Dextroproporphan: An Analogue for a Better Dextromethorphan?

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.

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...

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.

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...

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

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