Levorphanol, Opiate and Dissociative.

[polymath]

If you replace the n,n-dimethyl in BDPC with pyrrolidine or other nitrogen containing ring, it could become an NMDA receptor blocker, but it could also turn the opioid effect to naloxone-like similar to some of the other compounds in Lednicer's set.

 

[AlsoTapered]

Well don't NMDA antagonists produce analgesia? Only the N,N-dimethyl and N-methyl showed any analgesic activity.

That Dan started FROM PCP strongly suggests they were seeking a dual agent.... but they made lots of compounds and the p-Me or p-Br and the ketone were required.

He really DID write a lot of articles. One one each modification as far as I can tell.

 

[polymath]

If the data set contains molecules that cause their effect partly by blocking NMDA, then I believe there should be a different profile about which pain sensitivity test they're most effective in (compared to a typical opioid). But there's also going to be experimental randomness that messes up the picture.

 

[MedicinalUser247]

If you really want a compound thats both an Opiate and also Dissociative take a look at Racemorphan. Its a combination of two molecules that are similar. Dextrorphan and Levorphanol. The Dextrorphan acts as the antitussive and NMDA antagonist and the Levorphanol acts as the Opiate analgesic. Its funny how you can switch things around and come up with something entirely different such as Dextrorphan compared to Levorphanol. If you look at both molecules you can really see how related they are when you compare them to each other. What's really interesting is to look for is a single molecule that's both an Opiate and NMDA antagonist. I think that, that would have a lot of medical usages. As for Levorphanol I didn't realize how weak it is as an NMDA antagonist. As for Racemorphan it's the racemic mixture of the two stereoisomers of 17-methylmorphinan-3-ol with produces effects that differ from one another in the compound. Just compare Dextrorphan to Levorphanol.

 

[AlsoTapered]

If the data set contains molecules that cause their effect partly by blocking NMDA, then I believe there should be a different profile about which pain sensitivity test they're most effective in (compared to a typical opioid). But there's also going to be experimental randomness that messes up the picture.

There is no evidence to suggest that any NMDA activity was discovered - even when Dan was working on the BDPC class, they were able to test affinity by administering antagonists with known affinity values - it's in the papers.

 

[polymath]

There is no evidence to suggest that any NMDA activity was discovered - even when Dan was working on the BDPC class, they were able to test affinity by administering antagonists with known affinity values - it's in the papers.

Yea they already had naloxone in the 1960s and 70s... The amount of simultaneous delta and kappa binding could also affect the effect profile on different types of nociception, maybe also the amount of euphoria as discussed in that other thread.

The alkaloids in the plant psychotria colorata are also said to block NMDA receptors in addition to mu receptor binding, but there seem to be surprisingly few people who have tried that drug (at least last time I looked for reports about that on BL).

 

[AlsoTapered]

I would have to reread the papers - it has been a decade. I think John von Vogel is still alive but Dan contacted me, I don't feel I can hassle a retired guy.

But evidently they tried to make a dual agonist an couldn't. Then they asked 'why dimethyl' and their IS a good reason (it overlays an amine in the receptor pocket) and then the work being done on ciramadol (their were earlier papers) and realized that their were more binding sites.

To sum it up, Dan & Johh built one of the models that allied to bond-angle calculations shows the active conformation and Dan noted that BDPC overlays fentanyl.

I KNOW that sounds crazy at first but the key moieties are all in the same relative positions. THAT is why the p-Br is needed - to move the entire thing 1 methylene.

Overlay in ChemOffice (start just with the 2 benzene rings) and you will see.

 

[polymath]

I've seen those overlay diagrams appear in several articles and books, especially when it's about something binding to the opioid receptors.

The molecular docking simulations are also an interesting topic, but it is a hassle to find the potential binding sites from the 3D receptor protein model, to set the protonation of amine and carboxyl groups to correspond to physiological pH and so on. Even though it's based on just classical electromagnetism without any quantum mechanics that would make it computationally impossible at the current status of available computational power. I hope there will soon be some type of AI tool that makes this process easier.

 

[Skorpio]

I've seen those overlay diagrams appear in several articles and books, especially when it's about something binding to the opioid receptors.

The molecular docking simulations are also an interesting topic, but it is a hassle to find the potential binding sites from the 3D receptor protein model, to set the protonation of amine and carboxyl groups to correspond to physiological pH and so on. Even though it's based on just classical electromagnetism without any quantum mechanics that would make it computationally impossible at the current status of available computational power. I hope there will soon be some type of AI tool that makes this process easier.

Interestingly, there was just a study in elife assessing alphafold 2 based models for use in molecular docking to assess ligand binding. They found the actual protein models produced by alphafold 2 was more accurate than hand generated computational models, but the alphafold 2 models failed to better predict ligand binding events.

We are definately on the way to AI ligand binding predictions, but still pretty far away from it being a reality.

 

[sekio]

> The alkaloids in the plant psychotria colorata are also said to block NMDA receptors

Hodgkinsine, a mu-agonist and NMDA antagonist.
Looks like a relative of eseroline. Like they had a menage a trois but used Gorilla Glue as lube. Just a big ol' pile of indoles.

 

[AlsoTapered]

Benzylic tertiary amine. I seem to recall ersoline not having a particularly high affinity for either class of receptor and being somewhat toxic. Now is the monomer of the alkaloid an NMDA blocker OR is it the trimer (ish) we are considering? Because Dizocipine has the aromatic and 5-membered ring.

I know I keep banging on about dizocipine but it IS the reference compound used when testing newer NMDA antagonists and it would appear that at it's simplest level, the researchers specified that a benzene ring with an N: in an appropriate relative position and angle is sufficient. The 'magic angle is 107.5°.

Things like diphenidine aren't too rigid and thus an aromatic, methylene (sized) spacer and N: in at the correct angle seems to be the minimum. I mean, in effect PCP is an aromatic, methylene spacer and N: and so is the prototype. The rest of the molecule is to makeit RIGID and even that 'stray' methyl side-chain could simply be considered as part of an N-ethyl moiety....