picenadol - ketobemidone isomer

[haribo1]

One isomer of picenadol is an opiate agonist, the other an antagonist. If the propane was altered to have an alpha ketone in it, it would be 3-methyl ketobemidone. From the sparce information I have on ketobemidone, adding stuff to the piperidine ring destroys activity, but could it just be because nobody seperated the isomers?
Also, changin the N-methyl to an n-cinnamyl made demerol 29x stronger, any opinions on altering ketobemidone in said fashion. I expect it's NMDA activity to be destroyed, but it would make an interesting compound (I don't intend to make it, I'm just interested).

 

[mad_scientist]

Reference? That is quite interesting though, especially about substituting the N-methyl for an n-cinnamyl. And 3-methylfentanyl is way stronger than fentanyl, so it makes sense that 3-methyl ketobemidone might be active although im not sure if they bind in quite the same way.

From the overlay it looks like the nitrogen in ketobemidone is equivalent to the nitrogen in morphine, so i had speculated that a phenethyl group instead of a methyl might boost activity considerably, and a cinnamyl group is pretty similar to a phenethyl...now what i wonder is whether a 2-(thiophen)ethyl would be stronger again as with sufentanil.

 

[ralf2]

You might be interested in the patent GB948874. It deals with analogues of ketobemidone substituted at the nitrogen, among others the N-cinnamyl.
As I have mentioned before it seems that large groups on the nitrogen on ketobemidone makes mixed agonists/antagonists.

The compounds according to the invention possess valuable therapeutic properties. Thus, they exhibit a proncunced central analgesic action and also a marked antagonism to morphine. These two properties distinguish the compounds according to the invention from the known compounds 1- (3-phenyl-allyl)4-phenyl-4-carbethoxy piperidine and 1- (3-phenyl-propionyl)-4-phenyl- 4-carbethoxy piperidine, which possess analgesic properties but show no discernible antagonism to morphine.

The patent US3708597 also deals with N-cinnamylnorketobemidon.

 

[haribo1]

Found the patent

The pethidine version was x29 pethidine, but no information on the potency of this one. My guesstimate is x10 (so about heroin)

 

[haribo1]

Now I wonder what a 3 alkyl (methyl,ethyl or allyl) would do to the potency. Alkyls on ketobemidone (with the meta-hydroxy on the benzene ring) screw potency (the angle of the ring must be vital) but for these, who knows. Of course, if someone DOES know, then I would love to hear!
Wonder if anyone did anything bigger on the fentanyl piperidine?

 

[haribo1]

BTW my guesstimate comes from a list of N substituted pethidines (demerols) so I can see why the above patent made use of the N-cinnamyl... sorry it's so grainy!

Note number 29x pethidine. In fact, the whole page is interesting. The Azacycloheptanes analogs give some useful insights. 3 substitution of the reversed ester gives an opiate 10x pethidine.

Link to lots of pethidine/demerol type analogs

 

[haribo1]

BTW my guesstimate comes from a list of N substituted pethidines (demerols) so I can see why the above patent made use of the N-cinnamyl... sorry it's so grainy!

Note number 29x pethidine. In fact, the whole page is interesting. The Azacycloheptanes analogs give some useful insights. 3 substitution of the reversed ester gives an opiate 10x pethidine (so, a lot weaker than prodines, but still pretty good considering how weak the 7-membered rings usually are)....

Link to lots of pethidine/demerol type analogs

sigh