4DQSAR
Bluelighter
- Joined
- Feb 3, 2025
- Messages
- 809
I feel it worth noting that amphetamine begat phenmetrazine, phenmetrazine begat 3-Benzhydrylmorpholine, 3-Benzhydrylmorpholine begat nomifensine/dichlorfensine, nomifensine/dichlorfensine begat JNJ-7925476/McN5652.
What is important to note is that the ring-substitution of amphetamine and the ring-substitution of those two reseach compounds essentially follows the same pattern.
I think it worth noting that the 8-amino of nomifensine and the 7-methoxy moieties seen in nomifensine and dichlorfensine respectively appear to be sacrificial moieties i.e. they serve to provide the body with a simple metabolic pathway.
If one overlays all the (chiral) compounds it becomes evident that they all loverlay amphetamine. What we are witness to is researchers seeking to find compounds that provide a combination of a long enough acting compound to allow BID or TID consumption while attemtig to avoid the compounds being subject to abuse.
It's worth noting that the LogP of each generation increases and the pKa values combine to make onset slower (rapid onset being a commonality of misuse of medicines).
I don't think for one moment that those later compounds are facile targets. Complex syntheses and multiple chiral centres so yields of the sought enantiomer will almost certainly remain low.
But I draw your attention to the fact that the para thiomethoxy of McN5652 and para thiomethoxy amphetamine (4MTA) share selective serotonin activity. Now the problem with the p-SCH3 moiety is that it has the capacity to exhibit MAOI activity. What I don't quite understand is why para ethynyl as seen in the JNJ compound ALSO appears to produce selective setratogenic activity so it strikes me that para ethynyl methcathinone and para ethynyl (meth)amphetamine have not been explred.
Now I freely admit I'm unsure if the same syntheses can be applied if a para ethynyl replaces a para methyl BUT I note para ethyl methcathinone appeared on the market and reports were OK AFAIK.
It just strikes me as a very simple bit of research because it appears that almost everyone omitted para ethynyl PEAs. While I don't think it was in TiHKAL but 2C-Y N (2,5-dimethoxy-4-ethynyl) phenylethylamine has been made and has been tasted. So we at least know that it is compatible with 5HT2a affinity which is suggestive of the compound being at least safe to test.
Obviously one would VERY carefully titrate doses and if I'm honest, I would go for the methcathinone as with related compounds, they seem less toxic than their (meth)amphetamine counterparts. Of course, one issue here is that the body will most assuredly NOT oxidize the ethynyl so again, the methcathinone would seem the safer option.
I always consider safe>legal>active i.e. better legal trouble than harming people, better legal and then if it doesn't work, you wasted a little time and a little money but nothing else is lost.
That's my thought process on the topic.
What is important to note is that the ring-substitution of amphetamine and the ring-substitution of those two reseach compounds essentially follows the same pattern.
I think it worth noting that the 8-amino of nomifensine and the 7-methoxy moieties seen in nomifensine and dichlorfensine respectively appear to be sacrificial moieties i.e. they serve to provide the body with a simple metabolic pathway.
If one overlays all the (chiral) compounds it becomes evident that they all loverlay amphetamine. What we are witness to is researchers seeking to find compounds that provide a combination of a long enough acting compound to allow BID or TID consumption while attemtig to avoid the compounds being subject to abuse.
It's worth noting that the LogP of each generation increases and the pKa values combine to make onset slower (rapid onset being a commonality of misuse of medicines).
I don't think for one moment that those later compounds are facile targets. Complex syntheses and multiple chiral centres so yields of the sought enantiomer will almost certainly remain low.
But I draw your attention to the fact that the para thiomethoxy of McN5652 and para thiomethoxy amphetamine (4MTA) share selective serotonin activity. Now the problem with the p-SCH3 moiety is that it has the capacity to exhibit MAOI activity. What I don't quite understand is why para ethynyl as seen in the JNJ compound ALSO appears to produce selective setratogenic activity so it strikes me that para ethynyl methcathinone and para ethynyl (meth)amphetamine have not been explred.
Now I freely admit I'm unsure if the same syntheses can be applied if a para ethynyl replaces a para methyl BUT I note para ethyl methcathinone appeared on the market and reports were OK AFAIK.
It just strikes me as a very simple bit of research because it appears that almost everyone omitted para ethynyl PEAs. While I don't think it was in TiHKAL but 2C-Y N (2,5-dimethoxy-4-ethynyl) phenylethylamine has been made and has been tasted. So we at least know that it is compatible with 5HT2a affinity which is suggestive of the compound being at least safe to test.
Obviously one would VERY carefully titrate doses and if I'm honest, I would go for the methcathinone as with related compounds, they seem less toxic than their (meth)amphetamine counterparts. Of course, one issue here is that the body will most assuredly NOT oxidize the ethynyl so again, the methcathinone would seem the safer option.
I always consider safe>legal>active i.e. better legal trouble than harming people, better legal and then if it doesn't work, you wasted a little time and a little money but nothing else is lost.
That's my thought process on the topic.
