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.
In any case I appreciate the interesting ideas in your comment and the article.
> 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.
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.
"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...
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.
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.
[1] https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD...
Did a quick search and found this: https://www.healthline.com/health/robotripping