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"?
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.