New kinds of dissociatives?

[thesomoan]

Ok so first off i have to admit that I have not yet begun my O-Chem class, and much of my posting here is for my own educational purposes as I am extremely interested in biochemistry so please do not judge if this is a stupid question, however as i understand any arylcyclohexylamine is a dissociative. Yet only a few aryl groups have been used or even tested as far as I can tell. Is this because of limitations in bonding the aryl group to cyclohexylamine, or is there some other process involved? why would something like benzylcyclohexylamine not be active?

 

[Chauncey_GARDENer]

First of all, an aryl group may refer to any chemical that is a substituted aromatic, that is, the substance has a benzene ring attached to some functional groups. Many drugs can be classified as "aryl" groups, however, this information is limiting because it is so generalized. Furthermore, not all arylcyclohexylamines are dissociatives let alone pharmacologically active.

When it comes to transitioning chemical structures into pharmacological activity, there are many many factors to address. Ketamine, for example is an arylcyclohexylamine that is substituted with a chlorine halogen group. Using pure ketamine as a reagent, it would be fairly easy to substitute the chlorine on the 2 position with another functional group (For example, a heavier and larger halogen such as Iodine) using what are called Friedel-Crafts RXN's. As to whether different substitutions would be active, I can not say. The situation is much more complex than that.

On a side note, if you were wondering if it would be easy to synthesize a ketamine-like substance, it certainly isn't. The reaction is many steps long and requires a plethora of obscure and hard-to-find chemicals.

Thats great you are going into chemistry though! Keep up with your school work now, I'm currently taking O Chem and Quantitative Analysis... Its a lot of fucking home work! In fact... I'm going to go do some right now. Hope this helped.

 

[thesomoan]

Thanks that did help a lot! I thought that aryl groups were much more limited, and was under the impression that they all, like the amphetamine class, had some degree of activity. Ya i don't really intend to synthesize any of these things (at least at this point) i was more just curious of what prevented them from being made.

 

[Chauncey_GARDENer]

Actually, I do not believe that all amphetamines are active (not 100% sure, but I've heard of 3,4,5-methoxy substituted amphetamines being inactive). Not to mention that some, such as para-chloroamphetamine, are major neurotoxins. All I'm trying to say is not to associate certain chemical structures or "backbones" with certain pharmacological effects. Small changes, such as the alpha-methyl addition to phenylethylamine to create Alpha-MethylPHenEThylAMINE (notice the capitol letters spell out A-M-PH-ET-AMINE), cause serious effects on activity. Phenethylamine by itself is metabolized before it reaches the brain, but amphetamine is not fully metabolized for hours. Changes in metabolic activity as well as polarity, electronegativity, stereochemistry, geometry, etc. can all have effects on activity.

As you can see, whether or not drugs have an effect on you goes much deeper than nomenclature and individual functional groups... The many characteristics of molecules make these types of determinations tricky to say the least.

 

[thesomoan]

Damn well as i said what i know about this stuff is a bit limited, i always thought that it was the shape at the active site, and that all amphetamines shared a similar active site, once again thanks for the info this is very helpful.

 

[(zonk)]

There are tons of classes of dissociatives that are molecularly completely different from one to the other, check out wiki but here are some major classes...
Opioid based: DXO,Benzorphans,D-tramadol,D-Methadone,4-hydroxy-4-arylpiperidines, lefetamine
ArylcyclohexylaminesCP,ketamine,etoxadrol(totally different SAR), 8a-phenyldecahydroquinoline
Adamantane/memantine:Memantine,PCP-Ad,neramexane
L-2-MDP(only)
L-Arg:Agmatine,3-propylaminoguanidine,arcaine
DiArylGuanidines:aptiganel
MK-801,cycloOctyl-mk-801
APV:selfotel,3-phosphonomethylphenylalanine,cppene
simple gasses: Xe,N2O
peptides :conantokins,conotoxins
plus many many more!!!

 

[Limpet_Chicken]

I would be very hesitant indeed to taste-test any of those phosphonate NMDA antagonists, I was looking into one of them lately, AP3 (3 carbon n-propyl group, wheras AP4 has a butyl and AP5/APV a pentyl/valeryl and so on as it was available to me, but, I posted here, and before it was really much discussed, dug up a paper, where injection into some animal or other caused brain oedema at the higher of the two doses they used.

Not sure if this applies to other of the series, but I sure as hell would want to find out first.

That said, do any/all/many other NMDA antagonists, wether they are PCP site ligands, channel blockers or uncompetitive antagonists, or hell, even polyamine/glycine site antagonists cause brain oedema? that has the potential to be really nasty, swelling of the brain could cause some serious damage, not to mention increased intracranial pressure.

Anybody tried any of the uncompetitive antagonists?

 

[thesomoan]

I have not tried any of the uncompetitive antagonists but i do know that many of the animal tests done with NMDA antagonists used ridiculously high doses of the drug for the animal being tested, and also that these receptors behave differently in primate brains then in other mammals. For instance many NMDA antagonists are considered protective drugs against stroke and other conditions which would seem contrary to the idea of causing a brain oedema. Although i agree that checking with people with experience is a good idea.
(Zonk) thanks for the list it wikipedia actually had some pretty good information about this stuff

 

[thesomoan]

on a side note i did find some examples of arylcyclohexamines which do not use the phenyl group that PCP and ketamine do. Indolylcyclohexamines appear to have some activity, although any website which had information about them required a password. Does anyone know anything about these, perhaps I will post that as a separate thread.

 

[(zonk)]

I'm not sure about AP3 although I do know that of the series AP5 and AP7 are the only ones considered to be total NMDA antagonists. Quite a few of them are agonists as well and some only effect only a few NMDA receptors. AP4 is both agonist/antagonist depending on which isomer. The APs are a little complicated when it comes to SAR here's a link to help lay it all out http://books.google.com/books?id=O2...4Q6AEwBA#v=onepage&q=ap5 analogs nmda&f=false
it looks like selfotel is the best in terms of effect/potency/bioavailability(4-phosphonomethylpiperidine-2-carboxylate). That doesn't mean it's an analog of AP4, it doesn't work like that. It has alot todo with chain length... I don't think AP3 would b worth it, probly garbage, AP5 is really what you'd want however it's much more expensive that the other APs, unless u can get selfotel

 

[thesomoan]

Alright thanks, what about the meta and para substituted N-(phosphonoalkyl) phenylamino acids that were mentioned in the book. The author seemed to suggest that those could have promising activity, while AP-5 and AP-7 are limited in what you can do to them because it appeared only descending substitiutions on the carbon backbone had any advantageous effect while pretty much everything else inhibited activity, does anyone know anything about those compounds

 

[(zonk)]

I noticed PMPA(4-phosphonomethylpiperazine-2-carboxylate)the piperazine analog of selfotel is available, not sure the price tho. This is not to be confused w/PMPA(Tenofovir)which has a somewhat similar structure. Tenofovir is an HIV medication but PMPA(the 1st one)is not. It seems like it would be the same as selfotel which i read had PCP like effects being why it was discontinued. I'll check back if it happens...

 

[thesomoan]

phosphonomethylpiperazine-2-carboxylate) was used in a study to quantify the effect of chain length on NMDA receptor which certainly implies a high level of antagonism, and thus PCP like effects. The article also mentioned that this could decrease the effectiveness of other aspects of antagonism however, so any input on qualitative effects of PMPA would be great. Here is the article if anyone is interested:

The effect of competitive antagonist chain length on NMDA receptor subunit selectivity
Bihua Fenga, Richard M. Morleyb, David E. Janeb and Daniel T. Monaghana, ,

aDepartment of Pharmacology, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA
bDepartment of Pharmacology, University of Bristol, Bristol BS8 1TD, UK
Received 17 July 2004; revised 5 November 2004; accepted 27 November 2004. Available online 25 January 2005.