Here’s another one for the “no one ever realized this drug was also doing this” file. And let me tell you, it’s a big file. We develop drugs (for the most part) towards specific biochemical targets, and we assay them against panels of related targets and against common receptors and known toxicology pathways (the few that we know). But there’s a lot more out there, as we are constantly reminded.
This new paper is a perfect example. Everyone is familiar with the benzodiazepine drugs (famous as valium, librium, and many more), and we know that these exert a lot of their activity at GABA-A receptors. But one of the first-generation compounds, (clonazepam, which has a 7-nitro substituent on the “benzo” part of its structure), turns out to have other tricks. These authors find that it has potent activity against the ion channel TRPM8, and that goes for other 7-nitro compounds in this series as well.
This was discovered, interestingly enough, while the group was screening known compounds for activity against schistosomes, parasitic flatworms that are the cause of the tropical disease schistosomiasis/bilharzia. Clonazepam was a hit, and they found that its target was an ion channel that they carry, and inspection of the protein sequences and structures showed a surprising degree of homology with a ligand-binding pocket of human TRPM8. And sure enough, it’s a ligand! And only for that one, none of the other related homologs.
A quick natural products digression: ion channels have a whole range of such binding sites, often several on any given subtype, which has certainly made understanding their modes of action (and discovering drugs that modulate them) quite a task over the years. That TRPM8 pocket is where the natural monoterpene menthol binds, and that’s responsible for the “cooling” sensation of peppermint. Menthol is a chiral compound, but it’s almost entirely one enantiomer in nature. The enantiomer has a completely different smell, I’m told, although I’ve never encountered any. The effects of spearmint, by contrast, are more driven by another monoterpene R-carvone, which interacts with TRPV1 ion channels (and several others). Its enantiomer (which hits a range of the same sites and others) is found in nature as the chief flavor and aroma of dill and caraway, and the difference sensations of those and spearmint are probably the most dramatic and familiar demonstration of our olfactory receptors’ ability to distinguish chirality - at least in some cases.
It turns out that this activity fits neatly into another medical oddity. There’s a rare condition called “burning mouth syndrome” that is exactly what it sounds like, and it’s been known since the 1990s that clonazepam seems to alleviate it. The current treatment is topical (clonazepam-containing mouthwash), and it has been clear from the beginning that this effect is somehow separate from the anxiolytic properties of the drug and its other uses. For one thing, the other benzodiazepines aren’t much use; clonazepam really stands out on its own. And the topical route allows relief from the pain while avoiding the sedation, etc. that comes from systemic doses, which also tells you that something else is going on. The speculation has been that there’s some oddity of GABA signaling in pain sensations that’s at work, but now we know the real reason: TRPM8 activity, whose cooling sensations are exactly what are needed to cancel out the burning ones. This argues that the underlying pathology of burning mouth syndrome is impaired TRPM8 signaling, by some mechanism (but one that allows for an agonist like clonazepam to still exert useful effects).
As always when something like this is uncovered, I encourage everyone to spare a thought about the cases we don’t know about yet. What else are our drugs doing, and where else are they binding? There’s a lot more to find out. And I would also note that we found this out by studying flatworms involved in a tropical disease, which is one of the last places you’d expect to get insight into such a human neurological disorder. So beat the drum for basic research while you’re at it! Every year, every month, every day we understand a bit more.