Fasoracetam

So it is actually pretty complex, and I did not go into it as deeply as I would need to, to give it justice. I'll probably add more details later, as I am making a whole book on nootropics. I did not want to lose the new people this blog was targeted at.

Both Aniracetam and Piracetam bind to GluA2 and GluA3 subunits of the AMPA receptor. However, the specific binding site on those subunits is different. Aniracetam binds to a symmetrical site at the center of the dimer interface. Piracetam binds to multiple sites along the dimer interface, with one of those sites being completely unique to Piracetam. Piracetam binds to 3 asymmetric sites on the GluA2 and GluA3 S1S2 domain. Piracetam can actually fit in 6 different positions on the GluA2 subunit, due to each of the 3 sites allowing for asymmetric binding. However, Piracetam is a weak modulator of AMPA, even though it binds to multiple sites. Even so, its ability to bind to sites in varied ways, and its effects in other areas of the brain apart from AMPA, means it has a lot of unique effects compared to other AMPA modulators. Also, binding site 3 on the GluA2 subunit is unique to Piracetam, and sees the highest density of binding compared to all the other binding sites. Piracetam also binds to site 3 on the GluA3, but to a lesser extent than on GluA2.

Aniracetam, on the other hand, binds mostly to a single symmetric site on both the GluA2 and GluA3 subunits. It's also not site-specific, so it will bind almost equally to that site on both GluA2 and GluA3. Aniracetam is a more potent and specific to the AMPA receptors than Piracetam. However, it is rapidly and completely metabolized in the liver after oral administration. So keep that in mind when thinking about these relative affinities. Aniracetam is much more potent than Piracetam at the AMPA receptor if is is able to reach them. Most effects of oral Aniracetam are due to its metabolites, and are not going to be as potent at AMPA.

The reason for the differences in affinities and binding sites is actually due to the hydrophobicity. Piracetam occupies mostly superficial sites; due to its water solubility. The inner binding sites that Aniracetam binds to are exposed to less water in the body, and thus are more capable of being bound by hydrophobic molecules. Aniracetam binds to a single site at both GluA2 and GluA3, and in a single direction. Piracetam binds to 3 different sites on both GluA2 and GluA3, with the binding orientation being twisted one way or the other at each site. The 3rd binding site at GluA2 and GluA3 is unique to Piracetam, compared to other AMPA modulators. Aniracetam is more potent and specific to AMPA. However, very little of it reaches systemic circulation, due to very high first pass metabolism. So when people give anecdotes of Aniracetam, they are usually describing the feeling of N-anisoyl-GABA, as that is what 70% of a dose of Aniracetam becomes after oral administration. Then there is also some P-Anisic Acid, and 2-pyrrolidinone, neither of which have the same AMPA effects at the parent compound. Only 0.2% of an orally administered dose reaches the systemic circulation as intact Aniracetam in humans. So when looking at all the data on Aniracetam's binding and effects, keep in mind that oral administration in humans is not going to really give you that. You are mostly getting N-anisoyl-GABA, which is the calming part of Aniracetam. That metabolite modulates dopamine and serotonin through the mesocorticolimbic pathway.