complex chemical NMDA antagonists that are internal calcium channel blockers?

[Nagelfar]

According to Wikipedia:

Anesthetic gases used for surgery, such as nitrous oxide or enflurane, are believed to induce anesthesia primarily by acting as NMDA receptor antagonists, open channel blockers that bind to the inside of the calcium channels on the outer surface of the neuron, and provide high levels of NMDA receptor blockade for a short period of time.

This makes inhaled anesthetic gases different from other NMDA antagonists, such as ketamine, which bind to a regulatory site on the NMDA-sensitive calcium transporter complex and provide slightly lower levels of NMDA blockade, but for a longer and much more predictable duration. This makes a deeper level of anesthesia achievable more easily using anesthetic gases but can also make them more dangerous than other drugs used for this purpose.

OK, so are there drugs which function in the NMDA antagonist capacity of inhalants, as mentioned above, but are not so simple of, or water insoluble type of, molecules? For example, something that could be mainlined in a manner similar to ketamine? It seems as if it would be a much more potent dissociative if so, and not include the possibility of complications related to hypoxia.

 

[Cface]

Truly would be interesting to hear information on this. Let's indulge on the idea.

 

[sekio]

I thought just about every dissociative drug on the map were direct NMDA channel blockers. Ketamine is one of the few exceptions.

I sure would like to see a synthesis of etoxadrol. Selective NMDA blockers are a neat idea.

 

[TheAzo]

That list on Wikipedia sounds a bit questionable to me - Are they saying that all the PCP derivitives bind to a site located in the channel, EXCEPT ketamine?

It's most likely that PCP and all it's relatives (including K/MXE) bind to the same site - while the surgical anesthetics and their ilk (all small hydrophobic molecules) bind to a different site (presumably the one located inside the channel). The confusion on the list could easily arise due to ambiguous wording (their use of "non-competitive antagonist" to refer to a negative allosteric modulator and "uncompetitive antagonist" to refer to a channel blocker).

I'd love to see a source that clears this up, so one of us could go fix the wikipedia list.

 

[nAON]

What makes you think that the inhalant anaesthetics have a significantly different recreational effect to Ketamine, PCP, etc.? All NMDA drugs are anaesthetics / tranquillizers at medical doses.

 

[Nagelfar]

What makes you think that the inhalant anaesthetics have a significantly different recreational effect to Ketamine, PCP, etc.? All NMDA drugs are anaesthetics / tranquillizers at medical doses.

I wouldn't venture to know what the subjective effect profile would be if they created a molecule with that method of action without the harsh corrosive solvent like effects of the chemical type usual for it, altered in that manner. However it seems the routes of those two types of NMDA antagonists (inhalants & solubles) differ in subjective effects from colloquial reporting, and may do so consistently if the insoluble type can be made as a drug that could be a HCl or such; like how DRIs (MPH) and DRAs (N-methamp) differ, or benzodiazepines & barbiturates differ.

 

[specialspack]

That list on Wikipedia sounds a bit questionable to me - Are they saying that all the PCP derivitives bind to a site located in the channel, EXCEPT ketamine?

It's most likely that PCP and all it's relatives (including K/MXE) bind to the same site - while the surgical anesthetics and their ilk (all small hydrophobic molecules) bind to a different site (presumably the one located inside the channel). The confusion on the list could easily arise due to ambiguous wording (their use of "non-competitive antagonist" to refer to a negative allosteric modulator and "uncompetitive antagonist" to refer to a channel blocker).

I'd love to see a source that clears this up, so one of us could go fix the wikipedia list.

That seems odd to me too... the reference is to this paper - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1987274/?tool=pmcentrez

Which just seems to say that ketamine doesn't bind at the the glutamate site. Maybe the book referenced, CNS Neuroprotection where the illustration comes from offers more info?

 

[specialspack]

Coming back to this, every text book I've looked at lists ketamine as an NMDA channel blocker, so wikipedia is incorrect. I don't really understand the difference proposed between

their use of "non-competitive antagonist" to refer to a negative allosteric modulator and "uncompetitive antagonist" to refer to a channel blocker

- especially since all the substances listed under the "non-competative antagonist" section are listed in their separate wiki entries as channel blockers.

 

[Nagelfar]

Coming back to this, every text book I've looked at lists ketamine as an NMDA channel blocker, so wikipedia is incorrect. I don't really understand the difference proposed between - especially since all the substances listed under the "non-competative antagonist" section are listed in their separate wiki entries as channel blockers.

Perhaps it does have something to do with 'external' versus 'internal' calcium channel blockers? Both might be "un/non-competative". I know that sodium channel blockers, when external (or "extra-cellular") are neurotoxins like those found in puffer-fish, but when sodium channel blockers are internal (or "intracelular") they are local anesthetics like cocaine. Perhaps with the calcium channels they are both NMDA antagonists?

(interestingly, but off-topic, caffeine has been found to be a *sodium* channel blocker as well as stimulant like cocaine too, but the mechanism (inter-extra, etc) is unknown: it's been found to inhibit the positive charge current in ventricular cells of mammals for the sodium channel.)

I am not this well versed in molecular biology, but perhaps too there is a difference between voltage-gated calcium channels affected and ligand-gated calcium channels affected. I believe cocaine's effect on sodium channels is voltage gated, one would think usually of "ligand" due to a molecule's properties intuitively though, at least, I would.

 

[specialspack]

I don't think there are external vs internal blockers on the NMDA channel. I think the confusion has arisen because the ketamine article http://en.wikipedia.org/wiki/Ketamine - describes it as a "noncompetative anatagonist", and gives this reference:

Lipton SA (February 2006). "Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond". Nature Reviews. Drug Discovery 5 (2): 160–70 - PDF here - http://pharmacology.ucsd.edu/graduate/courseinfo/LiptonPaper1-NatRevDD.pdf

This article, about memantine, only contains one reference to ketamine, in the paragraph on "Uncompetitive, open-channel block" - so the description on the wiki ketamine page should probably be changed to uncompetitive channel blocker.

However, to add to the confusion that paper says that MK-801 has high affinity for the Mg²⁺ site, whereas the every other source says that it binds to the PCP site. I assume the Mg²⁺ site and PCP site are not the same thing..?

 

[Nagelfar]

I don't think there are external vs internal blockers on the NMDA channel. I think the confusion has arisen because the ketamine article http://en.wikipedia.org/wiki/Ketamine - describes it as a "noncompetative anatagonist", and gives this reference:

My OP cites that there are. It not being a difference between ketamine and other arylcyclohexylamine chemicals (that was never my suggestion and has derailed this thread); but rather between such more complex chemicals (external) and simple esters the likes of which compose most inhalants (internal).

i.e. Could larger, drug-like chemicals be composed that function (but bind more specifically) in a manner similar to inhalants without one's CNS needing to be over-saturated in such inhalant-type chemicals.

 

[specialspack]

Sorry that this got a little derailed! But I do think clearing up the wiki entries is important.. will get on that later.

Where in wikipedia is your original information from? I was unable to find it looking at the pages about inhalation/general anaesthesia. This paper seems to suggest we don't really know where N₂O binds on the NMDA receptor:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1821130/

 

[Nagelfar]

Where in wikipedia is your original information from?

Inhalant_abuse#Mechanisms_of_action

Though chemical structures as simple as nitrite, butane, haloalkanes, etc., intuitively would be too indiscriminate regardless of what their specific mode of action would be among what they have. Similarly to how imbibed ethanol works in many CNS depressing factors across the board lightly (GABAergic, opioid, NMDARA) and not just one firmly.

 

[specialspack]

Ok - but there's no citation for any of that paragraph, which suggests ketamine is an allosteric modulator, rather than a channel blocker, which is wrong. So the premise of your OP that that ketamine acts externally is incorrect. So it seems to me that the whole discussion of whether there are water soluble drugs that act in the same way on the NMDAR as inhalants - reduces simply to - yes, there are, and they are ketamine, PCP etc...?


Ref: "Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo" http://www.sciencedirect.com/science/article/pii/002839089500092K

 

[Nagelfar]

Ok - but there's no citation for any of that paragraph, which suggests ketamine is an allosteric modulator, rather than a channel blocker, which is wrong. [/url]

It isn't saying that it isn't a channel blocker or is a allosteric modulator, it doesn't even use the word "external" (I used that, in fact, it says inhalants bind to the "outer" (external) surface of the neuron in comparison to arylcyclohexylamines and that arylcyclohexylamines like ketamine/PCP don't)

Don't get me wrong, I am uncertain to all of this. I just want to be properly open to the intriguing idea that they very well could have different modes of action.

 

[specialspack]

Ok - I'm deeply uncertain about all this too, so please don't take my comments as criticism!

Anesthetic gases used for surgery, such as nitrous oxide or enflurane, are believed to induce anesthesia primarily by acting as NMDA receptor antagonists, open channel blockers that bind to the inside of the calcium channels on the outer surface of the neuron, and provide high levels of NMDA receptor blockade for a short period of time.

Here the "outer surface" could refer to the location of the calcium channel... either way, not enough is known about the actions of the anesthetic gases on the NMDAR, which seem to be varied and complex. Moreover, different agents probably have differing effects.
E.g this ref on xenon - http://www.ncbi.nlm.nih.gov/pubmed/20560662
Evidence the Xenon does not act as an open channel blocker - http://www.ncbi.nlm.nih.gov/pubmed/18234987

This makes inhaled anesthetic gases different from other NMDA antagonists, such as ketamine, which bind to a regulatory site on the NMDA-sensitive calcium transporter complex and provide slightly lower levels of NMDA blockade, but for a longer and much more predictable duration.

This seems to imply that ketamine is an allosteric modulator, as if you follow the link on "regulatory site" it says it's an allosteric site - http://en.wikipedia.org/wiki/Regulatory_site

That second paragraph seems to be completely wrong..?

 

[strat54]

Perhaps it does have something to do with 'external' versus 'internal' calcium channel blockers? Both might be "un/non-competative". I know that sodium channel blockers, when external (or "extra-cellular") are neurotoxins like those found in puffer-fish, but when sodium channel blockers are internal (or "intracelular") they are local anesthetics like cocaine. Perhaps with the calcium channels they are both NMDA antagonists?

(interestingly, but off-topic, caffeine has been found to be a *sodium* channel blocker as well as stimulant like cocaine too, but the mechanism (inter-extra, etc) is unknown: it's been found to inhibit the positive charge current in ventricular cells of mammals for the sodium channel.)

I am not this well versed in molecular biology, but perhaps too there is a difference between voltage-gated calcium channels affected and ligand-gated calcium channels affected. I believe cocaine's effect on sodium channels is voltage gated, one would think usually of "ligand" due to a molecule's properties intuitively though, at least, I would.

i would never be able to tell from structure, but i would think based on cocaines anesthetic properties that it is voltage gated as well. since it inhibits the action potential from propagating that would have to be voltage gated right imo.


also, regarding the OP from wikipedia... I doubt N2O binds inside the channel as it is bigger than Na2+ and hydrophobic correct? wikipedia needs a fixin