Comment by A_D_E_P_T
4 days ago
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 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.
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.