Author Topic: : DMT is a partial LSD bioisostere, how about this one?  (Read 1541 times)

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dormouse

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: DMT is a partial LSD bioisostere, how about this one?
« on: April 19, 2000, 02:18:00 PM »
Author  Topic:   DMT is a partial LSD bioisostere, how about this one? 
Rhodium
Administrator   posted 11-24-98 10:21 AM          
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On the right, I have superimposed the structure of DMT on that of LSD. It fits, right? How about making the left compound? Couldn't it have pretty good chances of at least being active? Has it been synthesized? How would it be synthesized?


beagle_boy
Member   posted 11-24-98 10:30 AM          
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I'm fairly certain that this cpd has been synthesized in Glennon's lab. In fact, I believe that I know the person that did the synth. Check medline for "isotryptamine". It should be a JMC paper. The cpd itself had little to no activity in their animal model and I was told that it was not evaluated in humans. I can't recall how it was synthesized, but I imagine through indole-4-carboxaldehyde. Let us know what you come up with.
 
Labrat
Member   posted 11-24-98 10:35 AM          
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Aha, the fine art of designing drugs...
But the most important thing to check for activity is... taking the compound! I don't know whether somebody has synthesized it before, but I do have a few clues to make it.

You'll probably have to start from indole, but a 4-subsituted indole would be the best bet. If you could find indole-4-carboxaldehyde, you could do a Knoevenagel on it, then reduce the nitrostyrene to the amine with LAH and finally N,N-dimethylation could be achieved with formaldehyde/sodium borohydride/H2SO4. There are more ways, but I think this is the easiest one. Lr/


Piglet
Member   posted 11-24-98 11:04 AM          
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The spatial arrangement will be somewhat different. Maybe keeping a vestage of side-chain would alter the orientation for more activity. I'm thinking here of drugs like pentazocine (overlay the morphine molecule).
I would start with an alpha methyl (where the LSD double-bond is). Maybe an ethyl.
Pure conjecture on my part,
Piglet 


beagle_boy
Member   posted 11-24-98 11:32 AM          
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I like the idea of an alpha methyl. I can't recall if the JMC paper used an animal model or an in vitro receptor binding assay, but if it was an animal model, then maybe lack of activity was due to deactivation of the cpd by MAO. The alpha methyl would solve this prob nicely. But seems like this paper was done in the early '80s, so they prob used receptor binding assay and accounted for MAO activity.
 
Rhodium
Administrator   posted 11-24-98 01:59 PM          
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Neither Medline, ACS or Beilstein gives me anything on "isotryptamines". The name "isotryptamine" cannot be found in Merck, nor does even an Altavista websearch give any answers... I want a better internet! 
 
beagle_boy
Member   posted 11-24-98 02:24 PM          
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OK, I think that this is the ref that I was thinking of:
J Med Chem 1984 Jan;27(1):41-5

Synthesis and evaluation of a novel series of
N,N-dimethylisotryptamines.

Glennon RA, Jacyno JM, Young R, McKenney JD, Nelson D

A novel series of N,N-dimethylisotryptamine (isoDMT) derivatives, i.e., derivatives of
1-[2-(dimethylamino)ethyl]indole, was prepared and found to be isosteric with their corresponding
N,N-dimethyltryptamine (DMT) counterparts with respect to serotonin receptor (rat fundus)
affinity. Whereas the isoDMT derivatives possessed a greater affinity than did their corresponding
DMT derivatives, they were relatively ineffective in displacing [3H]-5-HT binding from rat brain
(cortex) homogenates. In a drug discrimination paradigm, using rats as subjects, 6-OMe-isoDMT
produced effects similar to those of 5-OMe-DMT. Attempts to antagonize the discriminative
stimulus effects of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane
(DOM) using two of the isoDMT derivatives proved unsuccessful.

Looks like the dimethylaminoethyl side chain was moved to the indole N tho, not the 4 position. I could've sworn that I've seen those cpds B4 tho. I'll see what I can find.


drone 342
Member   posted 11-24-98 08:54 PM          
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Its a nice idea, but I'm a little skeptical. When it comes to tryptamines (ergoloids are not tryptamines; in spite of their inclusion in TiHKAL), what seems to be really important for activity is acidity at the 4-position; psilocin vs. DMT is a good example of this phenomenon. 4-methyl DMT is hardly active at all.
Still, I've wondered about this as well. The way I look at it, PEA's and tryptamines are very similar in structure: you have an aromatic system with an ethylamine side-chain dangling off the side. With indole, you have 5 choices of where you can add that ethylamine to the compound(1,2,3,5, and 6), though so far only the 3-position has been given extensive study. This means plenty more things are ready for investigation.

When one applies the sort of "natural" pyschedelic chemist attitude Sasha did to PEA's and tryptamines to all of these and their methoxylated, brominated analogs thousands of compounds become possible candidates. But why stop there? Replacing the nitrogen in indole with another electron-rich atom like O, S, or even Se, P, or As (icky), means thousands more. Or use pyridine instead, and you have even more options. Switching PEA's benzene with Pyridine or what have you means even more. Soon, we're up to our eyeballs in hundreds of thousands of compounds -- an intellectually directionless quagmire of a arylethylamine overabundance of interesting research projects still undone.

I'm not saying "don't look there; its doomed to be uninteresting"! What I *am* saying is that there are limitless options, but limited hours in a day. I suggest we focus our attention to other structures more similar -- thianapthalene- or benzofuran-derived analogs of tryptamines, substituted vairations of anabasine, etc. Plenty of psychedelic activity untapped right there, I sez! This looks like the area most likely to be the location of "the next big thing" (NBT, though admittedly, nobody can predict with any certainty -- who'd've imagined LSD?)

-drone #342


drone 342
Member   posted 11-24-98 08:58 PM          
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Hm, I don't think I expressed myself quite right there. Your compound may have analogs that are possibly psychedelic, but I think there are safe bets for some real mental fireworks elsewhere.
-drone #342


Piglet
Member   posted 11-25-98 04:01 AM          
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I think that it is interesting that different N-alkyl moeity's are optimum for related compounds. alpha-methyl tryptamine is active with a primary amine. The others seem to require di-substitution. The use of asymetric di-substitution (or possibly mono-substitution) will again alter the spacial arangement.
Drone is quite right about 4-position activity relationships. Am I right in thinking that 4-acetoxy DMT (acetyl psilocin) is twice as active as normal psylocybin? Is this due to enhanced brain uptake (like heroin/morphine)? If so, maybe the amide in LSD helps absorbtion? Anybody have data on the lysergic acid amines?
I'm a great believer in detailing receptor sites. (though no good at it!)
Piglet


 
beagle_boy
Member   posted 11-25-98 09:27 AM          
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Drones mention of DMT isosteres reminds me of a story. I knew this chemist that had worked as a grad student in the lab where the benzothiophene analog of psilocin was first synthesized, that is, the analog where S replaces the indole N (ref on req). Can't remember the name of the chemist that ran the lab, but he was famous and apparently a straightlaced kind of guy (Champaigne?). Anyway, after the student had finally completed the arduous synthesis, his boss comes into the lab and asked how the compound tasted. His student said that of course he didn't know. So the boss licks his finger, sticks it into the pile of powder and licks it off. He then went out to play tennis. When his partner was asked later how he was acting, she said that he kept talking about the rain, even though it was a sunny day. So the S analog of psilocin appears to have some activity. The Se analog has also been synth., but I don't know about activity (ref on req).
I'm interested in knowing about the analog that Rho proposes, but haven't found anything yet. One thing to remember tho is that LSD's profound activity is very dependant on the intact ergoloid ring system. Many structurally reduced ergoloids have been synthesized and they inevitably have greatly reduced activity. It is quite possible that comparison of LSD type cpds w/ tryptamines is a wild goose chase since they may bind at the (5-HT2) receptor in different manners. People have been trying to overlay PEA's on LSD's structure for years and now evidence is accumulating that this is prob. an invalid approach.

In any case, this is all just idle speculation till someone actually makes the cpd. and tastes it. Long live those willing to stick their fingers into the eye of the unknown and lick them off in the name of science!


Rhodium
Administrator   posted 11-25-98 12:29 PM          
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Nichols has synthesized DMT with an O instead of the pyrrole N. It was slightly less potent than DMT itself in serotonin receptor binding assays.
 
drone 342
Member   posted 11-25-98 01:20 PM          
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I've said it before, but I'll say it again. I really think lowering the pKa of psilocin would be very interesting -- replacing the OH with an SH, or SOOH, or SOOOH, or a COOH. perhaps making a readily hydrolyzable ester would stabilize it. How far can a good idea be pushed?
-drone #342


beagle_boy
Member   posted 11-25-98 01:42 PM          
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SH and SMe analogs of psilocin have been made and are of reduced activity. Sulfinic sulfonic and carboxylic acid analogs will be too polar to pass BBB.
 
Lilienthal
Member   posted 11-25-98 01:56 PM          
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J. Med. Chem. 27, 41 1984 (Glennon) deals with MeO substituted 1-isotryptamines (sidechain on indole-N). In rats the 6-MeO-iso-DMT has 1/3 the potency of 5-MeO-DMT in a DOM generalization test.
The right references for 4-isotryptamines are:

J. Med. Chem 32, 2128 1989: di-n-propyl analogues are potent D2 agonists (Dave Nichols)
J. Med. Chem 24, 238 1981: -"-
J. Het. Chem. 19, 1195 1982: lengthly synthesis
Eur. J. Med. Chem 26, 473 1991: ? (no time yet...)
Life Sci. 34, 1015 1984: ?

What's about LSD analogues with missing N1-C2, i.e. "depyrrole-LSD" and relatives? They have been relatively simple synthetized in the 60s and 70s and tested positively for oxytocic activity (as would be expected for psychoactive analogues).
Some references are:

J. Org. Chem 39, 1669 1974
Bull. Soc. Chim. Fr. 4463, 1968 (The good old Marc Julia)
Chem. Pharm. Bull. (Tokyo) 13, 420, 1965 (references to other simplified analogues)
Chem. Pharm. Bull. (Tokyo) 15, 1641, 1967
J. Chem. Soc. Perkin Trans. I 2911 1984
Heterocycles 22, 1719 1984
Chem. Ber. 86. 25 1953


beagle_boy
Member   posted 11-25-98 02:36 PM          
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Lilienthal: Good to have you on board! Why do you say that oxytocic activity is correlated w/ psychoactivity? Those "depyrrole" analogs you mention sound interesting, but I believe that indane analogs are of very reduced activity, so seems like N1 is needed.
 
drone 342
Member   posted 12-03-98 01:41 AM          
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I've had a change of heart, and I must say something about it. After much deliberation, I'e realized I was thinking far too "within the lines" and missing what is obviously a grand place to do some chemical probing. Being stuck thinking about the LSD paradigm of pharmacological activity (which I still don't think would fit anyways), I wasn't able to get past this first idea to see that right before me was a lovely range of arylethylamines with promise -- the isotryptamines. You guys were able to get to this point sooner than I.
THere is one bit of contention I foresee here. With that 3-position unprotected, the indole is much more prone to oxidation than otherwise. This means a generally less stable molecule. While not a *major* stumbing block, it is something to take into consideration.

-drone #342

-drone #342


drone 342
Member   posted 12-03-98 01:44 AM          
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P.S. - If I haven't said it yet, its great to have you on board, Lilienthal; you seem to have a lot of know-how and creative ideas. Plus, now that someone else is around with Beilstein, I'm sure the ref's will flow like wine. 
 
Lilienthal
Member   posted 12-03-98 11:17 AM          
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Thanks for your warm welcomes. Oxytocic activity means an uterus contracting effect, mediated through serotonin-2 (possibly A or B-type) receptors. Serotonin and LSD (as an partially agonist) contract the uterus, 5-HT2 antagonists inhibit this contraction. The same receptor (2-HT2A), localized in the brain, mediates some other interesting effects. So an ocytocic activity of a serotonin agonist analogue is a strong hint for central activity. To my knowledge (and to Mr. Beilstein's) indane or other aromatic portion analogues of LSD have never been made (with the possible exception of 2,3-dihydro derivatives as precursors in the total synthesis of LSD, but no data on this has been published).
 
Beagle
Member   posted 12-03-98 04:34 PM          
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I think I need to go back to bed for about a year. I seem to be spreading alot of disinformation on the net recently. Maybe I am entirely wrong, but I thought that indanyl-tryptamines had been synthesized. I have no references of such in my files, so once again I am in the unpleasant position of not being able to back up what I say. I know that the indanyl-tryptamines are quite different critters from what you are proposing tho.
If I can manage to contain myself, I think that I'll just shut up for awhile.


Lilienthal
Member   posted 12-04-98 02:19 PM          
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Hey beagle, come out of your bed and continue talking with us. Do you like a glass of wine? I was wrong too. Helv. Chim. Acta 47, 756 1964 gives the conversion of LSD to 2,3-dihydro-LSD - they made 12-OH-LSD from this. Michael Valentine Smith's Psychedelic Chemistry gives activities of 1/10 and 1/1, respectively, for these substances - without refs.
 
Beagle
Member   posted 12-04-98 02:48 PM          
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Of course I couldn't stay away. I enjoy this place too much. Regarding oxytocic activity as an indicator, I had just assumed that since smooth muscle contraction and psychoactivity are such different effects, they prob. would be mediated by diff. subtypes of 5-HT2 receptor. Not necessarily such a good assumption! LSD is not really selective for 5HT2A vs 5HT2B is it?
Picture this: An Aldrich account, independant wealth, and a fully equiped lab on a private island.


Lilienthal
Member   posted 12-05-98 01:07 PM          
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Nice to hear you again, Beagle. Don't you think that an island would be a bit too far away from the next library?
See also Brit. J. Pharmacol. 14, 265 1959 for the screening of some (not very interesting) 5-HT2 agonists and antagonists at a rat uterus preparation. Ergoline derived antagonists (like BOL in this paper) are antagonizing the uterus contracting effect.
But keep in mind the differences between rat and human 5-HT2A receptors (I have a pile of papers obout this...).
 
Lilienthal
Member   posted 12-08-98 04:56 AM          
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Piglet (11-25-98): O-acetyl psilocin has about the same activity as psilocin (but it's destillable...). Surprisingly, psilocin is more hydrophobic than 4-MeO DMT, 5-MeO DMT, or DET (Life Sciences 7, 267 1968).
 
Piglet
Member   posted 12-08-98 05:30 AM          
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I'm sure I read that increased potency in a book. Maybe IV it's more active (the book didn't mention method of ingestion). It was one of the underground chemistry books, I forget which, so maybe just crock info!
I suppose doing it off foil (lower BP) might give the impression? Who knows...
Thanks,
Piglet 


Lilienthal
Member   posted 12-13-98 06:57 AM          
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Here's a chemistry paper for 4, 5, 6, and 7-isotryptamines. The 6 and 7 substituted isotryptamines have a similar structure compared to methylendioxy compounds.
 
Rhodium
Administrator   posted 12-13-98 10:55 PM          
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Uh, did you forget to include the actual ref? Did they try them out for possible activity?
 
Lilienthal
Member   posted 12-15-98 03:33 PM          
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 Helv. Chim. Acta 51, 1616 1968. The route is: 4, 5, 6, or 7-Br-indole > -CN > -CHO > nitroalkenes > ethylamines and isopropylamines. It's a pure chemistry paper.
 
Beagle
Member   posted 12-16-98 11:38 AM          
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This may have been answered in the above refs, which I haven't looked at, but I just came across a mention of an "elegant synthesis and use of indole-4-carboxaldehyde":
Heterocycles '81, 16, 267. It was mentioned in the context of using indoles as lysergic acid precursors in JOC '84, 49, 4409-
 
Beagle
Member   posted 12-16-98 11:55 AM          
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Another indole-4-carboxaldehyde synthesis occurs in JOC 51(26) '86. Here 4-Br indole is synthed by Leimgruber-Batcho method, lithiated, and then reacted w/ DMF to give the aldehyde in 57% yield. 5, 6, and 7-bromoindoles are also lithiated and reacted with other electrophiles in this paper. Now if only there was some way to use this procedure to put oxygen at the 4 pos'n... 


PolytheneSam

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indole analogs
« Reply #1 on: April 02, 2002, 03:56:00 AM »
Here's an old thread with indole analogs in it. 

Post 276458

(PolytheneSam: "Benzothiophene analogs", Tryptamine Chemistry)


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