active in what? analgesia? receptor assay? 2 different things.. nb: ketobemidone (and related 4-arylpiperidines like meperedine) are potent NDRIs!!! and mu-OP and NMDAr antagonists..So even you reduce OP (eliminate m-OH), they still be active! thats why ketodemidone ("holy grail of OPs") is one the most euphoric yet. basically the ultimate speed ball in one @ doses affecting OP, DA and NMDAr! (the m-OH doesnt affect NMDA &dopaminergic activity much). the N-demethyl metabolites are even more potent NDRIs!
Have you actually tried ketobemidone (Ketogan)? I have only sampled it orally but compared with an equipotent dose of oral prodine (mixed isomers - made by a friend), their is not much subjective difference.
I can only go from the German paper in which the ethylsulfonyl moiety replaced both esters (i.e. prodines) and ketones i.e. ketobemidone. I haven't made the stuff. If you consider the synthetic strategy, it is not a simple procedure. But I would note that when Jannsen developed fentanyl, he also tried the ethylsulfonate of EVERY isomer. I know J was always a completest but to make 120 examples that were inactive shows that HE was pretty confident (wrongly) that the ethylsulfonate would be a bioisostere of the amide moiety. What IS interesting is that the carbamate ester IS a bioisostere of the amide so for every example of a fentanyl class drug, their is an uncontrolled carbamate ester.
A good example of J's completest attitude is dextromoramide. It is a sea of inactives or very low actives (like loperamide) but for people who like pills,'Peach Palfium' is the holy grail. Diconal is the holy grail of people who shoot opioids. So the ROA is an important consideration. Oh, and YES, I am old enough to have tried all of the drugs I mention. I cannot freely comment on drugs I have not taken. I HAVE sampled the carboxamide bioisostere of deoxymorphine-D (desoxymorphine), again, because another researcher swapped samples with me and all I can say is that it felt like H (smoked) when used orally but lasted a good 12 hours. Now no illicit drug maker is going to go through 2 steps to make a drug that most people can take just once a day. Krokodil (deoxymorphine-D) only lasts 1 hour so it's profitable.
I think elsewhere I have noted that in spite of all the fentanyl analogues, plain fentanyl i still king because it is almost the 'crack' of opioids. I have heard of $2 doses because a dealer can extract every penny from a user because they will come back 6-8 times a day.
U-47700 was an attempt to produce a safer, longer-acting opioid that would hold an addict for 12 hours which is why it was not the success of illicit fentanyl. Dealers cannot profit so much and people cut it and messed with it and as a result people were hurt. I think one of the things we should be doing is making the world safer for people who choose or need to take this class of drug. I might add that U4 was initially trialed because the 2 precursors can be made from commercially available chemicals in 1 step so the price was reasonable and the purity was high (we always got NMR and GC-MS) so we knew that at least it was a quantifiable chemical.
Theory is fine - but trying the stuff is more truthful.
