Higher potency PCP analogs

[Giza]

Even after reading that great SAR write up on PCP analogs (http://www.erowid.org/archive/rhodium/chemistry/pcp/sar.html) im left with alot of still unanswered questions. Mainly regarding the pharmacology, something not answered in the SAR data sufficiently.

Looking for higher potency analogs of PCP. The more exotic the analog the better (un-specifically-scheduled preffered but not required). Suggestions? Other than TCP... which is the obvious. Perhaps somone could dream up a TCP analog based on SAR data that would be even more potent, TCP being supposedly 4x potency of PCP. Any promising leads on something new would be taken serious.

Then there is the following;

Substituents at the 3-postition of the phenyl ring: A 3-methoxy group gives a compound that is capable of producing effects in man that are extremely similar to PCP in potency and quality (ref. 14). The 3-hydroxy compound however, has 8 times the affinity of PCP for its receptor but also has profoundly enhanced affinity for the opiate receptor (430 times the affinity of PCP), giving it an analgesic activity 1 order of magnitude lower than morphine. Substitution of the 3-OH_ group with an amino group results in other compounds with increased analgesic effects, again probably because of increased activity at an opiate receptor.

Does 8x affinity necessarily equal 8x potency, as in MG:MG potency comparison to PCP?

 

[fastandbulbous]

Not always as the substituent may increase the polar nature of the molecule and reduce blood-brain barrier penetration. In the case of a phenolic OH group, you can pretty much take it as written (the reason that heroin - diacetylmorphine - is more potent than morphine. Masking the polarity of the 3-OH group by esterification increases the potency to double that of the free OH group)

 

[Smyth]

Bear in mind that alot of opioids need a dimethylamine functionality for optimum activity. However the dipipanone/methadone dichotomy does mean that this is certainly open to debate.

 

[fastandbulbous]

Bear in mind that alot of opioids need a dimethylamine functionality for optimum activity.

No, they need a tertiary amine function (not the same thing), separated from an aromatic nucleus by 3 carbon atoms (or equivalent). The 4-phenylpiperidines cannot contain a nitrogen substituted with two methyl groups without becoming a quaternary compound (hence ineffective), yet some of the derivatives substituted at the nitrogen with groups like phenethyl etc are very potent (and not a methyl group in sight).

Dimethylamine is just one of the many tertiary amine substitution patterns that confers activity

 

[Giza]

I wish I could find information regarding the 3-hydroxy PCP analog and exactly what opiate receptor(s) its an agonist for. If it was a selective or even partly selective heavy mu agonist and 430x more potent than PCP at it then that should theoretically be 430x more euphoric than PCP, whilst also having more potent PCP receptor activity to boot. Noice.

you guys think something like 3-hydroxy-TCP could be done? Thus having increased MG:MG potency, PCP & opiate receptor affinity, etc. Or would this not work and if not why?


And fast, do you have any personal experience with the use of PCP? You sound like youve used alot of shit, maybe you've used TCP? :D

 

[C6H6]

The affinity of 3-OH-PCP for the mu-opioid receptor is still too low to be useful, because at doses where the opioid effect would start to kick in, the person is already knocked out by the NMDA antagonism.

 

[Giza]

How do you know this?? not saying your wrong just wondering where you got the data to make that statement?

And you dont happen to have access to the following do you;

V. H. Maddox, E. F. Godefroi, and R. F. Parcell, The synthesis of phencyclidine and other 1-arylcyclohexylamines, J. Med. Chem., 8, 230 (1965).

E. F. Godefroi, V. H. Maddox, H. Woods, and R. F. Parcell, Process for producing a depressant-like effect on the central nervous system, U.S. Patent #3,097,136.

 

[InfiniteBITCH]

I have that J. Med. Chem. paper but can't find it right now and my gateway to access online ACS publications is currently denying connections for some reason... I can try to post it later, though I can also tell you what it basically says if you're interested. For the patent, follow this link http://v3.espacenet.com/origdoc?DB=EPODOC&IDX=US3097136&F=0&QPN=US3097136 but have fun reading that, as patents suck.

Bear in mind that synthesizing hydroxy-substituted analogs introduces a few extra steps, since generally the aromatic portion of the molecule is added via a grignard reaction, which is incompatible with alcohols as well as ester-protected alcohols. The easiest way may perhaps be something like coming in with a benzyl ether-protected alcohol on the aromatic ring, then the product from the grignard can be subjected to atmospheric hydrogen and palladium on carbon hydrogenolysis to cleanly remove the belzyl group and expose the free phenol.

I'm very interested in PCP analogs, as it seems that variations in the aromatic portion can change the activity of the molecule in several ways, for example BTCP (benzothiophenyl analog) shows affinity in animal studies as a dopamine reuptake inhibitor and very little PCP receptor affinity (I have refs if interested).

-InfiniteBITCH

 

[Giza]

Yes and supposedly TCP has a more stimulant like profile as well.


LMK when you get access to that publication if you do. Id rather read the entire thing, as ive already heard the 'nutshell'. I should also state I have little interest in the synthesis of these analogs, just the pharmacology.

 

[InfiniteBITCH]

Well whaddya know, gateway came back up. Here's that J. Med. Chem. article:

http://rapidshare.de/files/3819319/Synth_of_1-arylcyclohexylamines.pdf.html

-InfiniteBITCH

 

[Giza]

thx alot! :D

 

[Smyth]

If you run a patent search on daniel lednicer you can retrieve an absolute crap load of pcpesque compounds bearing analgesic properties. Unfortunately most of these are reject structures but there is a wealth of information nevertheless.

If one has pure 1-(m-methoxyphenyl)-1-(dimethylamine)cyclohexane, then it should be possible to desmethylate it using refluxing 48% HBr since we have a hardy molecule and dont have to worry about spurious side reactions.