Today I will be discussing an interesting class of compounds referred to as racetams. Racetams are relatively simple molecules discovered over 60 years ago. Like many simple, aliphatic molecules with nitrogen incorporated, they have a distinct psychoactive effect. Looking at the physicochemical diversity among the five commercially available racetams I have studied, there is a distinct aspect that makes each molecule unique. They all have 2 amide groups, one of which is specifically a pyrrolidinone ring. From here, we can categorize each derivative of the parent compound based on whether it’s more or less hydrophobic and rigid. Phenyl piracetam, with an additional benzene ring, is more aromatic and hydrophobic. Oxiracetam is more hydrophilic with an additional hydroxy group. Fasoracetam is more rigid and hydrophobic, but not more aromatic than piracetam. Pramiracetam has a whole new positively charged chain, and coluracetam has a massive aromatic ring. It’s somewhat impressive that all these molecules have been recognized as both safe and useful. Let’s review what is experimentally known about racetams before diving into their computational pharmacology.
Racetams are, in general, stimulants. What is fascinating is that their stimulant property appears to be derived from totally different mechanisms depending on which racetam analog is being studied. There is no distinctly verified mechanism of action. Thus, they are a great test case for ligand-based target prediction. A very important in vitro observation of racetams is that, aside from muscarinic acetylcholine receptors, racetams do not appear to bind to any G-protein coupled receptors such as those for dopamine, norepinephrine, or serotonin. Indeed, their relatively small molecular weight makes them unlikely to bind to G-coupled proteins at orthosteric sites. Instead, more subtle and sophisticated mechanisms exist for how racetams appear to improve human cognition. Modulation of choline and glutamate producing neurons appears to yield the enhanced cognitive function associated with racetam use. With this information in mind, let’s peruse through what SEA and STP predict about racetams.
I have attached the respective molecules and their prediction snapshots. The SEA correctly identifies, in form or another, the choline modifying aspects of some racetams. Whether it’s binding to the vesicular transporter (phenylpiracetam), the acetylcholine receptor (fasocracetam), or cholinesterase (coluracetam) inhibition, the program makes a sensible prediction. Piracetam is incorrectly predicted to be a muscarinic acetylcholine receptor ligand, however other racetam including aniracetam analogs do bind there. An interesting anomaly. As for STP results, there is a lot “noise” with respect to which binding predictions are most relevant. Much of this noise includes binding to amino acid transporters, especially proline transporters. Cholinesterases and Acetylcholinesterases show up correctly as predicted targets for most of the racetams. Fasoracetam and Pramiracetam are predicted to also bind to dopamine receptors, which could definitely give them an extra boost in their nootropic profile. Scattered throughout the rest of the predictions are various neurotransmitter receptors including serotonin, cannabinoid, and even opioid receptors. These predictions are less likely to be true and more likely to represent a relatively low affinity (>1 Micromolar affinity constant), but they still demonstrate the neurochemically relevant “appearance” of racetams.
When looking at the interactions with G-protein coupled, there is no prediction for whether or not the interaction will be antagonistic, agonistic, or inverse agonistic. This type of question is always highly relevant to the actual pharmacological effect of a molecule. When it comes to pramiracetam and coluracetam as potential dopamine receptor ligands, it would be pretty easy to tell based on the emotional states produced by the molecule whether it is an agonist or not. Furthermore, the precise genetic isoform of the dopamine receptor will play an important role in the conformational changes that occur upon molecular interaction. So, based on these results, an interesting idea for a clinical trial would be to dose two populations with a specific racetam and to analyze the difference in reported outcomes with respect to attention, memory, and mood. Through scientific understanding of other drugs and computational pharmacology, we can better understand racetams in a more complete manner and continue to design newer, more effective analogs.
