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BUILDING A
BETTER MIGRAINE BLOCKER
SAN DIEGO—“There are a number of triptans now available for the treatment of acute migraine. By and large their pharmacology is all the same: They are agonists at both the 5HT1B and the 5HT1D receptors,” said Raymond G. Hill, PhD. By looking at this pharmacology, Dr. Hill suggested in his address to the 10th World Congress on Pain, it might be possible to develop strategies for producing new therapies useful for treating acute migraine, hopefully with a side-effect profile better than that for the current generation of triptans.
MECHANISMS OF ACTION
“We believe the central trigger for migraine leads to a vasodilator response in meningeal blood vessels,” related Dr. Hill, Executive Director of Pharmacology at the Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, United Kingdom. The first effect of the triptans in impinging on this process is a cranial selective vasoconstriction of the meningeal blood vessels. “The reason why you get this selectivity is, in fact, very simple,” he explained. “This is a 5HT1B pharmacology, and simply, there are many more 5HT1B receptors on the cranial arteries than there are on the extracranial arteries. So these drugs have a partial agonist profile on the extracranial blood vessels but are full agonists on the cerebral and cranial circulation.”
In terms of neuronal mechanisms of action, Dr. Hill indicated that the focus is on the 5HT1D receptors on sensory nerve terminals, whose activation blocks the release of neuropeptides, which cause neurogenic inflammation and neurogenic vasodilation. While blocking neurogenic inflammation is not believed to be particularly effective in the treatment of migraine, neurogenic vasodilation appears to be a promising therapeutic target. “Electrical stimulation of sensory nerves close to a cranial artery or addition of a pharmacologic agent such as calcitonin gene-related peptide (CGRP) will produce a big dilation of these vessels, and this is exquisitely sensitive to the effects of a triptan,” Dr. Hill said. “The blockade of the release of neuropeptides by the triptans acting presynaptically on these 5HT1D receptors gives you a reversal of this neurogenic vasodilation but does not block the direct effects of CGRP on the vessel.”
TRIPTANS—A SPRINGBOARD FOR FURTHER ADVANCES?
The perceived problem with triptans is cardiovascular adverse effects. “I think most of you who prescribe them know they’re actually very safe drugs and that the probability of having a coronary vascular event after administration of a triptan is extremely low,” Dr. Hill observed, “but nevertheless, we would rather not have even that small possibility of risk. So the next generation of compounds for acute treatment of migraine will probably not have this direct vasoconstrictor effect but will target neurogenic vasodilation, and perhaps neurotransmission, by stopping activation of peripheral nerve fibers by the dilation that’s triggered by the central phenomenon—most importantly, probably by inhibiting the central neurotransmission process and stopping the impulses from getting into trigeminal nucleus.”
According to Dr. Hill, one direct method of achieving this effect is to block the receptors for CGRP. “It was shown that CGRP is released into jugular circulation during a migraine attack, and if you give a dose of triptan sufficient to relieve the headache, you find that the levels of CGRP come back down to normal.” Studies using the 8 to 37 AA fragment CGRP receptor—which is an agonist—have shown that “you can very nicely block the neurogenic vasodilation, and recently [it has been shown that] the CGRP antagonist BIBN4096 is very good at blocking this neurogenic vasodilation and is effective in relieving migraine headache,” he added.
Another new strategy based on an understanding of triptan pharmacology is the use of an adenosine A1 agonist. In animal models these compounds looked very much like the triptans and their mechanism is similar to activation of the 5HT1D receptor—it inhibits the release of CGRP from nerve terminals, Dr. Hill said. “Again, these compounds have been put into clinical trial and are reported to be effective. The problem is that full agonists at the A1 receptor are quite powerful vasodepressor agents, so there may still be a problem with cardiovascular side effects.” Research is focusing on a partial agonist for the A1 receptor that has an antimigraine effect but is relatively free of unwanted cardiovascular adverse effects.
NMDA RECEPTORS AND BEYOND
Blocking the N-methyl-D-aspartate (NMDA) receptors is a possible treatment, Dr. Hill proposed. “This will block the spreading depression that may be part of the trigger for the headache, and it is also clear that the activation of neurons in the trigeminal nucleus is blocked with an NMDA antagonist such as ketamine or CGRP. The problem is that these are unselective NMDA antagonists that have quite severe side effects and could cause psychotomimetic reactions that could be very unpleasant for the patients—they may rather have a headache than the results of the treatment,” he said.
Recently, receptor-subtype selective NMDA antagonists have been discovered, and it will be interesting to see whether any of these agents might be useful for treating migraine and have fewer side effects than the ketamine-type drugs, Dr. Hill added.
There has also been somewhat promising research on triptan derivatives that work at the other receptors of the 5HT1 family, Dr. Hill said. Compounds that act as agonists at 5HT1F receptors apparently block the activation of the trigeminal nucleus after dural stimulation and affect extravasation. They are not directly constrictors, and they don’t affect neurogenic vasodilation. In clinical trials they were reported to be effective, but the cautionary note is that extremely high doses of the drugs have to be used, and so it is not completely certain that these effects were entirely 5HT1F selective, he noted.
A TAKE-HOME MESSAGE
“The triptans obviously do a lot of different things,” Dr. Hill remarked. “They’re vasoconstrictors, they block extravasation, they block vasodilation, they block the nociceptive transmission into the trigeminal nucleus, and most importantly, they work in migraine.
“Can you relieve migraine without vasoconstriction? The answer to that seems to be yes. We also know that you probably don’t need to block extravasation because compounds that do this—such as the substance P receptor agonists—don’t work in migraine. What we’re left with is the possibility that the neurogenic vasodilation and nociceptive neurotransmission might be the two keys, and my bet would be that a drug that would block both of these things without other effects would be a good way to treat migraine with fewer side effects. Many companies are working on this, and I think before long you will have new drugs that will be of benefit to patients,” he concluded.
NR
—C. Justin Romano
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