Removal of the N-cyclopropylmethyl from buprenorphine and replacing it with an N-Me or N-phenethyl would create extremely high potency full agonists.

[purplehaze147]

It'd be one of the most potent opioids in the Bentley Series. The N-phenethyl causes an extension of the binding and the semi-natural version akin to the N-phenethyl on the piperine ring of fentanyl vs fully synthetic opioids like pethidine or methadone. If I remember correctly the estimation was between 20k-40k times the potency of morphine, leaving fentanyl analogs in the dust; that's just the N-methyl analog.

I'm having a brain block as to how to remove the N-cyclopropylmethyl. First you would want to oxidize the amino and then react with an alkyl chain with a R-SO3 leaving group or something like that and then use methyl iodide or 1,1'-bromo(phenethyl). (I hate IUPAC lol). You think N-dealkylation would he so simple. O-demethylation is. Maybe I'm missing something.

 

[izo]

I just read somewhere that they dealkylated an amine with cyanogen bromide. But I don’t know the mechanism. All in all I think think that these super potent opioids are not too much fun. The high is too hard and working with it eG dosing is too much of a hassle.

 

[Feretile]

There are 4 different dealkylation procedures. I do not think BrCN will remove an N-methylcyclopropyl. Bentley et all carried out a 10 year study on the Diels-Alder abducts and I believe the 3-acetate of the isopentyl homologue of dihydroetorphine is the most potent example. Of course, the Chinese carried out a lot more work but I cannot read Hanyu Pinyin (and translations of such technical papers is very poor.

It could well be the case that the N-methyl homologue of thienorphine is as potent. Replacing the alkyl chain with 2 ethylene spacers and then an aromatic (e.g. 7-PET) increases duration drastically. I think thienorphine and R-4066 tie for longest duration.