Has anyone else noted that substituting the piperidine ring of phenampromide & propiram produces compounds with significantly more activity? A 4-phenyl moiety added to either yields a compound some x60 morphine (since they overlay fentanyl, not a big surprise) and that a 3,3-dimethyl increases potency by a factor of 7. Now, it seems like most researchers have carefully worked out the orientation of a single methyl substituent although there are many examples in which dimethyl is equipotent. I discovered that 3,3-dimethyl pethidine is as potent (when measured in umols) as 30methyl pethidine and compounds such as dimethylaminovalerone are much less potent when their is only a single methyl, More recent research has shown that the racemate of 3-methyl-3-hydroxy fentanyl is more potent than 3MF & 3,3-dimethyl prodine is slightly more potent.
I mention dimethylaminovalerone because the orientation of the N,N-dimethyl groups aren't symmetrical. I originally overlayed it with 3,3-dimethyl pethidine to confirm that the 3-dimethyl overlays the pethidine derivative but the N,N dimethyl moiety is novel. One of the methyl branches to form a residue of the piperidine ring while the other overlays the methyl seen in pethidine, MPPP, ketobemidone and so on. I extended that methyl to a 2-phenylethyl moiety and discovered that it overlaid PEPAP. Now I appreciate that in the pethidie scaffold, a 3-methylene spacer is optimal (ideally with an (S) hydroxy on the δ unit) but considering that there are more rotatable bonds, such a chain my act like that in diampromide (i.e. low potency) so I'm wondering if just 2 methylene spacers with a Oxpheneridine-like (S)β-OH moiety OR a δ-sulfinyl (seen in some methofoline derivatives) in addition to a p-NO2 on the pendant benzene. Of course, the ester/reversed ester can be substituted for an ethyane sulfonate thus:
1-[2-(4-nitrophenyl)ethyl]-1S-hydroxy-3-methyl-4-ethylsulfonyl-4-phenylpiperidine
I hope I spelled that correctly. Ethylsulfonyl replaces ester, p-NO2 on pendant aromatic & (S) β-OH. Kind of an oxpheneridine bioisostere. Now, I suggest it's going to be reasonably active. The parent is around x12 M in potency but the (R) isomer is somewhat more toxic. Just why this should be the case I don't know but I have seen seizures brought on by pethidine because N-dealkylation produces a metabolite that is a DRI. I explored quote a few DRIs until pyrophenidone tuned out to do the job. I'm just pissed off that the lazy chemists insisted on making the hydrochloride and it wasn't too soluble thus nasty to snort. That's the same idiots who made diphenidine hydrochloride. I made the sulfate & phosphate and the former was MUCH more potent... and the lazy bastards claimed it was 'too hard to produce' which is why people were swallowing and having bad experiences. They point black refused to make isophenidine because they removed the water from imine formation thermally and so claimed it was 'impossible' since the isopropylamine boiled off..... that I used MgSO4 (prepared by placing in an over for 4 hours to remove the .7H2O eluded them).
Pay peanuts and so forth...
I mention dimethylaminovalerone because the orientation of the N,N-dimethyl groups aren't symmetrical. I originally overlayed it with 3,3-dimethyl pethidine to confirm that the 3-dimethyl overlays the pethidine derivative but the N,N dimethyl moiety is novel. One of the methyl branches to form a residue of the piperidine ring while the other overlays the methyl seen in pethidine, MPPP, ketobemidone and so on. I extended that methyl to a 2-phenylethyl moiety and discovered that it overlaid PEPAP. Now I appreciate that in the pethidie scaffold, a 3-methylene spacer is optimal (ideally with an (S) hydroxy on the δ unit) but considering that there are more rotatable bonds, such a chain my act like that in diampromide (i.e. low potency) so I'm wondering if just 2 methylene spacers with a Oxpheneridine-like (S)β-OH moiety OR a δ-sulfinyl (seen in some methofoline derivatives) in addition to a p-NO2 on the pendant benzene. Of course, the ester/reversed ester can be substituted for an ethyane sulfonate thus:
1-[2-(4-nitrophenyl)ethyl]-1S-hydroxy-3-methyl-4-ethylsulfonyl-4-phenylpiperidine
I hope I spelled that correctly. Ethylsulfonyl replaces ester, p-NO2 on pendant aromatic & (S) β-OH. Kind of an oxpheneridine bioisostere. Now, I suggest it's going to be reasonably active. The parent is around x12 M in potency but the (R) isomer is somewhat more toxic. Just why this should be the case I don't know but I have seen seizures brought on by pethidine because N-dealkylation produces a metabolite that is a DRI. I explored quote a few DRIs until pyrophenidone tuned out to do the job. I'm just pissed off that the lazy chemists insisted on making the hydrochloride and it wasn't too soluble thus nasty to snort. That's the same idiots who made diphenidine hydrochloride. I made the sulfate & phosphate and the former was MUCH more potent... and the lazy bastards claimed it was 'too hard to produce' which is why people were swallowing and having bad experiences. They point black refused to make isophenidine because they removed the water from imine formation thermally and so claimed it was 'impossible' since the isopropylamine boiled off..... that I used MgSO4 (prepared by placing in an over for 4 hours to remove the .7H2O eluded them).
Pay peanuts and so forth...
