sunifiram/ampakine SAR and neurology discussion

[Ampa-omega]

hi everyone i just want to mention that i am not really seeking any recreational substance but what i am in need of is cognitive performance, and that is what i think the world is looking for. ampakines , allosteric modulators of dopamine as well allosteric pde4 modulators seem to be the cognitive boosters that is in need.

i have been reading around here a bit and searching the net for information on attainable ampa receptor modulators and desensitization modifiers

heres a post of mine on imminst:
http://www.longecity.org/forum/topic/13221-where-are-my-ampakines/page__st__20

and as you can see im trying to really find those ampakines , it seems people are dumb and just take a nootropic because people say so that it is, without even understanding the basic ways these substances are neurochemicaly working,that is why i really dont care about "racetam" but more so the things that are going to boost up the signal transduction, and glutaminergic/ampa signaling is where i hear its at..

so i basicly am asking where can i find decent alternatives that are better than the racetams for ampa potentiation and desensitization inhibition,

my goals in nootropics is to increase alertness, think waaay faster, have faster reactions, be more cognitively engaging and reduce tiredness+increase brain energy.

can anyone help me out here?

also does anyone know anything else other than cAMP , and allosteric modulators for my nootropic goals?

Also why sunifiram?
well another bluelighter was saying about how he was going to synthesize it, as well how it is pretty potent, so i looked at the chemical structure and well it seems 'attainable', i'de rather make my own than buy it overpriced..just need to get the help, and guidance.

 

[sekio]

We don't do sourcing or synthesis.

 

[Ampa-omega]

We don't do sourcing or synthesis.

ok thats fine, i expected someone to say that.
i think i just needed to ask in order to get more clarification, does that include everything or just illegal substances?

anyways, can anyone help with my other questions?
what does anyone best recommend in there opinion to enhance the glutaminergic pathway in a cost effective way? What do you guys see as a good alternative?

 

[sekio]

That means everything.

Overactivation of the glutaminergic pathway is a surefire way to neurotoxicity. It's an excititoxin you know. That said you can try contacting a domestic or international (maybe not Chindian) lab and see if they'll make you some sunifram or whatever. It's not controlled unless you state it's for consumption.

 

[Ampa-omega]

Definitely aware of that, thats the tricky deal with this pathway, but are modulators also able to cause neurotoxicity? From what i'm aware they aren't direct agonist, but i'm not exactly sure about their safety either, it seems to be what the major scientist and labs such as cortex pharmaceuticals are focusing on though.

yes i mentioned that lab synthesis is a bit expensive though..premiums and long term supply
is there anything you recommend or as another option to sunifiram?
also thanks very much for your post, feedback was appreciated.

 

[ebola?]

This thread is now about exploring the SAR and neurology for ampakaines and other relevant sites of activity for nootropics. This thread is no longer about syntheses applicable thereto.

 

[Limpet_Chicken]

I think in the presence of an orthosteric agonist, an AMPAkine would make for increased neurotoxicity. I am however, talking in the context of excitotoxins, such as AMPA or domoic acid (of amnesic shellfish poisoning fame)

AMPAkines have varying modes of action, some increase ion current flux intensity, and some stabilise open channel gating, also there are varying degrees of selectivity for flip vs flop receptor isoforms (which determines selectivity for Ca++ vs Na+ permeability).

They do, on the whole, appear to induce BDNF release, which is likely to be neuroprotective, from reports out there they don't appear to cause much behavioural alteration in lab animals whilst under the influence, just performance enhancement, rather than motor stereotypy etc as seen with stimulants.

There doesn't seem to be excitotoxicty, the safety profile seems fairly decent. Although one, farampator (one of the CX series) impaired episodic memory, I believe this was whilst the drug was acting, though.

Piracetam and Aniracetam are both AMPAr positive modulators, acting at different binding sites, there are quite a lot of allosteric binding sites possible at different AMPAr subtypes. Both show quite excellent tox profiles.

 

[Ampa-omega]

do you think piracetam and aniracetam is greater together? i know that there were recently new discovered binding sites for piracetam on the AMPAr. do you know if oxiracetam is ok to switch for piracetam?

do you think it is better to take multiple purported AMPAr modulators or just a few potent ones?
i know you mentioned the multiple components to target such as flip flop isoforms (which aniracetam sounds good for with other PAMs) and channel gating, and ion current flux, etc..

what exactly are the more potent ampar modulators known of doing that makes them stronger?
is it targeting the flip flop isoforms?

 

[Limpet_Chicken]

like anything else, there is the question of affinity and efficacy.

The way the ligand gates the channel dictates more the behaviour than potency.

A good example would be barbiturates vs benzos at GABAa allosteric sites. Benzos increase the efficacy of GABA, as do barbs, but while the benzos increase frequency of channel opening, whilst the barbs cause the channel open time to lengthen, resulting in increased current flux per opening, rather than more openings with average current passing. The body can compensate for an overly large dose of a benzo by releasing less GABA, but with the way barbs gate the channel, it can do far, far less about it, explaining the increased toxicity of barbs over benzos (and why whilst tolerance can build to the high or sedation, the LD-50 doesn't rise, as it does with say, an opiate, where a user can eventually build up such a monster monkey on his back that grams of H a day can be survived)

Incidentally, barbs are AMPA antagonists in addition to their GABAergic effects, unusual mode of doing it too, by getting into the ion channel, then stabilizing the receptor in an agonist-bound, desensitized state, sort of locking itself in there (the AMPA receptors structure is formed of subunit tetramers, and closes around the ligand like the shell of a bivalve mollusc)

Synergy between those AMPAkines that increase channel open frequency, and those that increase open times will be possible, most likely, the two effects seeing as they are occuring seperatly of each other in different ligands, suggests that seperate binding sites mediate the two effects.

A further action that some AMPAkines produce, is that they inhibit desensitization of the receptor, normally AMPARs desensitize very quickly on agonist binding of glutamate (although some exogenous direct agonists have very different desensitization kinetics) which allows for more efficient signalling before the receptor desensitizes.

However, weather its a good thing, may be another matter entirely. As has been stated, glutamatergic overactivation is dangerous, producing excitotoxicity. It looks like most AMPAkines are pretty safe, and don't appear to be excitotoxins, but its important to be careful. Combining one that increases channel open frequency, with one that gates the channel in a manner analogous to barbs at GABAaRs would of course produce a synergistic effect, weather or not its safe or not, I do not know. But the parallel between benzos and barbs should be born in mind, the body has mechanisms where excess glutamate can be very rapidly removed* but if the channel is forced to remain open whilst there is already excess stimulation, or a greater threshold of glutamatergic activity going on, I think there would be a greater potential for toxicity than either mode of action alone.

Also to remember, is that an allosteric modulator binds at a seperate site than the neurotransmitter agonist, in the case of the AMPAr, there are four sites per receptor that bind glutamate, a direct agonist will activate the receptor and cause influx of calcium, sodium and potassium, way too much Ca++, as there is a fine threshold and balance between enough, somewhat better, and extra crispy, which is why there is needed such an efficient, rapid removal system.

The body can't do that in the case of a direct agonist, reducing the level of glutamate released is going to have minimal effect at best,when a potent, artificial agonist gets in there and starts toasting neurons, but in the case of an allosteric positive modulator, the chance to reduce the effect, seeing as how PAMs have no effects on their own, unless the actual orthosteric agonist is bound, then quick lessening of released glutamate should be acheivable.

The Q/I editing site determines permeability to Ca++ or to Na and K, its present in the GluR2 subunit, and the presence of arginine, rather than glutamine at that position in the receptor protein results in vastly decreased capacity to conduct Ca++, and leaves it permeable to sodium and potassium. The latter, in GluR2 subunity expressing AMPARs is by a vast majority, the form expressed the brain.

Not so sure about flip vs flop, but there are a whole crapload of developmental changes during gestation and childhood, restructuring and adapting, pruning off the trash etc, and IIRC there is a switch betwen the two at some point, I think, if I remember properly that in adults its mostly flop-isoform that is present, if not nearly exclusively, but I don't know to what extent, and how it affects practical functioning of the AMPAr-mediated glutamatergic system.

 

[Ampa-omega]

The way the ligand gates the channel dictates more the behaviour than potency.

A good example would be barbiturates vs benzos at GABAa allosteric sites. Benzos increase the efficacy of GABA, as do barbs, but while the benzos increase frequency of channel opening, whilst the barbs cause the channel open time to lengthen, resulting in increased current flux per opening, rather than more openings with average current passing. The body can compensate for an overly large dose of a benzo by releasing less GABA, but with the way barbs gate the channel, it can do far, far less about it, explaining the increased toxicity of barbs over benzos (and why whilst tolerance can build to the high or sedation, the LD-50 doesn't rise, as it does with say, an opiate, where a user can eventually build up such a monster monkey on his back that grams of H a day can be survived)

Incidentally, barbs are AMPA antagonists in addition to their GABAergic effects, unusual mode of doing it too, by getting into the ion channel, then stabilizing the receptor in an agonist-bound, desensitized state, sort of locking itself in there (the AMPA receptors structure is formed of subunit tetramers, and closes around the ligand like the shell of a bivalve mollusc)

Synergy between those AMPAkines that increase channel open frequency, and those that increase open times will be possible, most likely, the two effects seeing as they are occuring seperatly of each other in different ligands, suggests that seperate binding sites mediate the two effects.


However, whether it's a good thing, may be another matter entirely. As has been stated, glutamatergic overactivation is dangerous, producing excitotoxicity. It looks like most AMPAkines are pretty safe, and don't appear to be excitotoxins, but its important to be careful. Combining one that increases channel open frequency, with one that gates the channel in a manner analogous to barbs at GABAaRs would of course produce a synergistic effect, weather or not its safe or not, I do not know. But the parallel between benzos and barbs should be born in mind, the body has mechanisms where excess glutamate can be very rapidly removed* but if the channel is forced to remain open whilst there is already excess stimulation, or a greater threshold of glutamatergic activity going on, I think there would be a greater potential for toxicity than either mode of action alone.


The Q/I editing site determines permeability to Ca++ or to Na and K, its present in the GluR2 subunit, and the presence of arginine, rather than glutamine at that position in the receptor protein results in vastly decreased capacity to conduct Ca++, and leaves it permeable to sodium and potassium. The latter, in GluR2 subunity expressing AMPARs is by a vast majority, the form expressed the brain.

ah, so its not so much the direct agonism that may be a concern but the ion current flux, is that correct?

and another thing to factor is the fact that arginine not glutamate is in the receptor protein of GluR2 subunit, which as you said GluR2 subunit axpressing AMPARs are the vast majority.

thanks for the wordy post.

 

[Limpet_Chicken]

What I meant, is that some AMPARs contain the GluR2 subunit, the AMPAr is a tetrameric ionotropic receptor that usually forms a heteromer, the possible subunits being GluR1, GluR2, GluR3 and GluR4, most AMPARs contain the GluR2 subunit and varying proportions of the others.

Its GluR2 presence/abscence that controls what cations the channel is permeable to, namely Ca++, Na+ and K+, GluR2 renders the ion channel impermeable to calcium, at least, in those receptors of the flop isoform, I believe, but am not sure that flip-type AMPARs are Ca++ permeable, but these are not at all common in the adult, actually, I'm not sure if they are present at all.

Additionally, there are more sites for phosphorylation, via the action of various protein kinases, than you have had hot bloody meals, for each of the subunits. Some sites when phosphorylated decrease channel open time, increase it, regulate delivery of AMPARs from formation to exocytosis and localization at the right place within the synapse itself, you name it, some kinase probably does it, anything but make your coffee just the way you like it

As far as direct agonism resulting in excitotoxicity, its the massive Ca++ influx, that results in excitotoxic damage, and like I said, an agonist directly gates the ion channel and makes it open, passing unregulated bucketloads of calcium into the cell, and making kentucky-fried brain cell while its at it. AMPARs are expressed to a high extent within the prefrontal cortex and hippocampus, which as is well known, are involved in rational higher cognitive function, learning and memory, as well as in the striatum, where they interact with DA receptors, I would guess, mediating the neuroplastic alterations seen in chronic stimulant (ab)use.

http://www.jneurosci.org/content/20/12/4480.full Source for some info on striatal interaction with dopaminergic pathways.

Jesus...I hate neuroscientists sometimes, at least the professionally employed ones. You really piss your humanity right down the toilet, when you get to the point when you can put a mouse in a microwave and cook it to death to extract its brain. I've seen some pretty sick shit in many papers, but that just about takes the biscuit. The fact that there is such a marketed product as a 'small animal microwave' makes me want to kill people with a rusty cheese grater and a wire mesh straitjacket....fuck...why in the name of Eris did I have to read that article?

 

[Ampa-omega]

interesting, the dopamine- ampa connection.
makes sense where the receptors are at as well, in the striatum.

so we got to still figure out the phosphorylation kinase's still huh.

truth be told im not sure where this info you provided leaves me with my original questions
yet i do understand everything you said, or most of it, im not sure where you are going with this though.

and sorry a bit about my late reply, i had to leave the computer for a bit.