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NMDA antagonists and anaesthetic threshold

Solipsis

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I was reading up on the 3-MeO-PCP wiki expecting that my SO who is not well versed in this stuff might check out soon...
It mentions that the substance is despite popular belief mostly a selective NMDA antagonist.

This raises so many questions: the mania and lack of or rather high threshold for anaesthesia were, I thought, explained by action on DAT remotely comparable perhaps of pipradrol deriv related side effects.

If not, then why do some dissociatives produce much more anaesthetic action (I thought it was pretty intrinsic to NMDA antagonists)? So much more that it determines what effects can be enjoyed while remaining functional or cogent?
In pure NMDAAs what is unavoidable primarily? Amnesia looking at dizolcipine/ diphenidines..?

Its hard to get a grasp of how these qualities link together..
Do you suppose it depends on where in the brain there is NMDA antagonism taking place or how selective or local that is? For example how strongly the cerebellum is affected in relationship to dosage ranges?
 
The anesthetic action is not intrinsic to NMDA receptor blockade. MK-801, for example, does not produce anesthesia. The anesthetic action of ketamine has been linked to blockade of HCN channels, which mediate the Ih current in neurons, and are targeted by other general anesthetics (propofol, etc). Mice lacking the HCN1 gene are insensitive to the anesthetic effects of ketamine. They haven't reported data with other anesthetic arylcyclohexylamines, but they would likely work through a similar mechanism.

http://www.ncbi.nlm.nih.gov/pubmed/19158287

http://www.ncbi.nlm.nih.gov/pubmed/23377220

http://journal.frontiersin.org/article/10.3389/fncom.2013.00022/abstract
 
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Wow, a very interesting find.

What does this implicate? Could the dissociation be separated from the anesthetic effect, leading to either a non-recreative pure anesthetic / and the possibility to push the dissociative / 'side effects' of ketamine even further by removing the amnesia and anesthesia?
 
You should be able to do that, depending on the relative SAR for HCN1 and NMDA-R. In fact, that is kind of what Parke-Davis did when they developed ketamine
 
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