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Opioids of the Future (2011) ver. 2

Adder: It seems like we are reading the same works & noticing the same things. Yes, the C-ring in particular can be modified in a vast number of ways to alter the activity of the drug in many ways. I don't know if the extra work of introducing a function at the 14 would be worthwhile. You are quite right in saying the highly potent agents rarely match plain morphine. People just read ED50s & assume the lowest number = best drug. I like the morphinans because they are 'elegant' in synthesis (so many routes developed) & activity (I would like to know just how much NMDA activity the different analogues have but find no data).

When you say no 'rush' I don't quite understand - but then I've only ever tried swallowing/smoking opioids (being a coward/sensible - delete as appropriate). Do you mean the euphoria mediated via cAMP? I know levorphanol's analgesia takes quite a while to kick in at medicinal doses which I just assumed was partly BBB & other transport factors. I haven't actually read any actual figures for the difference in onset/duration - they just make those flat statements. Of course I trust that particular source. I've also got some of Grewe's original work (but both sources give the same basic data).

Since you are very knowledgeable on this class, I wondered what you think of the work by Wentland et al on replacing the phenol with a carboxamido function? [snipped]

I am now re-reading work on the benzomorphans. You have obviously seen things I missed... I feel I need to catch up... I'm surprised there is so little work on the phenylmorphans.

BTW I had literally no idea that tianeptine was subject to abuse. I agree that it is sad that people will destroy their lives for a few hours euphoria.
 
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adder and lefetamine: You guys know I have a lot of respect for you, but honestly this recent discussion is reaaaaaly teetering on the edge of synth discussion.

I am actually inclined to close this whole thread as a non-specific discussion of potent-opioid chemistry does not appear to contribute anything to Harm Reduction (what BL exists for). There are other places where such discussions are better had :). If you can turn this thread into something HR-worthy, then you have my advance thanks!

To his credit, adder seems to have had HR in mind when he made the above post.

Tits: you know better not to ask about synth here, much less about THAT kind of synth which, IIRC, was prohibited even on the Hive!
 
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You may have noticed the previous thread is gone. This is because it was full of asinine rules-breaking chatter that contributed nothing of value. I have moved here the handful of posts I thought had some substance in them. If your post did not make it, don't take it personally - it may have simply been you replying to a deleted post. Or it may have been - in which case I welcome you to contribute within the following guidelines:

What this thread IS NOT about:

- This thread is NOT about exchanging patents that deal with the synthesis of powerful opioids.

- This thread is NOT about arguing why Salvinorin-A is so expensive in Sigma-Aldrich's catalogue.

- This thread is NOT about discussing ANY chemistry OR prices.


What this thread IS about:

- This thread IS about sharing personal experiences with novel opioids.

- This thread IS about speculating on the PHARMACOLOGY (n.b.: not chemistry) of novel opioids.

- This thread IS about giving HARM REDUCTION advice to people who post asking about novel opioids they intend to ingest.


Also note that I'm not being an asshole - I am intentionally making the opioids threads far more restrictive on this forum for reasons we are all well aware of.

Consider this post your informal warning.
 
Jamshyd said:


Tits: you know better not to ask about synth here, much less about THAT kind of synth which, IIRC, was prohibited even on the Hive!
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:o

Blasphemy!!!



But umm.. what do you guys think of the testing of ultra low dose naltrexone in pharmaceutical preparations?

can they get it too work?
 
My theory, which is supposedly not far off from the truth, is that combining naltrexone in doses WITH opiates has a different effect on the body that utilizing them after having an opiate in the system.

Basically, my idea is: when you take naltrexone simultaneously with an opiate, it does different shit than when you get it afterwards.

I was just throwing ideas around in another thread discussing the new combination of OC and naloxone, somewhere else, and this was the jist of it. Heres part of what I wrote, please guys feel free to dissect my ideas or help me develop them. I love forums its basically a giant wall for me to bounce ideas off of, and nice, smart, people come along and bounce the idea right back at me at a new angle and in a new light.

However, this is where it becomes interesting for oxy: how will this deter abuse? Does ingesting an opiate simultaneously with an ANTagonist (NOTE: actually reverse agonist) provide different effects (b/c they are both reaching the sites simultaneously)? Are they going to somehow encapsulate/coat the oxy in the naloxone, so that the naloxone is ONLY RELEASED WHEN THE PILL IS TAMPERED WITH?! This seems like it would be quite an effective idea if they managed to pull it off: since naloxone is so poorly absorbed (besides IM/IV) perhaps one would still be able to achieve the time release effects of the pill if it is NOT tampered with, however, tampering with it would, perhaps, release a large amount.
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Someone responded and basically said that their doctor told them that ingesting the two simultaneously DOES in fact have a different effect. All of that is anecdotal however, and I have not had a doctor/medical professional tell me that personally.

Take this for what its worth, this is just my 2 cents on the topic. I do feel that simultaneously taking these two opposing forces does have a different effect than letting 1 follow the other.

Also, i feel that Methylnaltrexone (Relistor) is gonna be somethin to watch with a close eye. I feel that this drug has the potential to be combined with quite a few opiates, and shows promise for developing the field. I'm not 100% on my whys yet, but its something i've been learning about and watching intently. I know its not TOO new, but relatively speaking, it is new.

Again, not 100% sure why (though I am working on developing my whys and abstractions in a precise way other than just saying "trust me for now", and I will come up with some good "whys"), I just have a feeling that its gonna lead the way for some interesting stuff.
 
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I was fascinated that the novel ligands discovered by Lednicer (the cyclohexanone/cyclohexanol scaffolds) act at both the DOR & MOR receptors. It appears that this dual activity may allow effective analgesia with a reduced level of tolerance/dependence. NOR antagonism appears to offer another possible target for dealing with (nociceptive) pain.

I know a Japanese team were looking at mitragynine as a lead compound for developing dual DOR/MOR agonists but I haven't found much information on what they actually achieved.

Norbuprenorphine also has interesting mixed activity. I cannot help but wonder it it is possible to derive an improved compound based on the Bentley derivatives. Pity that his teams lab-notes are tightly paced away somewhere in the McFarlane-Smith office...
 
BTW I was interested to read the research of one Mark P Wentland. Apparently the opiate receptors are involved in the addictive nature of cocaine. Cyclazocine was investigated as a possible treatment but of course it's oral activity & duration work against it. It appears that first-pass metabolism is the cause of the former and subsequent hepatic metabolism the latter. Replacing the phenolic -OH with a carboxamide solves both problems. Cyclazocine had a mean T1/2 of 2 hours in animal models whereas 8-CAC (8-carboxamidocyclazocine) was over 15 hours. The potency was obviously improved by quite a large margin.

His group have replaced the phenolic -OH on a large number of opioids & without exception the results were an improvement in activity. A general route for this replacement has been published. This modification would seem to be good news for those suffering from chronic pain or those taking antagonists to prevent relapse in cases of opioid addiction.

The CONH2 introduces an optical centre into the molecules & one isomer is a lot stronger than the other. In spite of this, overall, the racemates are still more potent. The activity is interesting, in itself, because it helps to reveal the pharmocore of the opioid receptors.

Further work revealed that there are more complex carboxamides with enhanced activity but I admit to not really understanding the biochemistry involved in their selection of moiety. The complexity strongly suggests that they had a pretty good idea of what they were aiming at!
 
n spite of this, overall, the racemates are still more potent.
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Wait, which racemates are more potent? If one isomer is 2 "potent points" and the other 1 potency point, potency being the average of each isomer's potency, how is (2+1)/2 > (2+2)/2? (1.5 isn't > 2 the last time I checked!) If it's true, though, it would be really interesting to read.
 
This post was warned. I recommend everyone read the instructions I added to the first post of this thread and figure out what happened here. Next time it will be an infraction. Thanks. -- Jam.

In the patents they modify things like ketobemidone; well basically they seemed to have modified every phenolic opioid they could find.

Can anyone give me a ref to compounds that are MOR1/MOR2 selctive? I know fentanyl is supposed to be MOR1 selective... but not very.

I was also interested to note that placing an ether on the 14 position of benzomorphan class opioids has a large Impact on their potency. I wonder if this same effect is why those piperazine opioids developed by Dianippon also have much more potency with a -OCH3 2 carbons from the basic amine?
 
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