(+)-O-Desmethyltramadol and analogs

[Tehuti]

Hello all

swim has footed about for a while now but decide to join after reading a post about O-Desmethyltramadol. Swim sees some great minds in this bit of the forum, so thinks it will be a good place to talk. swim understand this has been talked about before but was wondering if we can advance on it.

How do you think (+)-O-Desmethyltramadol could be made better and do you think the synth from Tramadol to (+)-O-Desmethyltramadol or other close relatives of it is doable by a pro?

swim have read what harobo1 seid “acetylation of the phenol would allow the drug to jump through the BBB” who agrees this will work in the same way as Morph to H?

What about other analogues of tramadol that are more opiate selective

This is what happened to some rats after getting some (+)-O-Desmethyltramadol notice how 5mg/kg led to sever respiratory depression but it was not until 30mg/kg that one of the rats died, is this normal in opiate use a long dose response curve? also is muscle rigidity normal?

5¿mg¿kg-1 led to severe respiratory depression, so that only two rats were tested with this dose. One of these rats exhibited myoclonic twitches before ADT determination (Table 1). ADT was not affected (not illustrated). At 10 and 30¿mg¿kg-1 (tested in two rats each), severe respiratory depression and catalepsy with muscle rigidity, but no seizures were observed. ADT was not affected at 10, but markedly increased at 30¿mg¿kg-1 (not illustrated). One of the rats treated with 30¿mg¿kg-1 died within 24¿h after drug injection. In nonkindled rats, severe respiratory depression was observed following 10 or 30¿mg¿kg-1 of the metabolite

Could this long dose response (if it is) curve be because of Stimulation of μ1-receptors more than (or only) and little (or not) of μ2?
Which one is responsible for the high μ1?


swim likes talking about opiate analogues there are so many of them also pharmacolagy

Many thanks

 

[Tehuti]

what piglet and ronald seid

This is what what piglet and ronald seid what do you think?


look up the structure of tramadol and look up heroin/morphine to get the general idea. This has been done with tramadol minus the methoxy group. However this particular compound does not appear in the literature anywhere but it should work all right.

the structure of tramadol is well researched. The patents explain that the most active of the series was O-desmethyl tramadol which the body converts tramadol into. It's about 3 times more potent. I suggested replacing the dimethyl moety with I piperidine or morpholine ring since these analogues in other opiates increase lipophilicy & so increase the speed of action (but reduce duration) for example methadone->diconal or dextromoramide.
I suggest that esterifying thst bare hydroxyl wil further increase the lipophilic character. The Quat hydroxyl will need protecting (with a triflate or something) during esterificatioh I guess, but you really SHOULD (knowing SAR of opiates pretty welll) produce something pretty damn nice.






get the structure of tramadol on your screen. Now imagine placing the hydroxyl (-OH) group with -O-C=O.CH3 by reaction with acetic anhydride and a catalytic amount of base (pyridine, triethylamine). In pharmacological terms compounds with hydroxyl groups are too polar to cross the blood brain barrier (BBB) easily. Hence compounds with hydroxyl groups have low potency. However once across the BBB if the molecule undergoes a transformation to make it more polar this will help with its retention leading to enhanced activity. [This is the sole reason why heroin is more potent than morphine] The acetyl tramadol should cross the BBB easily whereby the ester is hydrolyzed back to hydroxyl and thus retained (in the brain). Thus acetyl tramadol is behaving as a 'pro-drug'. Tramadol itself is still the active compound.


^^ Good explanation.
http://opioids.com/tramadol/structure.html
There is the structure. Most every opiate out there follows something called 'the morphine rule' which is:

1-Aromatic system
2-Quaternary Carbon
3-Two carbon chain
4-Tertiary amine

Test this with morphine, methadone, tramadol, demerol or whatever. Fentanyls, Tilidine, thiambutenes & etoniterzine are the only exceptions I know.

P-)

BTW Ronald, you don't need a 'catalyst' if you use anhydride, only if you use the acid chloride. It's not even really a catalyst since it salts to a quat amine to shift the balance to the right...

^^ No, the problem is that there are 2 -OH groups to acetylate. The aromatic one improves performance, the quat one decreases performance. That's why I said that the quat needed protection during acetylation. The patents point out the esterifying the quat reduces performance. If you just O-demethylate then add acetic anhydride you WILL get a less active compound. You need to go

1: Protect
2: Lewis acid (titanium tertachloride) to O-demethylate
3: esterify
4: deprotect.

You can, of course, swap the quat OH for a halide which is still active...

 

[Tehuti]

some ideas might come from these

some ideas might come from these...

(-)-(1S,2S)-O,N-Di-desmethyl Tramadol HCl

(+)-(1R,2R)-O,N-Di-desmethyl Tramadol HCl

N-Desmethyl Tramadol HCl

O,N-Di-Desmethyl Tramadol HCl

O-Desmethyl Tramadol-d6 HCl

O-Ethyl Tramadol

Tramadol-d6 HCl

sorry for all the posts

 

[Tehuti]

Ok swim will talk to himself. nothing new there then.
From what little info swim has, I think an actlated version of (+)-O-Desmethyltramadol would be the most reliable to preform, the dose is still high 4 -10mg a kg (for non actalated) but it looks very safe on the stopping breathing part

but swim is still very interested in


O,N-Di-Desmethyl Tramadol HCl

O-Desmethyl Tramadol-d6 HCl

If anyone has any info

 

[vecktor]

I don't think you need to be too concerned with the phenolic OH group, several people have reported taking desmethyl tramadol (M1) and it is active so it clearly crosses the BBB. perhaps there is internal hydrogen bonding that masks the slightly hydrophilic nature of the aromatic OH I do not know.

the aromatic acetyl derivative would rapidly hydrolyse in vivo, probably through the common plasma esterases, acetylated phenols are very rapidly cleaved.
the point is probably moot.. even when one takes the heroin morphine analogy, the phenolic acetyl group is cleaved off heroin extremely quickly to give 6-MAM, probably as quickly as it is cleaved from acetylsalicylic acid, half life of 5-10 minutes, so a significant amount of heroins effects and pharmacodynamics are that of 6 MAM.
perhaps a MAO activated nicotinic ester would be better as this would pretty much allow brain specific cleavage.

M1 would appear to offer greater recreational potential, because it would be immediate onset rather than the slower onset of tramadol whose opioid effects are pretty much M1's anyhow.
tramadol has limited potential because of its tendancy to cause convulsions with higher doses. what aspect of tramadols pharmacology this effect is linked to I don't know, I suppose they are most likely M1's effects, someone here will know...

also be very wary of extrapolating rat numbers to humans. Rats have evolved over millions of years to deal with pretty noxious substances they have fast metabolism and are efficient at detoxifying things.


Let us know how you get on with Grünenthal's patent lawyers.

 

[Tehuti]

Thanks for your reply
No point in acetalating it then as it could metabolize into something else which is not active?
(+) desmethyl tramadol seems like it would be swims favourite as swim cant stand stimulants, even one large mug of strong coffee! swim is so sensitive

 

[maumakmak]

I may have access to (-)-O-DESMETHYLTRAMADOL, CAS:144830-15-9
Does anyone here know if it's any good recreational wise?

I think when people talk about Desmethyltramadol they normally talk about (+)-O-Desmethyltramadol,right?

 

[Turing Machine]

I think when people talk about Desmethyltramadol they normally talk about (+)-O-Desmethyltramadol,right?

I suppose it depends on who you mean by "people" but generally yes. The M2 metabolite, N-desmethyltramadol is inactive.

It should be said that unless you are already an addict, you should avoid recreational use of all narcotic opioids. The combination of physical and psychological dependence which they are all capable of results in a high likelihood of LIFELONG addiction.

As far as recreational potential it depends on how much it costs, which enantiomer you are getting and what other opioids are also available to you and how much they cost. It is certainly able to produce a narcotic effect and the euphoria and addiction that go along with them, but going by experience reports it does not appear to have the level of euphoria present in opium morphine or heroin. It sounds like it would have potential as a good maintenance drug for younger people to whom the potential of lifelong addiction to methadone isn't going to be in their best interest. This is assuming it does indeed have a substantially lessened risk of inducing seizures. Ideally, I'd like to see a range of maintenance drugs targeted towards different users, perhaps something like methadone, suboxone, O-desmethyltramadol, and dihydrocodeine. Methadone or suboxone could also be used at first due to their ability to block or at least lessen the euphoria of other opioids, then once the patient has stabilized, has given clean urines and has shown themselves capable of responsible self titration, he/she could gradually be moved down in dosage and switched to a weaker opioid with a shorter half life. I've heard of clinics in europe switching patients to dihydrocodeine for the later half of their detox.

 

[benisalive]

interesting

I suppose it depends on who you mean by "people" but generally yes. The M2 metabolite, N-desmethyltramadol is inactive.

It should be said that unless you are already an addict, you should avoid recreational use of all narcotic opioids. The combination of physical and psychological dependence which they are all capable of results in a high likelihood of LIFELONG addiction.

As far as recreational potential it depends on how much it costs, which enantiomer you are getting and what other opioids are also available to you and how much they cost. It is certainly able to produce a narcotic effect and the euphoria and addiction that go along with them, but going by experience reports it does not appear to have the level of euphoria present in opium morphine or heroin. It sounds like it would have potential as a good maintenance drug for younger people to whom the potential of lifelong addiction to methadone isn't going to be in their best interest. This is assuming it does indeed have a substantially lessened risk of inducing seizures. Ideally, I'd like to see a range of maintenance drugs targeted towards different users, perhaps something like methadone, suboxone, O-desmethyltramadol, and dihydrocodeine. Methadone or suboxone could also be used at first due to their ability to block or at least lessen the euphoria of other opioids, then once the patient has stabilized, has given clean urines and has shown themselves capable of responsible self titration, he/she could gradually be moved down in dosage and switched to a weaker opioid with a shorter half life. I've heard of clinics in europe switching patients to dihydrocodeine for the later half of their detox.

Wondering i take suboxone but am trying to get off using iboga though its highly recommended if not required to be on a full agonist for two months prior. do u think that O-desmethyltramadol would be a good thing to take for that peroid .... do you know of what dosages you would recommend for a 16mg suboxone user due to theceling effect? ****** just wondering what you would think i would never do anything without docs supervision this isall just hypothetical thanks

 

[AntiNociception]

4-Benzyloxytramadol and its O-desmethyl derivative

If you are interested in highly active Tramadol analogues, I would recommend looking into 4-Benzyloxytramadol.

4-Benzyloxytramadol has an ED50 (mouse tail flick, i.v.) of 0.05 mg/kg and Ki at mu receptor is 4 nM.

The O-desmethyl analog of 4-benzyloxytramadol has an ED50 of 0.07 mg/kg and Ki at mu receptor is 0.1 nM.

See Example 1 (page 8 of the patent PDF) for the synthesis of 4-Benzyloxytramadol and Example 6 for the synthesis of the O-desmethyl derivative. Both compounds are derived from the same precursor, 4-benzyloxy-2-dimethylaminomethyl-cyclohexanone, by reacting the cyclohexanone with the corresponding Grignard magnesium complex of 1-bromo-3-methoxybenzene or (3-bromo-phenoxy) synthon, which is subsequently de-protected after the Grignard reaction to yield the O-desmethyl derivative.
For more information, check out these interesting articles

(1) Title: μ—selektive Opioide ohne Morphinanstruktur Alte und neue μ-Opioide
Authors: Helmut Buschmann, Bernd Sundermann, Corinna Maul
Pharmazie in unserer Zeit, January 2002, 31(1), pp 44-50

(2) 1-Phenyl-2-dimethylaminomethyl-cyclohexan-1-ol Compounds as Pharmaceutical Active Ingredients - Ivars Graudums, Ernst Frankus, Elmar Josef Friderichs - US5801201 (1996) - 4-Benzyloxytramadol

By the way, if anyone out there is looking for the full-text of ANY article(s) from any medical or scientific journal, please send me a message. I have full access to thousands of journals and would be more than happy to help you locate a difficult to find article. I also have access to CAS SciFinder database, so you may also send me request for compound specific information/references. Thank you.

 

[ebola?]

do u think that O-desmethyltramadol would be a good thing to take for that peroid ....

No, IIRC, it's a full agonist at mu receptors.

ebola

 

[sekio]

please avoid posting large amounts of synthesis text here, this is a harm reduction forum, not a forum designed to tell people how to make drugs.

running reactions involving pyrophoric organometallics in ether/thf at 5000 bar pressure is not what i would call kitchen chemistry anyway.

 

[Fruitofknowledge]

Tramadol analog

A good Tramadol analog would be N-phenylethylnortramadol or it's 0-desmethyl counterpart or by adding the phenylpropoxy ether group.

 

[clubcard]

Swapping the -OH for an -F increases potency the most potent modification. The O-desmethyl of that is VERY potent.

 

[roi]

Swapping the -OH for an -F increases potency the most potent modification. The O-desmethyl of that is VERY potent.

Are you sure? LD50 is same as tramadols, at least in mice.

ref: https://www.thevespiary.org/rhodium...minomethylcyclohexanoles6462.pdf?topic=3395.0

Der Ersatz der sauerstoffhaltigen Funktion durch Halogene oder Halogenalkane schwächt die Analgesie ebenfalls sehr stark ab.

 

[neurotic]

it's the alcohol which is bonded to the quarternary carbon that is swapped for the fluorine - otherwise there wouldn't be a O-desmethyl metabolite like clubcard mentioned

 

[roi]

Whoopsie, I see. http://www.google.com/patents/US5733936

20x as potent as tramadol. Not bad.

 

[clubcard]

You're laughing now - but just TRY replacing the -OH with an -F.... or, frankly, DON'T.

 

[dopamimetic]

As I've just posted over in BDD (sorry for cross-referencing, should have initially posted here as it does more fit):

They should really just approve O-desmethyltramadol as an independent medicine. I don't get it why they haven't done that because it would even have been patentable. Instead they came up with tapentadol which (based on my limited experience with it and opioids in general) is inferior to O-DMT.

A modification of O-DMT that has less or no affinity to NET would be of even more benefit. Then one could independently consider if one wants an additional SSRI/SNRI or not.

Also tianeptine is really remarkable seeing it's an opioid that possibly has less or no potential for respiratory depression, it should just be much longer lasting (an osmotic retard formulae a la Concerta would be great too for the depressed ones). Then there of course is that intriguing peptide DAMGO that seems to be devoid of tolerance development ...

 

[serotonin2A]

As I've just posted over in BDD (sorry for cross-referencing, should have initially posted here as it does more fit):

Tapentadol is a newer drug entity and hence would probably yield longer patent protection. Additionally, they may not be able to get O-desmethyltramadol approved because it probably doesn't work better than any of the other moderately strong mu agonists that are already available.