Comment by TheToadKnows | Hacker News Reader

Comment by TheToadKnows | Hacker News Reader

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Indeed, you're correct in stating that psilocin is dephosphorylated psilocybin, and the core indole structure with the side chain is preserved. However, my point is that psilocybin would never make it to most cells in the body. I suggest researching the known pharmacokinetics of psilocybin to better understand the nuances here.

In terms of physical properties, psilocin and psilocybin differ significantly due to this transformation. These differences have meaningful consequences at the receptor level, which is where the physiological and psychoactive effects are primarily mediated. The key concern is how the resultant psilocin molecule interacts with cellular receptors and proteins, which almost certainly differs from psilocybin's interactions.

This distinction is quite similar to drug design concepts, where seemingly minor modifications to structure can drastically alter a drug's efficacy and interactions. The difference between a phosphate group (as in psilocybin) and a hydroxyl group (as in psilocin) may appear subtle, but in pharmacological terms, this can easily distinguish between an active and inactive compound.

Do you mean that it is the OH group on psilocin that binds with the receptor? There probably are many other compounds with an OH group and another backbone, and they are not supposed to bind with 5HT2a.

The OH group is ~0.62% of the whole molecule, so there are way more molecule positions in space in which the OH group will be facing away from the receptor, so the active compound will not react.

I honestly cannot tell if you are trolling now, but I'll oblige one last time. In good faith, I think you might be oversimplifying the situation a bit. The binding of psilocin (or any other ligand) to its receptor is not just about the presence or absence of a particular functional group such as the OH group. The entire structure and dynamics of the molecule, including its overall conformation and the spatial orientation of its functional groups all play crucial roles in how it interacts with the receptor.

In the case of psilocin, the 4-hydroxyl group does not act alone, but is rather a part of the larger molecule. Apart from it's induction effects with the indole ring, this group has been shown to form a very unique intramolecular hydrogen bond with the distal amine that significantly influences the overall conformation of the drug, and this in turn affects how the drug binds to and activates the receptor. Remarkably, this intramolecular hydrogen bond is largely responsible for many of the unique pharmacological and physical properties of psilocin.

( https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002... )

Moreover, receptors like 5HT2A do not interact with their ligands in a one-size-fits-all manner. Rather, they have unique, intricate 'lock-and-key' or 'induced-fit' relationships with each ligand, where the spatial orientation of every atom matters. Hence, just because a molecule has an OH group doesn't automatically qualify it to bind with the 5HT2A receptor; it needs to have the right molecular structure and conformation.

Lastly, while the OH group constitutes a small percentage of the overall molecule, its position and the way it influences the conformation of the psilocin molecule cannot be overlooked. Drug-receptor interactions are not solely dictated by the size or quantity of a particular group, but by the precise alignment of these molecular features. This is the reason even minute changes in the structure of a drug can dramatically alter its pharmacological activity.

I'm not trolling, this probably is some effect of the psychoactives' field itself and thinking about it.

I am researching the topic about how signalling molecules find their intra- and extracellular targets amongst multiple potential "distractions" along their way. What you describe as 'lock-and-key' or 'induced-fit' relationship is established only at the direct contact of a ligand with the receptor. While the ligand in vivo if not injected locally first needs to move fast through vast distances (relative to its size) until it reaches the receptor. It seems that it is just accepted for granted, as if the ligand "knew" where the receptor is.

Your link and explanation are very informative, it seems like this intramolecular hydrogen bond completes a "virtual" third heterocycle in the whole molecule. While senolytic quercetin, for example, also has 3 benzene rings.

There's a doctor in my contacts who weighs heavily on heterocycles due to the delocalized electron they contain.

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