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David Triggle on Ion Channel Drug Targets; Health Care Public Policy

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At A Glance

Name: David J. Triggle

Position: University Professor and Distinguished Professor, School of Pharmacy and Pharmaceutical Sciences, SUNY Buffalo

Background: Dean, Graduate School, SUNY Buffalo — 1995-2001; Dean, School of Pharmacy, SUNY Buffalo – 1985-1995; Chairman, Dept. of Biochemical Pharmacology — 1971-1985; PhD in chemistry, University of Hull

The bulk of your career has been primarily spent on voltage-gated calcium channels as drug targets, correct?

Yes, I've spent a fair amount of my life working in this area, certainly the last quarter-century or so. I started as a physical chemist — that's what I've really got a PhD in, reaction kinetics. And then I did a couple of post-docs, one in Canada, and that sort of led me into synthetic organic chemistry, and what we were synthesizing then were bio-logically active molecules — largely from trying to do stereospecific syntheses, which in 1959 was a fairly new era, and this was not so easy then. Today, it would be regarded as fairly trivial stuff. And in order to confirm what we'd made, we needed to get some pharmacology done, which sort of got me interested in how pharmacology worked. Then when I had started my own career, I had decided that, broadly speaking, what you could call pharmaceutical chemistry is where I wanted to go. But we always did it in conjunction with doing our own biology, so we've always run a mixture of chemistry, and pharmacology, and more recently molecular biology, which I think has been a fairly profitable way of trying to define biological pathways.

The assays we were setting up were relatively simple ones, because we were learning pharmacology … so most of it was isolated pieces of smooth muscle, and we became interested in not just using them in assays, but asking the question: 'Why do the muscles contract?' The answer was, of course, that they are mobilizing calcium, and that got us very early on into saying: 'Well, these will be interesting pathways to investigate.'

And that led us very quickly into looking at calcium-mobilizing pathways, and I venture to say that was probably ahead of most people in terms of thinking of these as pathways for drug development. And so I pretty much stuck with ion channels, and in particular calcium channels, for the rest of my career.

Recently, Steven Oldfield of Molecular Devices told Inside Bioassays that ion channels are potentially the most important long-term therapeutic target in cells? Do you agree with this?

Well, I think they are very good drug targets for a whole host of reasons. Whether they will all be universally good targets is another matter.

First, ion channels are, in essence, integrating loci in a cell. So each cell typically has a whole host of excitatory and inhibitory inputs that all basically come in and out through ion channels. So the ion channels represent an integrating device, if you like.

Second, they are extraordinarily efficient molecular machines. They can translocate ions at diffusion-controlled rates, which are basically about as fast as a chemical reaction can go. And they can do that with virtually absolute selectivity, so they can distinguish sodium from potassium and calcium from barium, et cetera.

And then most important of all, I think, from a pharmacological perspective, is ion channels are, in a sense, pharmacological receptors — they have specific binding sites for drugs. You have activators and inhibitors. And, what's really important is that they're pharmacological receptors with a vengeance, because each ion channel typically has not just one drug binding site, but may have a dozen or more. The voltage-gated sodium channel, for example, probably has eight to ten separate drug and toxin binding sites. So these are huge opportunities for drug development.

And finally, to sort of cap it all off, in the voltage-gated ion channels, the access of the drug and the affinity for one or more of these receptor sites is often governed by the state of the channel — that is, whether the channel is closed, or open, or inactivated, so you have all these state-dependent interactions. And so you have the opportunity of fine-tuning the affinity or selectivity of a drug for a particular ion-channel binding site, by manipulating the voltage and/or the chemical potential by changes, for example, in phosphorylation status. So if you put all of those things together, then it does make ion channels a major continuing target, and a continuing major opportunity for drug development.

If you look around, there are an enormous number of drugs on the market, and toxins and pesticides and insecticides, et cetera, which exert their actions on ion channels. You know, many of the things you use in the garden are ion channel toxins — pyrethroids and DDT, which of course we don't use anymore, but that's why DDT works; it interacts with a sodium channel. And in the animal kingdom, nature has evolved some absolutely wonderful chemicals for ion channels — toxins which are incredibly potent and selective. I mean there are many species of animals you simply don't want to go near, because they'll knock out one or more of your ion channels with lethal effects. So, nature's already been there, and has worked out that ion channels are really very, very good targets for toxin interactions.

What are some of the most important therapeutic areas that ion channels are good drug targets for?

Well, they've certainly involved significantly in the cardiovascular system: Drugs that interact with sodium channels — anti-arrhythmic agents, for example. Take the lidocaine-type agents, for example, which are routinely used for certain types of people with cardiac arrhythmias. And there's ongoing investigation into anti-arrhythmic drug actions elsewhere in the cardiovascular system — for instance the whole series of calcium-channel blockers, which are still used extensively as anti-hypertensive and anti-angina agents, and as anti-arrhythmic agents. There's a role for potassium-channel drugs as anti-arrhythmic agents, too.

And then there are anti-diabetic drugs that are very widely employed. These are drugs that act at so-called ATP-sensitive potassium channels present in pancreatic beta cells.

Then there's pain — that's an area for some sodium drugs, and an area under prominent investigation for calcium-channel drugs and calcium-channel blockers interacting at the so called "N" type of voltage-gated calcium channels. In fact, there is one toxin — a polypeptide agent on the market that has just been approved for chronic pain — that is a complex peptide. And clearly, other people are looking extensively at that area, with the aim of coming up with small-molecule drugs that would do the same thing and be generally more desirable than a peptide agent.

People are continuing to investigate — although it hasn't been successful yet — whether ion-channel drugs will be successful in stroke. For example, in preventing the damage during neuronal ischemia; this has been an area of very significant investigation for both voltage-gated ion channels of the sort we've been talking about, but also for ion channels associated with excitatory amino acid receptors, and the NMDA type of ion channels. Stroke and neuronal ischemia are very significant disorders, and there isn't much available for them at all.

What do you think of the evolution of cell-based screening since you started working in this area, and the continued push towards high-throughput methods?

Well, I think screening for pharmacologically active compounds has progressed in a whole host of ways, and in a sense is coming full-circle.

When I started, the only techniques available to you were either whole animals or pieces of tissue. Some bolder individuals were using cell cultures, but these were pretty much primary cell cultures. The disadvantage was that they were immensely slow — you know, one animal or half-a-dozen pieces of tissue a day was sort of the standard throughput.

On the other hand, the advantage was you got data that related very directly to the pharmacological endpoint. So that if, for example, you were interested in an anti-angina agent — a coronary vasodilator — you could do all of your pharmacological screening on pieces of coronary artery, or if you had enough money, you could do this stuff on open-chest dogs — you know, watching the coronary arteries dilate and contract as we gave the drugs. And if you were using a whole animal, you often got the opportunity to see side effects at the same time. If you were looking for a coronary vasodilator, and the wretched animal went into convulsions at the same time, you certainly knew you had a side effect. The disadvantage of course was that it was expensive and very slow.

So the next step, basically, was to use isolated membrane preparations through radioligand binding, which of course gave you an enormous increase in throughput, but the disadvantage was that, despite being able to get much more data out quickly, you're one or more steps removed from actually seeing the pharmacological endpoint. So just because you can measure an affinity in a membrane prep, doesn't mean that you necessarily know whether the drug is an agonist or antagonist or inverse agonist, et cetera. So it certainly gives you a lot of data, but then you have to go back, and eventually, with a small handful of compounds, choose the ones for which you want to do more extensive pharmacology.

The great advantage of where we're coming to, now, which is cell-based assays, is that in a sense you can combine the high throughput you get with radioligand binding and other biochemical assays with getting some of the data that you get with a tissue preparation or whole-animal preparation. You don't get all of it, but you get some of it. And for ion-channel drugs, what's important for the cell-based assays is that you're working with a living system where you can manipulate the membrane potential, and you can manipulate the chemical potential … and that enables you to investigate whether the molecules are agonists, or antagonists, or inverse agonists, and whether there's an influence of membrane potential to the extent that you get state-dependent interactions. Because often what you really want in a voltage-gated ion channel, you want to get an antagonist which has, for example, significant voltage-dependent binding affinity, and will act preferentially when the ion channel is activated or inactivated, because that may reflect more closely the pathologic state.

Switching gears, you recently wrote a comprehensive article on the improvements needed in public policy and health care in the 21st century (Drug Development Research, 59: 269-291 [2003]). Even as we continue to use cutting-edge techniques to develop new therapeutics, do you think that economically disadvantaged groups of people or countries will benefit?

No. I think this is one of the major issues facing the world in general, and individual countries in particular. People talk about the third world and the other world, but it's better to talk about the rich world and the poor world. But in either case, we have increasing inequality. Even if you take a rich country like the United States, we're not very egalitarian. We have huge discrepancies between the richest part of the population and the poorest part — that's why we have close to 45 million people without access to health care. And clearly a link has been demonstrated by epidemiologists between inequality in a society and the overall health of the population — the greater the inequality, the worse the health pattern. Even the rich world has its own set of problems, and the US is almost unique because it has almost no mechanism to deliver health care on an equitable basis. We have the very best if you've got money and good insurance, but if you've got neither, we've got amongst the very worst healthcare in the world. So, a new medication which costs $20,000 to $50,000 a year to deliver to a patient is not much help to a lot of people. That's part of the problem, and that's a social issue that needs to be grappled with, in the US in particular. And in my opinion we need to be very careful not to deliver our market-driven dogma to the rest of the world, because it doesn't work terribly effectively for systems where you need a great deal of public control and public input.

And the other set of issues is that the poor world is in a disastrous state — and not just because of disease, but because of a lack of public health infrastructure. If one could deliver clean water — clean water — to the rest of the world, the alleviation of death would be enormous. Approximately 11 million children under the age of 5 die every year in the poor world, and most of them die from eminently treatable disorders. About 50 percent of them die of diarrhea, which you basically get from impure water and lack of sanitation. What the poor world needs is not a drug that fixes you after stroke, but what the poor world needs in addition to anti-tuberculosis and anti-AIDS drugs is public health infrastructure. And if you take that attitude and then think about the rest of the disease in the world, most of them are actually diseases of living. The rich world is now facing an epidemic of obesity and type-II diabetes, and that's because we eat too much and don't exercise enough. And so almost paradoxically, the pharmaceutical industry is investing billions of dollars of very expensive drugs aimed at alleviating a condition which is basically self-treatable — a more sensible diet and walk a few miles a day, and we wouldn't have this epidemic. And these are some of the things that have interested me more towards the end of my career — how does one make science serve society rather than society serving science?

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