4DQSAR
Bluelighter
- Joined
- Feb 3, 2025
- Messages
- 5,449
The title compound appears to have turned up in a few seizures. In the book by Lenz et al. it is suggested that a 14-OH and an N-phenylethyl will both increase activity. But that's quite an old book...
So yes, it IS a more potent analgesic. 2a is the title compound. So looking at the affinity seems to suggest it's VERY potent. But look at the EC50. So yes, it is more potent than oxymorphone but note how swapping the N-methyl for an N-phenylethyl has a much more profound effect on plain morphine (1a).
It's unclear if the title compound is a dualist (hence that increased analgesia) BUT what Lenz et al et al failed to note was that various researchers had previously swapped the N-methyl for an N-phenylethyl in various phenanthracene opioids. Some with and some without that 14 hydroxy moiety. Some claimed the former was the more potent, other claimed the latter was. May I suggest that the species used for the in vivo studies could have demonstrated the differences between species? BUT overall it seems that the 14-OH is not compatible with larger N substituents. Why? Who knows? My guess is that the lone-pair of the N inteteracts with the lone-pairs of the O so the active conformation may not be the lowest energy conformation.
It's sort of crazy because I posted the Schmidhammer papers some years ago so it's not as if there wasn't data.
To me this and that crazy RC with an N cyanoethyl moiety were produced because animal models demonstrated potent analgesic activity. But in that case even studies from the 1970s showed that the N cyanoethyl homologues did NOT substitute for morphine... which hinted at what we now know - there are multiple classes of opiate receptor.
It's not as if a candidate need be totally selective but from my own research, one really needs the MOR activity (affinty and effacacy) to be at least an order of magnitude higher than DOP and two orders of magnitide higher than KOP activity.
Because this is why W-18 turned up. Medicinal chemistry like all sciences requires one to extrapolate from incomplete data so if an N-cyanoethyl results in either an inactive compound or a compound that is non-selective, if you find another class in which the N-cyanoethyl is the most potent by orders of magnitude, likely the latter is the case.
I feel that these idiots are queering the pitch for people who actually design based on ALL the data, not on a single paper. Buy hey, that's thousands of hours of extremely dull reading whereas if one can simlly give a Chinese manufacturer an IUPAC name, that avoids the dull. At the expense of safety and utility, obviously. But it's an 'elevator pitch' to say 'I have a design for a legal opioid as potent as carfentanil' which is what seems to have happened.
It's pure unalloyed greed. Noroxymorphone wholesales for around $2500/Kg.
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