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...
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"?
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.
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.
...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.
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...
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.
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.