LONGECITY

It has been previously shown that NMDA is toxic to cell. What exactly I want to know is what are the NMDA Agonist are and which one are considered safe (I am guessing that it is possible to reverse the toxicity)

From wikipedia : Activation of NMDA receptors results in the opening of an ion channel which is nonselective to cations. This allows flow of Na+ and K+ ions, and small amounts of Ca2+ .

I have just read an acceptable amount of information about those receptor and from what I read when they are activated it greatly improve the brain to form memories (long term memory/apparent to learning when young). On wikipedia they also say racatems might affect the NMDA receptor.

Wikipedia list a tons of antagonist but no agonist, but anyway I've found a great list (link below). I really find it promising, well thanks in advance. Feel free to just discuss, but well, has you know I feel totally interested in having additional research. I would probably buy some if they would not be pricey/accessible (and obviously not-excitotoxic)... but well as you see I'm looking for more info first!

http://www.komabiote...y/NMDA_site.htm
Edited by rhakshasa, 10 January 2007 - 07:54 PM.

Thanks Addison Strack, I actually had it right at some spot and wrong at other. Even tho very different I keep mistaking because of MDMA.

NMDA Agonists

Activation of NMDA receptors requires binding of both glutamate and the co-agonist glycine for the efficient opening of the ion channel which is a part of this receptor. In addition, a third requirement is membrane depolarization. A positive change in transmembrane potential will make it more likely that the ion channel in the NMDA receptor will open by expelling the Mg2+ ion that blocks the channel from the outside. This property is fundamental to the role of the NMDA receptor in memory and learning, and it has been suggested that this channel is a biochemical substrate of Hebbian learning, where it can act as a coincidence detector for membrane depolarization and synaptic transmission.

 

Since the NMDA receptor was first identified by the selective activation by N-methyl-D-aspartate (NMDA, see below), it has become clear that many different subtypes of this receptor could be expressed due to the multiple combinations of individual subunits. The challenge for medicinal chemists in recent years has thus been to synthesis compounds that can discriminate between these multiple sub-types. In addition to the glutamate (NMDA) binding site, there are also multiple binding sites on the NMDA receptor for modulatory compounds. Efficient NMDA receptor activation requires not only NMDA but also a co-agonist, glycine. Activation can also be modulated by the binding of polyamines. Each of the binding sites (glutamate, glycine, ployamine) has been used as a potential target for the development of both receptor and sub-type selective compounds. Many of the agonists and competitive antagonists described here have been developed by Prof. Jeff Watkins and Dr David Jane, here at Bristol and are available through Tocris Cookson. Click on the links for details of compounds that act on AMPA and mGlu receptorsCompounds named in Red are as yet commercially unavailable; click on the y symbol for a PubMed link.

NMDA Receptor Agonists

Most of the selective NMDA receptor agonists available are, not surprisingly, based on NMDA, the diagnostic ligand for these receptors. NMDA itself is an analogue of aspartate (can also act as a weak agonist at most glutamate receptors). Although this compound acts selectively at NMDA receptors, it cannot dicsriminate between receptor subtypes. Homoquinolinic acid, on the other hand, is a conformationally constrained analogue of glutamate. This compound shows higher affinity for NMDA receptors that contain NR2B and is thus the first NMDA receptor agonist to display sub-type selectivity. A radiolabelled form of homoquinolinic acid, available through Tocris Cookson, has beeen shown to selectively label regions of the brain that express NR2B-containing NMDA receptors.

Opening the gate

The smart mice were originally created by Joe Tsien and his colleagues from Princeton University in New York. They engineered the animals to make extra copies of a brain receptor subtype called NMDA.

Memories in the brain are thought to consist of clusters of neurons that activate simultaneously when the memory is recalled. NMDA acts like a gate, only activating the neurons if it receives at least two signals from other neurons. The most common subtype of NMDA in adult mouse brains is NR2A, but new-borns have mostly NR2B and this holds the gate open for longer.

Tsien's smart mice have extra copies of NR2B, and perform better in tasks such as learning to avoid mild electric shocks (New Scientist, 4 Sep 99, p 15).

But Min Zhuo and his colleagues from the Washington University School of Medicine now report the mice are overly sensitive to prolonged pain. The researchers injected formalin into animals' paws and watched how often they licked the wound.

After the first hour, the smart mice did so more often. The smart mice also had more active forebrains following the injection. "We believe that these areas of the brain are coding the unpleasantness of pain," says Zhuo.


Pain reliever

When the mice were tested for their sensitivity to acute pain, both groups of animals reacted the same. Zhuo thinks that this could make NMDA a potential target for pain relieving drugs. "We want to get rid of chronic pain, but not to affect acute pain," he says.

But Tsien doesn't agree with Zhuo's explanation of the results. He says the smart mice lick their paws more often long after the injury because of their better memories. "It is just that they haven't forgotten the injury," he says.

The increased brain activity could also be related to the injury, not the pain. "We know that the hippocampus is crucial for the formation of memory of places and events," Tsien explains.

He believes that drugs targeting NMDA could be developed to enhance memory in people whose ability to remember is deteriorating with age: "We would be restoring juvenile brain features."

Here some of what I have read, the last part is the most interesting I must say. It especially explain the memory, I'm not sure if it's more about having more of NDMA receptor or activating them (most likely both would work).

I have taken an extra modafinil tablet and will now start work on your question. I am a great believer in the power of glutamate to activate receptors such as the NMDA to treat neuro and bon neropsyciatric disorders. Will write a response back shortly.

I have taken an extra modafinil tablet and will now start work on your question. I am a great believer in the power of glutamate to activate receptors such as the NMDA to treat neuro and bon neropsyciatric disorders. Will write a response back shortly.

Great, Great, I'm totally believing in the same thing! :-P I'm looking forward to your post.

Glutamate is the main excitatory neurotransmitter in the brain. 60-70% of all connections in the brain use glutamate to transfer messages. Glutamate functions to contribute to neural information transfer, ‘rewiring’ of the brain and behavioural state changes.
Glutamte acts upon 4 types of receptor, NMDA, AMPA, Kainate and metabotropic. The main receptors being targeted at the moment for medical conditions are the NMDA and the AMPA, there is evidence to suggest that agonists for either could increase cognitive performance.

The NMDA receptor is a rich new source for future pharmacology. Pscyodelic drugs such as ketamine “special K”, Phencyclidine “angel dust” block this receptor to cause their effect. Just like the receptor GABA (you may know from benzodiazepines (Valium), picamilon, alcohol and the debatable nootropic phenibut which all work here) NMDA (an ion channel) allows electrical charge to enter cells, however it works oppositely instead of inhibiting, causing relaxation, it excites).
NMDA are so called because of their specific activation of N-methyl-D-aspartic acid or NMDA. The amino acid glycine also needs to be present to activate it, it binds at a different site to glutamate. As mentioned the endogenous (already in the body) agonist glutamate activates this receptor. Another endogenously present amino acid, aspartic acid also binds but to a lesser affinity. NMDA was developed as a hybrid, between these two and is unique because it shows selectivity to this receptor over the other 3 (AMPA, Kainate mGlu). NMDA is used as an experimental tool only.
Therefore we have two sites to activate the receptor plus there are another couple of areas on the receptor where we can modulate it, and increase activation.

Agonists at the Glutamate (NMDA) site
L- aspartate
Quinolinate
Homocysterate

Agonists at glycine
D-serine
ACPL
L-alanine

Positive modulators
Polyamin, spermin and spermide like compounds
Magnesium

As mentioned above ketamine like drugs cause a psychotic like state which resembles Schizophrenia. Long term administration leads to pathology in the brain indistinguishable from the disease. Anti schizophrenic drugs are tested on animals treated with such drugs to give them the symptoms. There belief that NMDA together with dopamine are implicated and therefore pharmaceutical companies are developing agonists like the ones mentioned above to activate the receptor. Presently glycine, D-serine, D-alanine and D-cyclosine are being evaluated in clinical trials for what is known as the “negative symptoms” of schizophrenia (withdrawal, flatness, ahedonia (lacking pleasure or interest in previously enjoyed activities), avolition (lacking drive) and most importantly for cognition attention deficit disorder). These symptoms persist in schizophrenic patients after standard therapy which mostly works on the positive (delusions, hallucination, disordered thinking).

I believe that a cognitive enhancing drug is going to come from the AMPA receptor. It is very similar to the NMDA receptor, being activated again by Glutamate. It Modulate rewiring of the brain, more strongly and quicker and is thought to be the receptor which allows us to store our memories by strengthening signal paths. The racetams are thought to act at this receptor, Aniracetam has been shown to alter response at this receptor. One class of agent being tested here for Alzheimer’s is the ampakines, with CX-717 and CX-516.

Besides schizophrenia and Alzheimer’s, drugs targeting this group of receptors are being developed for other conditions including
Epilepsy- Tamapanel, an AMPA antagonists
Parkinsons disease – Ifenprodil – NMDA antagonist
Anxiety – LY354740- metabotropic receptor mGlu5 antagonist
Adiction – ifenprodil
Edited by paul, 11 January 2007 - 12:32 AM.

Quote "Just don't fry your brains, guys. We're talking neuron death here."

Your right, forgot to say Glutamate is involved in the neural death after a stroke. Blocking the NMDA receptor with an antagonist immediately after suffering one could prevent brain loss, dementia and movement problem. MK 801 has been through clinical trials but many side effects, the most sever being memory impairement, further evidence that an agonist here could boost cognition.

To summarise what I was saying above, there are 4 types of glutamate receptors NMDA, AMPA kainate and mGlu. Drugs both FOR agonists and antagonists are in the pipeline for a range of conditions from anxiety to stroke. Glutamate is a bit of a double barrel, too much and it will kill brain cells, but in the right amount it will modulate them to store memories easier.
Attempts to improve cogniton at the moment are mainly being targeted at the AMPA receptor, agonists like CX 517 and CX717, I believe this is the most promising area.
As for the tittle of this page NMDA agonists, I do not think that anything will come from it. The trouble is the NMDA receptor is activated at very low concentrations and acts in a way to promote the activation of AMPA, which are really quick and shown to work in short term memory. But instead of an agonist being developed there is more hope of an antagonist having effectiveness. To much excitation causes brain cell death. This is why they are developing antagonists for stroke. By blocking this receptor partially we could prevent excitotoxicity, a pubmed search on the NMDA antagonist memantine will show results in this area. Huperazine A as well as working as an anticholinergic like aricept for Alzheimer’s also has been shown to be an NMDA antagonist. Hence the NMDA ANTAGONIST is far more promising.
Finally another very interesting glutamate receptor antagonist LY354740 is in clinical trials for anxiety. It has not been shown to have memory impairing results like the benzodiazepines. Inadvertedly this could improve memory since raised anxiety is not good for the brain.

I have already used NMDA antagonist myself. I've used Ketamine and Dextromorphan (DXM), both are very very fun drugs, but since I was told they cause Olney's Lesions and also reduce plasticity of the brain I really don't see an use to do any of those.

The reason I am interested in NMDA agonist is really because of the possibility to form long term memories much more easily, so basically the ability to make a new memory that have an equal signification to the long term memory made during youth. I don't think the AMPA receptor enhance the plasticity in the brain right? I haven't read as much about AMPA so I'm not really sure if it is working in the same way than NMDA (Not exactly sure about the difference amongs NMDA, AMPA, Kainate and mGlu->Haven't read at all about this one)

metabotropic glutamate receptor, belongs to a slightly different family of receptors but still bind glutamte. Its getting the balance to much antagonism and you get ketamine effect but if you block it the right amount you will get protection when you need it, ie when something is wrong, stress etc. This will provide long term improvement in brain function as less brain cells die. AMPA makes signalling in the brain easier, It is like a well troden footpath, if something light goes over it it will take a long time to make, something heavy and the path (memory (rewiring)) will be stringer. CX 717 and related molecules have already prooven as effective as amphetamines in ADDH but there is a concern at the moment about toxicity. It does not cause the excitation of amphetamines. Other even more selective AMPA agonists are in the pipeline.

So from what I understand NMDA and AMPA both have an important role in memory formation.

Honestly I feel really confused about NMDA, try giving a read to this :

http://www.nature.co...full/nn744.html

I probably read wrong but they are saying blockage would boost plasticity? I honestly tought it was the opposite. Unless in this case blockade mean preventing NMDA to leave the receptor, which I seriously doubt.
"Chronic NMDA receptor blockade increases the density of putative presynaptic boutons."
Edited by rhakshasa, 11 January 2007 - 08:26 PM.

They are saying that the situation is complex. In early development i.e. in the womb, the brain is growing rapidly. NMDAs function then is to stop thing getting to complex or else they will get jumbled up. Less neurones were found to be formed in when an NMDA antagonist was present. Now in later life the function of NMDA in LTP/LDP could be to stop neurones getting "too cemented in" NMDA calms thing down enabling thing to be remodulated later on, hence plasticity. Going back to the foot path example, the path is well trodden on by AMPA but NMDA can allows this path to diverge of else where. That is how I understand it.
NMDA appears to act as a modulator to AMPA, think of a new memory as the new foot path mentioned above, AMPA controls its formation ie the new memory, but NMDA allows it to be expanded.
What does this mean? I would be guessing at saying maybe a NMDA antagonist would prevent cell death from neurotoxicity (to much excitation) and allow an instant quick AMPA memory (the new path) but a developed angonist would allow adaptability ie plasticity. Selectivity is the principle behind drug development, the NMDA receptor is further split up into 7 other subtypes and the AMPA into 4. Putting agonists and antagonists in the right places of the brain could allow the benefits of both but this is way of in the future. In the mean time keep an Eye out for these glutamate drugs, there are many in development for different disorders, but the ampakines (AMPA agonists) look the most promising for cognitive improvement, I base this on real clinical phase 2 trials in ADHD patients.

Great paul, thanks.

- AMPA controls its formation ie the new memory, but NMDA allows it to be expanded. ; I'm not exactly sure, do you mean that AMPA allow the new memory to be created while NMDA would allow it to make complex link with other memories (making it a more important memories?)

Ketamine and Dextromorphan (DXM), both are very very fun drugs, but since I was told they cause Olney's Lesions

Ketamine has never been proven to cause Olney's lesions in humans. Not saying it's any safer because of this, but they have only been proven in non-human trials, and most of those doses, including human anaesthetic ones (still used in a few surgeries because it doesn't repress the respiratory system), are up in the grams whereas typical recreational dose is in the milligrams.

This is a very interesting topic and I wish I had more to contribute than that [tung] as you were!

Yes I forgot to mention it's not proven, some people had told me before (possibly include you [thumb] ). I understand that Olney's lesions is made from constant use over a long period of time. Friends of mine have abused it, I don't really think they report the brain fog. Thing is that dissociative are hella fun and give no unpleasant feeling, so it's not obviously addicting, so my friends were less vigilant.

Btw I have something for you to contribute mitkat [wis] , just sended you a PM.

Edit : You look badass on that new pic btw [tung]
Edited by rhakshasa, 12 January 2007 - 12:13 AM.

Rhakshasa,
Looking very scientifically between the two AMPA functions only to transmit messages along, it lets positive ions into the cell, depolarising them. It is an electric cable you could say. NMDA will excite but less so then AMPA. It finds it harder and usually need a bit of help possibly from AMPA (gives it a kick start). NMDA however can do something else, it lets calcium into the cell when it is activated. Calcium has a major intracellular function, it activates enzyme cascades which can upregulate or down regulate processes, cause changes in genes etc. This may influence receptors on the cell surface.

AMPA gets the initial current through NMDA modulates it, and yes causes plasticity. But plasticity has to be right for it to be useful. If I was to take one of the drugs I would rather take AMPA, store my memory and then later on let my own body decide if its important, whether to change, modulate it etc.

healthy NMDA antagonist: magnesium

Paul, thank you for taking the time to explain the interactions of the AMPA and NMDA. I was wondering if you had any knowledge on the kainate system and the roles it may play? I am interested in sulbutiamine and have seen some research that points to an interaction with the kainate family of glutamate receptors. Thanks!

Functions of kainate are currently not very well understood. They are a bit like AMPA receptors in some respects but also have a modulatory affect on other transmitters owing to the fact that their receptors are not in areas other then just the nerve connections (synapse). This means that as well as causing the excitation and neural signalling, (speed of thought) that AMPA does it also has an affect on other transmitters such as GABA. Low levels of GABA cause anxiety but also epileptic attacks due to over excitation in certain brain regions or in the entire brain. Hence agonists at kainate such as Kainic acid, APTA, 5-iodowillardine have been shown to be potent convulsants, I am not sure if affect on anxiety have been observed but i would guess no. There is some research into Kainate antagonists as potential anti epileptic drugs.
Silbutamine is a vitamin B1 analougue similar to thiamine. I dont know how tightly to the receptor but would imagine it would be safe at the right dose.

DXM-induced olney's lesions are also contentious.

ketamine is a profoundly interesting drug at subanaesthetic doses, though the inability to recall much of the experience upon returning is its greatest let-down... perhaps of benefit to the otherwise shattered self.


also, am i missing something -- why do you believe that extra glutamate could cause cell death? just remember that LTP is caused by repetitive firing of these receptors, so it doesn't seem as simple as glutamate causing excitotoxicity... maybe it's to do with the absence of oxygen e.g. stroke.

Paul mentioned that Magnesium was an agonist.

This reminds me of one of my strange theories about flotation tanks. They are filled with 800 lbs of magnesium. People who float in the tanks have amazing and sometimes out of body experiences. My theory is that the magnesium is absorbed through the skin and creates a NMDA agonist action in the brain.

It might also be worth noting that the inventor of the flotation tank (aka sensory deprivation tank) was Dr. John Lilly, who also had a love affair with the NMDA agonist drug, ketamine. I guess he knew which brain receptors he liked to manipulate.

Full disclosure: I own a flotation tank!

Aisha777 I am pretty sure Magnesium is antagonist and ketamine too.

"Increasing the plasticity of synapses" is not the same as "improving memory". The NMDA receptor increases plasticity. Activating it increases the chances of remembering what you are learning at that moment, and of forgetting anything you learned previously. I draw your attention to this study showing that the NMDA agonist D-cycloserine increased fear extinction, meaning use of an NMDA agonist erased memories formed earlier.
Edited by Phil Goetz, 29 January 2013 - 04:42 PM.

also, am i missing something -- why do you believe that extra glutamate could cause cell death? just remember that LTP is caused by repetitive firing of these receptors, so it doesn't seem as simple as glutamate causing excitotoxicity... maybe it's to do with the absence of oxygen e.g. stroke.

See this article:
Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse

• Chris G. Parsons, Albrecht Stöffler, Wojciech Danysz^,

• Merz Pharmaceuticals, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany

• http://dx.doi.org/10...arm.2007.07.013

Abstract

The neurotransmitter glutamate activates several classes of metabotropic receptor and three major types of ionotropic receptor – α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-d-aspartate (NMDA). The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD) is finding increasing scientific acceptance. Central to this hypothesis is the assumption that glutamate receptors, in particular of the NMDA type, are overactivated in a tonic rather than a phasic manner. Such continuous, mild, chronic activation ultimately leads to neuronal damage/death. Additionally, impairment of synaptic plasticity (learning) may result not only from neuronal damage per se but may also be a direct consequence of this continuous, non-contingent NMDA receptor activation. Complete NMDA receptor blockade has also been shown to impair neuronal plasticity, thus, both hypo- and hyperactivity of the glutamatergic system leads to dysfunction.

Memantine received marketing authorization from the EMEA (European Medicines Agency) for the treatment of moderate to severe AD in Europe and was subsequently also approved by the FDA (Food and Drug Administration) for use in the same indication in the USA. Memantine is a moderate affinity, uncompetitive NMDA receptor antagonist with strong voltage-dependency and fast kinetics. This review summarizes existing hypotheses on the mechanism of action (MOA) of memantine in an attempt to understand how the accepted interaction with NMDA receptors could allow memantine to provide both neuroprotection and reverse deficits in learning/memory by the same MOA.

Wikipedia list a tons of antagonist but no agonist, but anyway I've found a great list (link below). I really find it promising, well thanks in advance. Feel free to just discuss, but well, has you know I feel totally interested in having additional research. I would probably buy some if they would not be pricey/accessible (and obviously not-excitotoxic)... but well as you see I'm looking for more info first!

http://www.komabiote...y/NMDA_site.htm

Link broken. Wikipedia now lists NMDA agonists and antagonists.
Edited by Phil Goetz, 29 January 2013 - 04:50 PM.