(±)-McN 5652 (US Patent 6,162,417 by Goodnam and Shi) is an interesting one. https://doi.org/10.1021/jm00391a028 & JNJ7925476 have
been mentioned before. but it's worth noting that at the time (late 70s to late 80s) there was a huge investment into the research of triple reuptake inhibitors as they were strong contenders for being a new class of highly efficacious antidepressant. Then biologists discovered that depression is a much more complex illness than was believed.
You will note that the amphetamine skeleton is buried in there. In fact, this class is the culmination of a huge body of work that produced dozens of transport inhibitors.
-Amphetamine derivatives
-(Desoxy)Pipradrol/Difemorex/SCH-5472/AL-1095
-Nomifensine & dichlorfensine
-Desotraline/Sertraline
But it's WELL worth your time looking at https://en.wikipedia.org/wiki/JNJ-7925476 because their is a huge table with the given & relative DAT/NET/SERT transport inhibition. It also shows the synthetic pathway. I think it reasonable to say that while they are fascinating since homologues with different ratios (so it should be possible to tailor the exact effects you seek), nobody is going to be making any of THEM in the near future.
I have had a quick look but I do not see any with examples of cyclic 3,4-disubstitution i.e. no MD or benzofurans. Likely the fact that the amine is tertiary will impact the QSAR.
What it DOES do is make me interested in p-ethynyl (meth)amphetamine. Sasha made some 2,5-dimethoxy-4-ethynyl examples, but their isn't much about them.
OT - has anyone else considered the fact that 2CN is noted as being good - almost like MDMA and at a similar dose range. Now, DON on the other hand has a steeper dose response curve, lasts twice as long but was not psychedelic but rather caused amphetamine-like stimulation. Well, in fact Shulgin was reporting on a raecemic mixture of (R) & (S) DON. He did resolve a few of the compounds he made & noted that the (R) isomers of the PIPAs were the ones with 5HT2a affinity but with MDMA, the (R) isomer is the more active.
So, I wondered if the positives noted about 2CN could be carried across to DON by resolving the isomers and using the (R) isomer alone? It's rather a lot of work but I have always been acutely aware that even now, most drugs are not optically pure. Often this is to extend patents. First a company patents the mixture, then the active isomer. I mean, fenfluramine--->dexfenfluramine, citalopram --->escitalopram and so on and so forth. It's worrying how they could PROVE that the enanthiopure compounds were superior.... which I guess they knew damned well 2 decades before.
Anyway, I know this is quite complex but it's a highly refined scaffold if hard to make BUT maybe the substitutions would work on some simpler examples e.g. dichlorfensine. a p-thiomethoxy or p-ethynyl on those IS possible by a decent chemist who hasn't got a $25 million lab.
been mentioned before. but it's worth noting that at the time (late 70s to late 80s) there was a huge investment into the research of triple reuptake inhibitors as they were strong contenders for being a new class of highly efficacious antidepressant. Then biologists discovered that depression is a much more complex illness than was believed.
You will note that the amphetamine skeleton is buried in there. In fact, this class is the culmination of a huge body of work that produced dozens of transport inhibitors.
-Amphetamine derivatives
-(Desoxy)Pipradrol/Difemorex/SCH-5472/AL-1095
-Nomifensine & dichlorfensine
-Desotraline/Sertraline
But it's WELL worth your time looking at https://en.wikipedia.org/wiki/JNJ-7925476 because their is a huge table with the given & relative DAT/NET/SERT transport inhibition. It also shows the synthetic pathway. I think it reasonable to say that while they are fascinating since homologues with different ratios (so it should be possible to tailor the exact effects you seek), nobody is going to be making any of THEM in the near future.
I have had a quick look but I do not see any with examples of cyclic 3,4-disubstitution i.e. no MD or benzofurans. Likely the fact that the amine is tertiary will impact the QSAR.
What it DOES do is make me interested in p-ethynyl (meth)amphetamine. Sasha made some 2,5-dimethoxy-4-ethynyl examples, but their isn't much about them.
OT - has anyone else considered the fact that 2CN is noted as being good - almost like MDMA and at a similar dose range. Now, DON on the other hand has a steeper dose response curve, lasts twice as long but was not psychedelic but rather caused amphetamine-like stimulation. Well, in fact Shulgin was reporting on a raecemic mixture of (R) & (S) DON. He did resolve a few of the compounds he made & noted that the (R) isomers of the PIPAs were the ones with 5HT2a affinity but with MDMA, the (R) isomer is the more active.
So, I wondered if the positives noted about 2CN could be carried across to DON by resolving the isomers and using the (R) isomer alone? It's rather a lot of work but I have always been acutely aware that even now, most drugs are not optically pure. Often this is to extend patents. First a company patents the mixture, then the active isomer. I mean, fenfluramine--->dexfenfluramine, citalopram --->escitalopram and so on and so forth. It's worrying how they could PROVE that the enanthiopure compounds were superior.... which I guess they knew damned well 2 decades before.
Anyway, I know this is quite complex but it's a highly refined scaffold if hard to make BUT maybe the substitutions would work on some simpler examples e.g. dichlorfensine. a p-thiomethoxy or p-ethynyl on those IS possible by a decent chemist who hasn't got a $25 million lab.
