A call to develop tramadol enantiomer for overcoming the tramadol crisis by reducing addiction

[4DQSAR]

https://www.tandfonline.com/doi/pdf/10.1080/17568919.2025.2463314

I quote “The (+)-enantiomer of tramadol acts as a mu-opioid receptor (MOR) agonist and by inhibition of the reuptake of serotonin, whereas (–)-enantiomer inhibits noradrenalin reuptake”

I've already noted that the unexpected toxicity of tramadol appears to be mediated by it's (-)-enantiomer because it is a pro-convulsant. So I suggest that in truth, they missunderstant the true cause of the 'crisis'. In the UK we have mostly switched back to prescribing compound analgesics containing codeine or dihydrocodeine,

Sci-Hub | A Practical Procedure for the Resolution of (+)- and (−)-Tramadol. Organic Process Research & Development, 4(4), 291–294 | 10.1021/op000281v

Sci-Hub | Highly efficient resolution of (±)-Tramadol with di-p-toluoyl-tartaric acid (DTTA). Tetrahedron: Asymmetry, 12(11), 1663–1670 | 10.1016/s0957-4166(01)00293-2

Sci-Hub | Development of Highly Efficient Resolutions of Racemic Tramadol Using Mandelic Acid. Organic Process Research & Development, 6(5), 729–737 | 10.1021/op0255276

I suggest it's done.

Tramadol (the cis pair) sells for just $50/Kg. O-demethylation is just about the simplest reaction possible. But what nobody seems to have done is producced the (+) enantiomer of ODMT. Yes you only end up with (just under) twice as much but it's twice as potent as an opioid and actually SAFER, or rather I should say that in human trials, 20mg of the (+) enantiomer had the analgesic activity of 50mg of the racemate. So rather than synergy, you have dischord.

US-5733936-A '6-dimethylaminomethyl-1-phenyl-cyclohexane compounds as pharmaceutical active ingredients'

The table in column 19 shows a chiral derivative that is some 21.25x more potent in it's analgesic activity in animal models.

Now don't get too excited, this only means your product has about ¾ morphine in potency. I guess the difference is that this one is legal.