I'm sure people are aware of IC-26 and I have posted the homologues of pethidine & ketobemidone with an ethylsulfone bioisostere. Here's the 3,3-dimethylpethidine example:
On the Pharmacological Effect of Dimethylpethidine and its Alkylsulfone Substituentes https://doi.org/10.1248/yakushi1947.76.2_132
I'm trying to remember where the hell I put the German papers (there was a series) in which compounds like 4-(ethylsulfonyl)-1-methyl-4-phenylpiperidine & 3-[4-(ethylsulfonyl)-1-methylpiperidin-4-yl]phenol are disclosed. I just find it interesting that a sulfone can replace an ester as well as a ketone. AFAIK nobody had explored the N-substitution, especially the phenolic example because the QSAR of ketobemidone hasn't been well explored. Substitution of the piperidine produced mixed agonist/antagonist compounds but I suspect it's because at the time nobody could resolve the 4 isomers. Later, Lilly developed picenadol and succeeded in producing a terrible synthetic pathway to what is in the end interesting results.
I guess ketobemidone interests me in the same way dextromoramide does. Only someone like Janssen would have exhaustively searched the QSAR because the thing doesn't so much have an activity cliff, it's sat on a small activity mesa and you can't touch anything without destroying activity. https://doi.org/10.1111/j.2042-7158.1958.tb10268.x Lacking even the terminal alkyl of the 3,3-diphenylheptanone, you can't sneak in an -F (which for methadone works.... and steps out of MoDA).
Compared to every other class of psychoactive drug, the amount of data on the opioids is truly vast. I quickly realized that 'Opiates' by Lenz et al still only covers a fraction of what was known even at the time of publishing. People have asked about AP-237 but of you start with a smaller chain on the amide & make it a sub-structure, there are examples of substitution on the piperazine ring that eventually lead to the 3,8-diazabicyclo[3.2.1]octane derivatives but there really is a lot of stuff on what appears to be a pretty sketchy set. Put simply, even without the bridge (2,6-dimethylpiperazine), you can still get some pretty potent examples.
It ALL goes into the training-set.
Last mention is to 1-phenyl-8-(1-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (see fluspirilene). Commentary at the time wondered why the N-benzyl was required, especially since it need not be chiral. I guess it's because the body debenzylates basic amines REALLY well. That said, someone took that compound and found 1-phenyl-8-[2-(thiophen-2-yl)benzyl]-1,3,8-triazaspiro[4.5]decan-4-one. If you care to overlay it with thiofentanyl, you will get the idea. The difference being that there are 2 bonds in the latter that are quite freely rotatable. While the former LOOKS like it has rotatable bonds, force field calculations clearly show that they aren't THAT free. I don't know what the US CsA would do. I mean, what is it derived from?
On the Pharmacological Effect of Dimethylpethidine and its Alkylsulfone Substituentes https://doi.org/10.1248/yakushi1947.76.2_132
I'm trying to remember where the hell I put the German papers (there was a series) in which compounds like 4-(ethylsulfonyl)-1-methyl-4-phenylpiperidine & 3-[4-(ethylsulfonyl)-1-methylpiperidin-4-yl]phenol are disclosed. I just find it interesting that a sulfone can replace an ester as well as a ketone. AFAIK nobody had explored the N-substitution, especially the phenolic example because the QSAR of ketobemidone hasn't been well explored. Substitution of the piperidine produced mixed agonist/antagonist compounds but I suspect it's because at the time nobody could resolve the 4 isomers. Later, Lilly developed picenadol and succeeded in producing a terrible synthetic pathway to what is in the end interesting results.
I guess ketobemidone interests me in the same way dextromoramide does. Only someone like Janssen would have exhaustively searched the QSAR because the thing doesn't so much have an activity cliff, it's sat on a small activity mesa and you can't touch anything without destroying activity. https://doi.org/10.1111/j.2042-7158.1958.tb10268.x Lacking even the terminal alkyl of the 3,3-diphenylheptanone, you can't sneak in an -F (which for methadone works.... and steps out of MoDA).
Compared to every other class of psychoactive drug, the amount of data on the opioids is truly vast. I quickly realized that 'Opiates' by Lenz et al still only covers a fraction of what was known even at the time of publishing. People have asked about AP-237 but of you start with a smaller chain on the amide & make it a sub-structure, there are examples of substitution on the piperazine ring that eventually lead to the 3,8-diazabicyclo[3.2.1]octane derivatives but there really is a lot of stuff on what appears to be a pretty sketchy set. Put simply, even without the bridge (2,6-dimethylpiperazine), you can still get some pretty potent examples.
It ALL goes into the training-set.
Last mention is to 1-phenyl-8-(1-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (see fluspirilene). Commentary at the time wondered why the N-benzyl was required, especially since it need not be chiral. I guess it's because the body debenzylates basic amines REALLY well. That said, someone took that compound and found 1-phenyl-8-[2-(thiophen-2-yl)benzyl]-1,3,8-triazaspiro[4.5]decan-4-one. If you care to overlay it with thiofentanyl, you will get the idea. The difference being that there are 2 bonds in the latter that are quite freely rotatable. While the former LOOKS like it has rotatable bonds, force field calculations clearly show that they aren't THAT free. I don't know what the US CsA would do. I mean, what is it derived from?