Possibility of new PCP and MXE analogs

[clubcard]

Replace the cyclohexane ring with a Tetrahydropyran ring, then it's UK legal. Just need to adjust solvents by comparing LogP. Just try overlaying it and chacking benzene & amine lone-pair are in the same position as the original.

 

[adder]

As for that 2,6-dioxo derivative, look up 2-methyl-PCP. The most active isomer has the configuration (1S,2R) and it's more potent than PCP itself, both in vitro and in vivo. The methyl group in the most active isomer is on the opposite side to the ketone in S-ketamine and S-methoxetamine. Here's the abstract from one article (actually very informative unlike abstracts of many contemporary articles):

The (-)- and (+)-isomers of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines have been synthesized and the achiral cis-
and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines were prepared, and their in vitro <displacement of (3H)TCP (1-(1-(2-
thienylcyclohexyl))piperidine) from the PCP (1-(1-phenylcyclohexyl)piperidine) binding site> and in vivo (rotarod assay) activities determined.The 1-
(1-phenyl-2-methylcyclohexyl)piperidine isomers were resolved by classical crystallization procedures, through the diasteromeric salts obtained with
d- and l-10-camphorsulfonic acid.The relative stereochemistry of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines and the achiral
cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines was established by using 13C and 1H NMR.Both (-)-trans-1-(1-phenyl-2-
methylcyclohexyl)piperidine ((-)-2) and (+)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((+)-2) were examined by single-crystal X-ray analysis,
and the absolute configuration of (-)-2 was determined to be 1S,2R.The (-)-2 was found to be about five times more potent than PCP in vitro and twice
as potent in vivo.It is the most potent of all of the simple methyl-substituted cyclohexyl PCP isomers and is among the most potent PCP-like compounds
which have been synthesized.It was nine times more potent in vitro and four times more potent in vivo than (+)-2.The racemic cis-1-(1-phenyl-2-
methylcyclohexyl)piperidine (3), and its enantiomers ((+)-3 and (-)-3), were essentially inactive in vitro and in vivo.The cis-Ph/Me 1-(1-phenyl-4-
methylcyclohexyl)piperidine (18) was more potent than trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (17), but considerably less potent than (-
)-2.The enantioselectivity observed as the PCP binding site for (-)-2 could indicate that this site can discriminate between enantiotopic edges of the
achiral PCP (choosing the pro-1-S edge), as does the ě-opioid receptor in the prodine series of opioids.Benzimidoyl or benzoyl group replacement of
the phenyl ring in the 1-(1-phenyl-2-methylcyclohexyl)piperidine series gave compounds which showed little in vitro and in vivo activity.

I have Ki values written down for both, but unfortunately I have no idea what the source was (11 nM for the (1S,2R)-isomer of 2-Me-PCP vs. 53 nM for PCP, edit: also, 25 nM for racemic trans-2-Me-PCP and 100 nM for (1R,2S)-isomer), certainly it wasn't calculated in any way, perhaps it's actually from this very article, but I can't find the full text.

 

[Hammilton]

What if you take a barb and use same substitution pattern as on PcP

 

[dopamimetic]

sekio, thanks for the correction, I didn't know about glutethimide. So it looks pretty good overall ...

 

[Osogun]

Please, make this alive

 

[clubcard]

The cyclohexane in the scaffold makes it illegal.