http://postimg.org/image/sw6xekj0t/
US Patent 2777850
Anyone who has plowed through the original fentanyl patents might have wondered why, as well as the amide, sulfonamides were also tested. The reason is simple, in all of the cases where a ketone is present in an opioid, the sulfonyl group works equally well. Only IC-26 and one other (it escapes me now) are listed in Wiki but there is a large amount of research into the limits of ketone->sulfonyl ether. First they tried pethidine, then they tried ketobemidone (i.e. the aromatic bears a phenolic group). In all cases, they found that 2 or 3 carbons beyond the ether worked, being equipotent but strangely, the 3-carbon analogues were more toxic! THAT is a riddle I would love to solve.
They went all the way to phenoperidine and, accounting for LogP, the potency was identical.
As for the phenolic group itself, the rash of papers dealing with 8-CAC also showed that the phenol itself can be replaced by a carboxamide moiety. They tried it on everything from phenanthrocenes to the prodines and all points in between.
Between these 2 substitutions, the number of known opioids more or less doubles BUT it is easy for legislation to stop them.
I am of the opinion that the last thing the RC market needs is strong opioids which is why I'm only posting information that a medicinal chemist may find interesting.
Ideally, I would love to write a book unlike Opioids (R.Lenz et al) where EVERY modification tried is listed. A book where each of the major scaffolds has a history (like the saga of Metopon) and to locate all of the binding-sites are described in 3D. I'm pretty sure the alkene I mentioned are not in any papers.
For the practical, I'm strongly in favour of compounds that stop the breakdown of the endorphins. Something where the user has to put in some physical effort to get the most from it. A prodrug of RB-101 is available in France to treat diarrhea. Apparently it does pass the BBB to some extent but as a treatment for dependence, this kind of medication has a lot to be said for it.
US Patent 2777850
Anyone who has plowed through the original fentanyl patents might have wondered why, as well as the amide, sulfonamides were also tested. The reason is simple, in all of the cases where a ketone is present in an opioid, the sulfonyl group works equally well. Only IC-26 and one other (it escapes me now) are listed in Wiki but there is a large amount of research into the limits of ketone->sulfonyl ether. First they tried pethidine, then they tried ketobemidone (i.e. the aromatic bears a phenolic group). In all cases, they found that 2 or 3 carbons beyond the ether worked, being equipotent but strangely, the 3-carbon analogues were more toxic! THAT is a riddle I would love to solve.
They went all the way to phenoperidine and, accounting for LogP, the potency was identical.
As for the phenolic group itself, the rash of papers dealing with 8-CAC also showed that the phenol itself can be replaced by a carboxamide moiety. They tried it on everything from phenanthrocenes to the prodines and all points in between.
Between these 2 substitutions, the number of known opioids more or less doubles BUT it is easy for legislation to stop them.
I am of the opinion that the last thing the RC market needs is strong opioids which is why I'm only posting information that a medicinal chemist may find interesting.
Ideally, I would love to write a book unlike Opioids (R.Lenz et al) where EVERY modification tried is listed. A book where each of the major scaffolds has a history (like the saga of Metopon) and to locate all of the binding-sites are described in 3D. I'm pretty sure the alkene I mentioned are not in any papers.
For the practical, I'm strongly in favour of compounds that stop the breakdown of the endorphins. Something where the user has to put in some physical effort to get the most from it. A prodrug of RB-101 is available in France to treat diarrhea. Apparently it does pass the BBB to some extent but as a treatment for dependence, this kind of medication has a lot to be said for it.
Last edited:
Only that I never had any professional training in biochemistry and I simply was interested in them as a kid perhaps because I was impressed with their power as euphoric anxiolytics. Organic chemistry has always been my biggest interest, but SAR studies still fascinate me, so perhaps one day I'll be able to mix these two hobbies in some productive way. Having 3D models of all types of opioid receptors was one of my dreams to work with new selective opioids.