Dextroproporphan: An Analogue for a Better Dextromethorphan? | Hacker News Reader

Dextroproporphan: An Analogue for a Better Dextromethorphan?

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39 pointsznano16 comments

Isn't CYP2D6 inhibition the surer and more convenient route? Adding a bulky isopropyl group might reduce affinity at sigma1 receptors. Think about it: Going from 3-methoxy to 3-hydroxy makes for a very different drug. Wouldn't you expect that going from 3-methoxy to 3-isopropoxy would also make for a very different drug -- and not just "the same thing but more resistant to first-pass oral metabolism"?

Selective deuteration seems like another potential option with good prospects. Here it reduced CYP2D6 metabolism in a broadly similar case: https://pmc.ncbi.nlm.nih.gov/articles/PMC8724172/

Deuteration in a position like that is so simple that you can do it at home.

I was curious and checked out the wikipedia page on CYP2D6 and it says CDB is also a strong CYP2D6 inhibitor but I don't have a formal background in this stuff.

https://en.wikipedia.org/wiki/CYP2D6#Ligands

The CYP[XYX] enzymes process just about everything that isn't a starch, a protein, or a lipid. So whenever you eat anything, something in that food is going to interact with a CYP enzyme somehow -- even the plainest white bread contains acrylamide, which is metabolized by CYP2E1 and others.

Point is, there's a huge laundry list of drugs and dietary chemicals that inhibit or induce CYP enzymes. That Wikipedia list is far from complete.

These guys claim that something in goldenseal can inhibit CYP2D6 by >50%: https://pmc.ncbi.nlm.nih.gov/articles/PMC2562884/

...If there's a phamacological interest in CYP2D6 inhibitors, whatever goldenseal constituent is responsible (and it's assuredly a small molecule that is metabolized by CYP2D6, because that's how these things work,) can be isolated and improved upon. This is relatively simple and predictable in comparison with making new drug analogs and estimating their effect.

So if I were OP, I'd focus more on CYP2D6 inhibition as the surer thing.

I get what you're saying but I think there's a problem, gobs of common drugs have 2D6 as a metabolic pathway. Increasing 2D6 inhibition puts recipients at greater risk of serious adverse events or drug toxicity. Can't say much about pharmacodynamics of candidate compounds, that remains to be determined experimentally in live subjects including animal models and possibly phase 1 trials.

In any case I appreciate the interesting ideas in your comment and the article.

If you're OP and you're considering clinical trials... well.... I hate to be the bearer of bad news, but you've got another problem. The compound you've described was also described in the scientific literature (back in the 90s) and it's in at least one patent application:

> https://patentimages.storage.googleapis.com/37/75/89/204db4e...

See claim 16 and "compound 102." So, unfortunately, fatal prior art exists. (On the bright side, those scientists arrived at exactly your hypothesis.)

My own hypothesis, that deuteration would be useful, is also in the patent literature: https://patents.google.com/patent/US10406155

As is the deuterated isopropoxy!

I'd suggest an alternative, but merely mentioning it here might constitute prior art. If you're interested in discussing, my email is in my profile.

This is pure speculation, and he really doesn't know what he's talking about:

"The main problem is that DXO also contains an amine, and that amine can react during the process. So the first step would be to temporarily protect the amine so that it doesn’t interfere."

Anyone who's taken introductory org chem knows better than this. That's a tertiary amine, so you're not going to be protecting it. Not that the compound can't be made -- it probably has been already. I'd check on Reaxys but I don't really want a morphinan in my search history...

Confirmed: the compound proposed by the author has been made and studied since at least 1992 (https://pubs.acs.org/jmcmar/article-abstract/35/22/4135/7112...). It had activity interesting enough to be published, but like almost all active molecules, it wasn't interesting enough to push into the clinic.

Some other inaccuracies I noticed in the post:

"DXO is more lipophilic, meaning it’s attracted to fats and lipids."

Dextrorphan is more polar, and therefore less, not more, lipophilic than dextromethorphan. It is still able to cross the blood-brain barrier because it is still a fairly lipophilic molecule.

"My first thought was replacing the methoxy group with 3-fluoromethoxy. On paper, this seemed like it could be an effective way to interfere with CYP2D6-mediated demethylation, but synthesizing a fluorinated DXM analogue would be difficult and costly."

There is no such thing as a "3-fluoromethoxy" group. What I think the author meant was "trifluoromethoxy" ("3-" and "tri" have very different meanings in chemical nomenclature). The trifluoromethoxylated derivative of dextrorphan has, in fact, been synthesized and patented (https://pubchem.ncbi.nlm.nih.gov/compound/24997117).

"The structure of DPO is (+)-3-(isopropoxy)-N-methylmorphinan, with the 3-methoxy group of DXM replaced by a 3-isopropoxy group."

The "+" indicates the direction that a chiral nonracemic compound rotates plane-polarized light in solution. While there are computational methods to predict it, it can't be assumed that the derivative of a "+" compound will also be "+". Better to use "R" and "S" (CIP nomenclature), since they are determined entirely by the 3D structure of the chiral compound and don't require a physical measurement to determine.

The article discussed "CYP2D6 inhibitors like Wellbutrin and DXM" and I can offer one data point. An officemate came in with a bad cough one day. I had over-the-counter cough medicine with DXM handy and he took some. He had never taken DXM before; it is apparently not common in his country of origin.

He felt "shaky" and generally terrible after taking the DXM, and almost went to the hospital. I had never encountered anyone having that reaction before.

That particular colleague was also, it turns out, on a pretty hefty dose of Wellbutrin. I never knew there was a possible connection between the two until now.

I think they've changed the recipes since I was younger but we used to take a bunch of Nyquil or Robitussin... they had DXM in them and they would definitely make you feel euphoric if you took enough. The street term at the time was 'going robo'.

Did a quick search and found this: https://www.healthline.com/health/robotripping

I remember hearing about people chugging cough syrup for a "Robobuzz" and I could not bring myself to do it. It seemed to be the most unpleasant way of altering my state.

It was work. You had to force it down. After doing it enough times you get used to it I guess. I could never stand alcohol and never understood it... beer neither. After drinking it enough, I understood it. Definitely not a good thing on either account.

Normally people robo-tripping buy Delsym now since it only contains DXM. I remember doing it a few times as a teenager, would have a fun night hallucinating the craziest things, listening to music was like a full body experience. The next day you'd be left with this "glow" that just made you extremely happy, assuming due to the increase in serotonin.

Calling it very effective for cough is probably a bit of stretch. Some studies have shown that DXM is marginally better than placebo [1].

[1] https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD...

in my experience it can be effective for some people but mostly at much higher dosage than usually recommended.

It takes at least a full bottle or two to begin robotripping.

"Better" sounds like a proportional evaluation, e.g "5x better". How do you get "better" than Zero?

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