Dre

https://www.science.org/content/blog-post/epibatidine-siberia

This weekend brought news that the Russian opposition leader Alexei Navalny was poisoned in prison by the compound epibatidine. That is not (to put it delicately) the first thing one would have expected, so I wanted to give a little background on this compound first.

It’s a toxin isolated from a frog species found in Ecuador and Peru (and a few of its relatives), and like all poison frogs it is a very festive-looking creature indeed. That is of course a warning to potential predators, as with many brightly colored species around the world, a little evolutionary message to any hungry onlooker that they can afford to be so bright and prominent for a very good reason that you should have had a chance to learn by now. Many such frogs are used by native groups in the New World jungles as arrow-poison sources, although this particular species doesn’t seem to be.

It has a simple structure with one rather unusual feature, that 2-chloropyridine group. You do see halogenated natural products, but more often from marine organisms where chlorine and bromine are more easily available. An even weirder-looking related alkaloid with the same group in it (phantasmidine) is also found at lower concentrations in the frogs. Unfortunately, the biosynthesis of these compounds has not yet really been worked out (to my knowledge). It is known, as with most other poison dart frogs, that if you raise them in captivity they do not produce the toxin: there is something in their natural diet or environment that allows for it that is not found under terrarium conditions. Even under jungle conditions, sometimes one population of frogs will have the toxin while another in a different location does not.

It is very likely that the frogs do not have the ability to produce the compound on their own, but instead acquire it from their diet of local insects, etc. and then sequester the epibatidine in their skin. This has been documented with both birds and frogs with another such case, batrachotoxin - that one is chemically distinct from epibatidine and is found in a different genus of frogs, but it’s likely a similar underlying story. Not knowing the exact species that produce these compounds has made studying the chemical pathways behind them rather difficult!

And as with all such compounds, an immediate question is how the creatures that produce or sequester them manage to avoid poisoning themselves. Epibatidine works as a ligand for both the muscarinic and nicotinic receptors - it’s an agonist, substituting for the natural ligand acetylcholine, and in general messing with the cholinergic system is going to lead to some strong effects. If you strongly block such signaling, you have replicated the mode of action of nerve gas, and if you strongly enhance it (as in this case) you can get a range of effects including analgesia and muscle paralysis. That latter one is especially unwelcome in the respiratory and cardiovascular system, clearly, and there is no antidote. The compound’s pharmacologic window between interesting pain relief qualities and seizures-n’-death is unfortunately quite narrow. 

People have tried to widen it, most notably Abbott (AbbVie) in the 1990s. They did a lot of work in this area looking for a nonopioid pain compound and took a chemical cousin of epibatidine (ABT-594, tebanicline) into human trials. They had definitely gotten rid of the “death” side effect by that point, as the FDA tends to insist on, but the window between analgesia and the remaining side effects was still too small. These included nausea, vomiting, impaired coordination, and apparently rather weird dreams as well. People were dropping out of the treatment group in the Phase II with alarming frequency, and the compound was abandoned. There are still a number of possible opportunities in the selective-nicotinergic-agonist area, but realizing selective cholinergic agonists is a problem that stretches back many decades and no general solutions have been found.

OK, back to the present day. The presence of the compound in Navalny’s body seems to be beyond dispute. He died two years ago in a “special regime” prison in Siberia, and his body was returned to his mother. Numerous toxicological examinations have confirmed the epibatidine, which does not undergo much metabolism in the human body. That along with its unusual structure make it very easy to identify. I am in agreement with those who believe that this was a deliberate choice by Vladimir Putin’s regime. After all, they had tried to kill Navalny in 2020 with what was obviously a Russian-manufactured nerve agent, and that was after previous chemical attacks in 2017 and 2019. The use of a tropical frog poison in Siberia is to me a grim joke and a statement that this was obviously an unnatural death that was carried out by people with obvious knowledge of human poisons. You don’t need the frogs: epibatidine itself is not that hard to synthesize in the lab by a variety of published routes. It can be made in quantity by any competent organic chemist who knows enough to take the proper precautions, and Russia as a country has a great many skilled organic chemists.

The Russian military and security services have been experts in poisoning people with exotic materials for a long, long time. They know exactly what they are doing from a chemical point of view, even if some of their assassins have not been particularly competent or well-informed themselves. Some have speculated that the authorities wanted to try out the epibatidine route to see how well it worked, but let’s be realistic: they could have done that on all sorts of other Siberian prison inmates without anyone ever hearing about it. I don’t think that the Russian state services have many review-board problems when it comes to running human trials. 

No, this was murder, obvious murder, and it was set up to be an obvious murder. Vladimir Putin is a corrupt, lawless poisoner, and he has had no qualms about demonstrating this over and over. He’ll order it done again the next time the opportunity presents itself.

https://www.science.org/content/blog-post/epibatidine-siberia