References

An Interview with Dave Nichols

Sattelkau, Tim; Trip Magazine, Vol 5., Spring 2000, p 42.

Let's talk about your research. There was an article in the first Heffter Review and of course in the Journal of Medicinal Chemistry about these new, extremely potent phenethylamines you came along with. Can you tell us about that?

Most of the phenethylamine psychedelics are very flexible, floppy molecules. We have essentially tried to constrain portions of those molecules into particular shapes with the idea that when these things bind to their brain receptors, if we could lock them into the same shape that the receptor had, their potency would increase, and that would give us some idea of what the shape was, much in the way — to use a simple analogy — that you might start grinding on blank keys and sticking them into a lock and trying to turn it, then grinding them some more until you finally find one that turns the lock. It is sort of the same kind of idea, except we were locking parts of the molecule. We had played around with the two-carbon side chain and locked it into a lot of different shapes. Some years ago we started to lock the methoxy groups in 2C-B or DOB and found that there were particular orientations that they had to be in to have the most potency. And that defined the shape that they had when they bound to the brain serotonin receptors. That increased the potency. Then I had a student working with me on his PhD — Matt Parker — and he was talking to someone in another research group who was making aromatic compounds and realized that what we had in some of the rigid compounds we'd made with the methoxys locked was the possibility of converting them into completely aromatic compounds. So he took some of these precursors and made them completely aromatic with three flat rings. When we tested them they proved to be extremely potent in the animal models and had extremely high potency at the receptors. In fact, as far as we know, in the models we have, in the animal models and the receptor binding assays, those are the most potent drugs in binding to these particular types of brain receptors that have ever been discovered.

Are they more potent than LSD, which was the so-far unmatched standard?

Yes. If you actually look at the ability of LSD to bind to the serotonin 2A receptor, which is the presumed brain target, LSD isn't actually quite as potent as things like DOB or DOI. They are slightly more potent. But in terms of the animal model, when you look at the whole animal, LSD was far more potent than any of the simple phenethylamines. We think there is possibly some sort of interaction in the brain between the different things that LSD does that amplifys its potency beyond what you would predict just from its ability to bind to serotonin receptors. When we tested these rigid phenethylamines in rats, they turned out to be more potent than LSD. That is the first example of phenethylamine compounds that we've tested in our animal model which actually were more potent than LSD. They are also tremendously more potent in receptor binding than LSD, about a hundred times more potent. In rats, of course, the increase in potency is not as great. It's maybe two- or three-fold more. But still, to find a very simple amine that has such high affinity tells you it is binding and activating that receptor very well.

You mentioned lysergamides. What are the recent developments there? LSD is fifty years old.

We did some early work where we played with the methyl group on the nitrogen of LSD and replaced it with propyl, ethyl, and allyl. All those compounds were at least as potent or even more so than LSD. But that wasn't really exciting, because it kind of made sense from what we knew about what the receptors were looking for. We have focused most of our attention on the diethylamide, because the potency of LSD is so exquisitely dependent on what that amide is. We've made a lot of compounds that we haven't even published data on. We have receptor binding or rat assays, and I think it won't be too long before we write some sort of review and summarize everything we know. We have some new compounds now where we've also used this rigid analog approach to constrain the diethylamide into different orientations. We know from our receptor binding data that one of those orientations is much more potent than the others. We will be in the process of getting further biological data on those in the near future. I think that will be very important work because in that paper we will define what the shape of those two ethyl groups is when LSD actually binds to its receptors, or the key receptor that the rats are responding to, at least. LSD binds to a large number of receptors, not just serotonin 2A receptors. One of the things we're hoping is that by constraining the diethyl groups into these differing orientations, these molecules, three different rigid LSD analogs, may bind to subsets of the total set of receptors that LSD binds to. That may give us a better clue as to why LSD is so potent, beyond what you'd predict from the binding to serotonin 2A receptors. I'm really hoping that those will be key compounds. When we write that paper, we'll probably put some other compounds in and follow it up with some of the things we haven't published, really try to define the nature of that part of the binding site in the receptor, and some of the other receptors, dopamine receptors, and some of the other serotonin receptors. I think that's really an interesting area to look at. We've done some work already with another serotonin receptor called the 5HT1A receptor. LSD binds to that receptor as well, as do things like DMT and psilocin. And we know that receptor has a very different shape around the amide group than the serotonin 2A receptor. So we think we might be able to target lysergamides to different kinds of receptors by very carefully tailoring the nature of what's attached at that location of the molecule.

You have already done a very good job of tuning the potency of the molecules. Would that be a step toward tuning the effects?

Well, I think it would certainly be interesting if you could ever do clinical studies on these molecules. You have a molecule like LSD that binds to fifteen receptors and has a certain qualitative effect, then you somehow parse that into three molecules that all have a subset of the receptor actions of the parent molecule. Now if you can do clinical studies I think you're going to be able to relate some of the clinical effects to those specific receptors. The analogy I use is having a series of simultaneous equations with X unknowns. With LSD you've never had that possibility before. You've had this unique potent agent that binds to all these different receptors. The only way it was discovered that the serotonin 2A receptor was a target was by having other classes of psychedelics, the phenethylamines and tryptamines, and the only thing they had in common with LSD was binding to the serotonin 2A receptor. So in a sense, you had a series with those. But still, when you go back to LSD it's a unique compound which has unique properties, and we still don't have other examples to really be able to pin down what effect LSD has at all these other receptors. We are hoping that by playing with the amide function we can develop a series of compounds that will really help us to understand the importance of that particular part of the molecule in targeting different receptors and subsequently in producing different behavioral effects.

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