3 replies to this topic

[3AlarmLampscooter]

So I had some time to kill, and decided to start browsing around pubchem for relatively unknown amapkines with high potency.

Well that, and spent a while gawking at oddities like Deuterium-Substituted Modafinil.

I'll try to post some more later.

PF-4778574 (N-[(3R,4S)-3-[4-(5-cyanothiophen-2-yl)phenyl]oxan-4-yl]propane-2-sulfonamide)
http://pubchem.ncbi....gi?cid=44462786

Working memory impairments are a core aspect of schizophrenia, yet current medicines do not address such cognitive dysfunction. We have developed a model of these working memory deficits by acutely disrupting glutamatergic synaptic transmission by administration of the N-methyl-d-aspartate (NMDA) antagonist ketamine in the nonhuman primate. The current studies evaluated the effect of positive allosteric modulators ("potentiators") of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors on the working memory and behavioral effects of ketamine. AMPA receptors mediate fast excitatory synaptic transmission throughout the brain and play a critical role in the activity-dependent regulation of NMDA receptors. We find that positive modulation of AMPA receptors with LY451646 (0.1-1.0mg/kg, SC) and structurally distinct PF-4778574 (0.01mg/kg, SC) robustly ameliorates ketamine-induced working memory impairments without altering behavioral effects of acute ketamine we consider related to positive- and negative-like symptoms. These results support AMPA receptor potentiators as a potential adjunctive treatment for cognitive impairment associated with schizophrenia (CIAS).

http://www.ncbi.nlm....pubmed/20347881

CMPDA (N,N′-(2,2′-(1,4-phenylene)bis(ethane-2,1-diyl))dipropane-2-sulfonamide)
http://pubchem.ncbi....cgi?cid=9969799

At the dimer interface of the extracellular ligand-binding domain of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors a hydrophilic pocket is formed that is known to interact with two classes of positive allosteric modulators, represented by cyclothiazide and the ampakine 2H,3H,6aH-pyrrolidino(2,1–3′,2′)1,3-oxazino(6′,5′-5,4)benzo(e)1,4-dioxan-10-one (CX614). Here, we present structural and functional data on two new positive allosteric modulators of AMPA receptors, phenyl-1,4-bis-alkylsulfonamide (CMPDA) and phenyl-1,4-bis-carboxythiophene (CMPDB). Crystallographic data show that these compounds bind within the modulator-binding pocket and that substituents of each compound overlap with distinct moieties of cyclothiazide and CX614. The goals of the present study were to determine 1) the degree of modulation by CMPDA and CMPDB of AMPA receptor deactivation and desensitization; 2) whether these compounds are splice isoform-selective; and 3) whether predictions of mechanism of action could be inferred by comparing molecular interactions between the ligand-binding domain and each compound with those of cyclothiazide and CX614. CMPDB was found to be more isoform-selective than would be predicted from initial binding assays. It is noteworthy that these new compounds are both more potent and more effective and may be more clinically relevant than the AMPA receptor modulators described previously.

CMPDB (phenyl-1,4-bis-carboxythiophene) has no pubchem listing yet

http://www.ncbi.nlm....pubmed/21543522
http://molpharm.aspe.../2/267.full.pdf


JAMI1001A (2-(2-(4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7
tetrahydrobenzo(b)thiophene-3-carboxamide)
http://pubchem.ncbi....gi?cid=24967421

Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors facilitate synaptic plasticity and can improve various forms of learning and memory. These modulators show promise as therapeutic agents for the treatment of neurological disorders such as schizophrenia, ADHD, and mental depression. Three classes of positive modulator, the benzamides, the thiadiazides, and the biarylsulfonamides differentially occupy a solvent accessible binding pocket at the interface between the two subunits that form the AMPA receptor ligand-binding pocket. Here, we describe the electrophysiological properties of a new chemotype derived from a structure-based drug design strategy (SBDD), which makes similar receptor interactions compared to previously reported classes of modulator. This pyrazole amide derivative, JAMI1001A, with a promising developability profile, efficaciously modulates AMPA receptor deactivation and desensitization of both flip and flop receptor isoforms. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

http://www.ncbi.nlm....pubmed/22735771

1-BCP (1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine)
http://pubchem.ncbi....ry.cgi?cid=1370

Systemic administration of the drug 1-(1,3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP) has been reported to enhance monosynaptic responses in the hippocampus in vivo and to improve spatial and olfactory memory in rats. The drug's mechanism of action was investigated in the present study using membrane patches excised from cultured hippocampal slices. The decay time of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor mediated inward currents was greatly increased by 1-BCP in a concentration dependent and reversible fashion; peak current was also enhanced but to a lesser degree. In vitro slice experiments indicated that the drug has parallel effects on the field EPSP. It is concluded that 1-BCP is a centrally active modulator of the AMPA receptor.

http://www.ncbi.nlm..../pubmed/7911064

[Reformed-Redan]

I'm not sure what is your goal here. From my limited understanding of neuroscience the glutamergic system is mostly located as a loop between the hippocampus to PFC area. I think there is little therapeutic value for compounds like IDRA or the above mentioned ones in actually normalizing brain chemistry for schizophrenics. They would mostly enhance LTP to a certain degree; but, that is questionable since I think AMPA receptors are mostly limited by the activity of NMDA receptors. You can look into alpha-7 nicotinic receptors. They have strong nootropic value (for example GTS-21) and seem to be as effective as most typical and atypical anti psychotics today. The holy grail is normalizing hypoactive NMDA receptors since they are the most abundant in the brain and would have the most impact. I'm waiting for more news from Naurex and hopping they enter the market, unless Baxter decides to just keep privately funding them since they have a great product on hand.

[xks201]

How about a GTS-21 group buy yada? lol

[Charles Lee Ray]

The glutamatergis system expands far beyond the hippocampus and the pfc. Dopamine, noradrenaline, acetylcholine, serotonine, neuropeptides, neurosteroids and so forth modulate the glutamatergic (ang GABAergid systems). The actual chemical that conveys excitatory information from one neuron to the next is essentially glutamate. Yes, one can find acetycholine and noradrenaline transmission in neuromuscular juntions, enteric system and sympathetic/parasymapthetic system... but the one driving the excitatory computational machinery underlying cognition (attention, episodic memory, flexibility, etc) is glutamate.

 

Other systems ehance glutamatergic transmission in different ways. For example, through dopamine, D1 and D5 receptors purportedly function as a gain mechanism for excitatrory-inhibitory networks in the dorsolateral prefrontal cortex (at least). That is, the increase the signal to noise ratio.

 

Glutamatergic transmission is essentially everywhere in the nervous system. Alpha-7 nicotinic receptors enhance glutamateric function.  

 

Given the limitations of NMDAr modulation, ampakines are quite promissing. There are several issues that, for what I understand, limit their potential. For example crossing the blood brain barrier, AMPAr subunit selectivity, subunit isoform selectivity, etc.  

 

In my humble opinion, they are still impressive. Most experiments usually asses LTP induction. However, that is just a small part of a computational system that we don't understand. Some even argue that the main forms of LTP induction are not physiologically realistic. Further, that they are pathological. At any rate, the cognitive processes that allegedly make you smart relay on very short lived of LTP at the most (seconds). That is not LTP but potentiation. At any rate, the deal is that ampakines have been able to enhance working memory of non-human primates beyond the maximum performance reached by training. This task is notoriously highly correlated with human IQ (when humans do it). 

 

The most mind blowing thing was that, as seen by fMRI, the primates actually recruited new cortical areas... which is bonkers. They were probably actually qualitatively improving computation by recruiting new modules.  

 

I mentioned some of the problems with ampakines. However, the biggest problem is that clinical trials mostly involve pathology. So most of the compounds are tried on animals which may recruit massively different systems to complete a task (when compared to humans). Then, in order to justify trials, they have to go on to be tested in disorders. Which, again, tend to preclude extrapolation to healthy function. So many compounds are tailored for the atypical brain.   

 

At any rate, I don't know how they work in healthy humans and how they rank. I am new to this forum and, come to think about it, probably commenting on an outdated post... what I do know is that enhancing working memory beyond normal peak performance has a high probability of increasing the IQ. Way more than being able to memorize random stuff.

 

So, anyway, those are my thoughts on capitalizing on AMPA receptors.