astralprojectee
Greenlighter
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Hi all, I am trying to find out what are some of our endogenous ketamine like compounds we naturally make in our bodies.
Thanks.
Thanks.
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N&PD Moderators: Skorpio
What are some endogenous ketamine like molecules?
- Thread starter astralprojectee
- Start date
sekio
Bluelight Crew
Can you elaborate? There are endogenous ligands for e.g. the NMDA receptor (e.g. glutamic acid, spermine/spermidine), but I would not call them "ketamine-like". They are not high affinity channel blockers like K/MXE/PCP/DXM are.
Maybe you could make the argument that ethanol is "endogenous", but that is a stretch.astralprojectee
Greenlighter
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Well I read there is a theory that endogenous ketamine like compounds can give one a NDE type hallucination or something like that. So I want to know what Ketmaine like compounds are they talking about?
If you think you know please let me know.
Thanks, peace.
sekio
Bluelight Crew
As far as I know, there aren't any "endogenous ketamine like compounds". Where did you read that?
A commonly held myth is that endogenous release of DMT is responsible for near-death experiences, though that has never been proven with any sort of rigor.Well yes it is theorized that to prevent glutamatergic encitotoxicity, the brain may be subdued in case of emergencies or trauma, and this could cause NDEs in a similar way that NMDA antagonist dissociatives do or emulate... but that doesn't necessarily mean that there is one master neurotransmitter to control this, just that the CNS is possibly set up to do this.
Personally I think a reaction like that would be WAY too complex to reduce to just one endoligand, or even one class/type of biochemical.astralprojectee
Greenlighter
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OK well I was talking about the hypothesis proposed by Dr. Karl Jansen that NDEs are caused by ketamine like compounds. I think this is the main paper on it.
http://www.mindspring.com/~scottr/nde/jansen1.html
Though I disagree that NDEs just hallucinations he might have a point in that ketamine like compounds can cause or at least facilitate an NDE right around the time death.
He does suggest some groups of molecules but nothing specific enough to say yes this is ketamine like.
Do you have any input on this.
Thanks.The reason that there probably isn't an endogenous molecule that acts like ketamine is because it binds to the allosteric site on the NMDA receptor. Wikipedia provides a good graphic that helps explain this:
from:http://en.wikipedia.org/wiki/File:NMDA_receptor_activation_and_antagonists.PNG
Ketamine falls into category D
Ketamine doesn't bind to the receptor's active sites (for glutamate and glycine) or the channel, it binds somewhere else on the protein (the allosteric site) and causes the channel to close. As far as I can tell, there aren't any known endogenous ligands that bind there.
amanitadine
Bluelighter
Great graphic dr drugs. The NDMA receptor, as someone once mentioned here, blows all arguments for "intelligent design" out of the water. As does everything else, but I love the complexity and all around weirdness of said receptor. MUCH work to be done here in the coming years, this I guarantee. .@ Dr. Drugs:
Isn't that a bit like a tautology? It is called an allosteric site because it is a site on the receptor other than the active sites. It is not one of the active sites because no endogenous compounds are known to bind there.
So saying that the reason that we don't know of an endogenous compound to bind there is because it is an allosteric site is hardly a reason at all because it is implied and self-referential (thus tautological), correct?
Either we need to admit that such a compound (binding at that site, making it an active site and not allosteric) might have evaded our studies or instead are confident, and can then be satisfied without such an aforementioned reason.
Am I missing something? (Also, how sure are we that such an endoligand doesn't exist? I do believe that it doesn't, but wonder how sure we are and how misplaced such confidence may be... can we prove it, for example?)
In any case, even though it may not seem like it, I found your post very useful. :D
ebola?
Bluelight Crew
Solipsism said:
Not quite. That a ligand is allosteric signifies that it modulates the response of the receptor to another ligand, the latter binding to the receptor's active site. We can imagine a hypothetical ligand that induces an effect irrespective of what's going on at the active site for the endogenous ligand while binding elsewhere.
Not exactly. We can again imagine a hypothetical scenario where the activity of one endogenous ligand influences the activity of another endogenous ligand within the same receptor complex (I blame ethanol and fatigue for my inability to recall a real example, if one exists
) (I don't think that magnesium really counts, as it simply modulates flows through ion channels).
ebola
lenses
Bluelighter
D-serine is an interesting natural substrate often overlooked when talking about NMDA receptors. Its similar to glycine but I believe has a higher activation and can substitute for it.
Epsilon Alpha
Bluelighter
Mainly at extrasynaptic NR2B subunit containing receptors, you do not want to activate extrasynaptic NMDA. It does bind to the glycine site however.
http://www.ncbi.nlm.nih.gov/pubmed/22863013 (this one claims synaptic NMDA is responsible for excitotoxicity which is the minority opinion)
http://www.ncbi.nlm.nih.gov/pubmed/19625523
lenses
Bluelighter
Are there any D-serine or glycine analogues that affect NMDA function? I'm curious as to what is psychoactive and worthwhile , from what I read D-serine analogues tend to be antibiotics and so forth.
Well now that I think of it, noopept is somewhat of a glycine analogue, yeah? It's a prodrug for Cyclo-L-prolylglycine, and I tend to enjoy the subtle psychedelia of noopept,and I dont mean to stretch it, but it somewhat reminiscent of the beauty of detail in vision found under the DMT trance...
If you want the biological answer to your original question: Kynurenic acid is an endogenous NMDA antagonist.Last edited:Thanks ebola, you learn something every day at ADD
Does supplemental phosphatidylserine get coverted to the free amino acid, and is it centrally active theoretically?
I have tried taking that for a while because of reported nootropic value and it was actually one of the few that I felt actually doing something. It is hard to explain though, like other nootropics it just made me feel like a better version of myself. Increased lucidity maybe.
lenses
Bluelighter
From how i've had magnesiums role on the NMDA receptor explained to me, it cuts down on signal "noise" and allows for a cleaner impulse... low levels allow noisier signals...
NMDA pharmacology is quite complex!
ebola?
Bluelight Crew
And that's likely why this claim is so often extended to memantine, as it 'attacks' the same site (albeit with far greater affinity and efficacy). However, given how 'tricky' maintaining a balance for 'clean' signaling likely is, I'd be surprised if the same claims could be extended to both substances.
ebola
specialspack
Bluelighter
Sorry, but this just isn't true. Wikipedia states that ketamine binds to an allosteric site with only one reference from a 1985 paper to back this up - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1987274/ - which is speculative, to say the least!
Surely this sticks out like a sore thumb? PCP, MK-801, PCE, methoxetamine, tiletamine are all in group C - uncompetitive channel blockers. Yet ketamine, despite its close structual similarity, is lumped into group D as a non-competitive/allosteric antagonist. Why?
On top of that, all the binding studies I've ever seen use radiolabelled MK-801 or PCP (or TCP) as the hot ligand for screening, which show that ketamine does indeed bind to the same site in the channel that all the others do.
As far as I can tell, this is simply a wikipedia error that has crept in along the way. Probably due to someone not being clear about the difference between uncompetitive and noncompetitive antagonists (I've seen some papers where the terms are used interchangeably).
Of course, if there is some good evidence to back up wiki's claims I'd love to see it.
Last edited:endotropic
Bluelight Crew
- Joined
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Sorry, but this just isn't true. Wikipedia states that ketamine binds to an allosteric site with only one reference from a 1985 paper to back this up - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1987274/
Surely this sticks out like a sore thumb? PCP, MK-801, PCE, methoxetamine, tiletamine are all in group C - uncompetitive channel blockers. Yet ketamine, despite its close structual similarity, is lumped into group D as a non-competitive/allosteric antagonist. Why?
On top of that, all the binding studies I've ever seen use radiolabelled MK-801 or PCP (or TCP) as the hot ligand for screening, which show that ketamine does indeed bind to the same site in the channel that all the others do.
As far as I can tell, this is simply a wikipedia error that has crept in along the way. Probably due to someone not being clear about the difference between uncompetitive and noncompetitive antagonists (I've seen some papers where the terms are used interchangeably).
Of course, if there is some good evidence to back up wiki's claims I'd love to see it.
I'm glad you brought this up, because I've always thought the same thing. I remember a thread recently where someone referenced a paper that suggested that NMDA had to be activated before Ketamine could bind, which is pretty much the definition of uncompetitive.
That would also explain why onset of effects are delayed and gradual when you snort this drug.
sekio
Bluelight Crew
I'm with Soli, I thiink you can chalk K's "delayed effects" with insufflation up to diffusion/absorbtion issues.
