything like HEROINE in molecular structure but simply relating the organic bond "AcO" (SWIM belives this is "organic" as acetylation occurs naturaly after the breakdown of ethanol in furmentation [curse SWIMS BIOLOGY MAJOR parents who have some how passed infinite knowledge to SWIMS mortal mind])

Edit: And Smyth, that hypothesis seems just as valid (the 4-ACO-DMT has immediate access, but cannot stimulate the receptor as effectively until it undergoes hydrolysis. Hmm ... I'll have to think about this for a while.

SWIM is glad that SWIY's ideas are alike with like minded individuals (smart minds think alike?)

But, SWIM would like to point out in the article on erowid that something else besides "hydrolysis" could potentialy be ongoing inside the BBB...(afterall who has a probe that can penetrate this membrane and NOT interfer with normal function [kinda like the black-hole of the universe inside the workings of a living individual])
SWIM will now stop smoking bubble hash out of hookah pipe as SWIM is sleepy...

 

[Smyth]

Ok, I think I brought the topic off the rails yesterday by bringing heroin into the equation.

While monoacetylmorphine (MAM) is known to have superior potency to morphine, I think the phenolic AcO drops of fairly easy, whereas the aliphatic hydroxy does not.

So it might be that this intramolecularly bound -O(-)-H-N(+)- species enables better BBB penetration than the acetoxy.

I dunno though because if the acetoxy is that readilly hydrolyzed then it should not interfere with the pharmacodynamics at all.

I just occurred to me that if codeine is so poor this would indicate that anything blocking the phenol oxygen might be detrimental to potency. On top of that we know that the phenolic position is very susceptible to hydrolysis oweing to its low pKa value (PhOH is weakly acidic).

I think I started drifting OT and should have just stuck with the earlier post accrediting C6H6's H-bond theory. Appologies for bringing heroin into this topic.

 

[Dondante]

OK! SWIM wasn't saying that it "hangs around" to be hydrolisized (although this is the leading theary, but what SWIM Was saying is that HEROIN (Di-ACETYL-morphine) is more potent and quicker acting becuase of the ACETYL bond wich enables it easier passage than haveing 20k in gold coins when the "bridge farrier" to the netherlands ask's you for toll (seeing as their is no other passage to the neitherworld without a fair, this would make you increadible adept to passage back and forth MULTIPULE times before the "managers" caught on).
SWIM has been smoking illegal "cannabis" hashish (cold water extraction 'bubble' hash) and has been drinking but SWIM has been thinking about this ALL DAY LITERALLY! and has been processing countless algarithims inside a solitary isolation chamber (i.e. the human mind while participating in a systematic JOB that requires multiple repetition of a single acitivity multipile times [i.e. a certain 'salamander' genetic stock center wich happens to house 2k+ aquatic amphibians.]) now SWIM has forgotten what SWIM was going to say
ok wait let SWIM re-read....

This is ADD, why don't use use your self-proclaimed infinite knowledege, and leave out the storytelling (which doesn't even make sense by the way). And maybe post when you're not high. Sorry, I don't mean to be a dick.

Shulgin quote: "In the 4-hydroxy indole world, an obvious quinonic product would be the cross-conjugated product with the loss of the hydrogen on the hydroxy as well as the hydrogen on the indolic nitrogen. This compound would certainly be colored and, still having no polar locations, might be OK to cross the BBB [blood brain barrier]. Once inside the brain, it could be reduced to the parent hydroxy tryptamine or an even more appealing explanation might be that the absorbed 4-AcO-DIPT (4-AcO-DET in your immediate example) might, after loss of the acetyl group once inside the brain, be oxidized to this very quinonic product and it just might be the true active factor for both original forms!" If this had been true, it may have required some major revision in what we believe about the way drugs like psilocybin work. Further data seems to point in yet another direction, however."

Anyway, so is there anything to Shulgin's idea of the quinonic product resulting from oxidation? I mean if he though of a far out idea like that, wouldn't he have considered that it's just a H-bond that's doing the trick?

 

[Smyth]

If 4-MeO DMT shows up this will solve the decomposition issue once and for all.