Abstract
Professor Goadsby
Now it is a particular pleasure to introduce Helen Connor to talk about building on the sumatriptan experience and the development of naratriptan, in which she was so pivotally involved.
Helen Connor
Good afternoon, ladies and gentlemen. As a member of Pat Humphrey's team working on the preclinical pharmacology of sumatriptan, it is a great pleasure for me to be here. The objective behind the development of naratriptan was to identify a compound that would have even better metabolic stability than sumatriptan, with improved oral bioavailability, longer duration of action and enhanced therapeutic action. Many compounds were synthesized and tested in an attempt to achieve this profile; naratriptan was first evaluated in early 1988. It is structurally similar to sumatriptan, the main difference being an N-methyl piperidinyl group on the indole nucleus, designed to confer metabolic stability (Fig. 1).
The chemical structures of naratriptan and sumatriptan.
We wanted a potent agonist at 5-HT1B/1D receptors, the activity by which we now define a triptan. The compound should have no activity at other receptor sites or channels, in order to avoid side-effects, and should have the expected profile of action in animal models indicative of efficacy in migraine. Naratriptan is indeed a potent agonist at 5-HT1B/1D receptors, actually being 3–6 times more potent than sumatriptan. Both compounds also have relatively high affinity for the 5-HT1F receptor (Table 1), about which there is interest as a possible target for the acute treatment of migraine. Perhaps the most informative data with respect to the importance of the 5-HT1F receptor for efficacy of the triptans are clinical data with alnitidan, a Janssen compound now dropped from development. This triptan has very low affinity for the 5-HT1F receptor (1) and at clinical doses is unlikely to have 5-HT1F receptor effects, yet it is clinically effective (2). This suggests that the 5-HT1F receptor activity possessed by some triptans is not essential for clinical efficacy with this class of compound in the treatment of migraine.
Profiles of 5-HT1 receptor activities of naratriptan and sumatriptan
Values are pKi or pIC50 values from radioligand binding studies, (from Connor H et al. Cephalalgia 1977; 17:145).
So what is the relative importance of the 5-HT1B and 5-HT1D receptors? Recent data on Pharmacia-Upjohn's potent and highly selective 5-HT1D receptor agonist, PNU-142633, indicate it causes the characteristic triptan side-effects, but is not effective in the acute treatment of migraine (3). From these data, I conclude either that 5-HT1B receptors are the important target for effective treatments or that a combined target on 5-HT1B and 5-HT1D receptor activity is required. Targeting the 5-HT1D receptor alone appears not to be enough for clinical efficacy.
Both sumatriptan and naratriptan have selective cranial vasoconstrictor effects, causing contraction of isolated cerebral arteries taken from dogs and humans. Both are also potent selective constrictors of the carotid vascular bed in anaesthetized dogs, naratriptan being about 2–3 times more potent (Figs. 2 and 3). Neither agent causes significant coronary vasoconstriction in anaesthetized dogs. In humans the situation is a little different, as each can cause very small contractions of human isolated epicardial coronary arteries, through activation of a small population of 5-HT1B receptors present on these vessels (Fig. 4). Ergotamine has a more potent and greater effect, and while the contractile effects of sumatriptan are rapidly reversed by washing the tissue, those of ergotamine are not, which obviously has safety implications (4).
Contraction of canine isolated cerebral arteries in response to naratriptan and sumatriptan (grey symbols) compared with 5-HT (black symbols).
Selective vasoconstrictor effect of naratriptan in the carotid vascular bed compared with (A) vertebral and (B) coronary vascular beds in anaesthetized dogs.
Contractile effects of different triptan molecules on human isolated coronary arteries [from Van Den Brink M. et al. (4)]. E, ergotamine; N, naratriptan; R, rizatriptan; S, sumatriptan; Z, zolmitriptan.
Sumatriptan acts upon the peripheral terminals of the trigeminal nerve, an effect first identified by Professor Michael Moskowitz and co-workers. They developed an animal model in which the trigeminal ganglion could be electrically stimulated, activating the trigeminal nerve and evoking protein extravasation in the dura. This response could be inhibited by sumatriptan (5). This rodent model was used at Glaxo to show that both naratriptan and sumatriptan inhibit plasma protein extravasation in the dura. However, to date it has not been proved that neurogenic inflammation actually occurs in man during a migraine attack, so the relevance of the animal model to the proposed pathophysiology underlying migraine is uncertain. Moreover, other drugs that block plasma protein extravasation in the dura in this animal model are ineffective in treating migraine. One example is the neurokinin-1 receptor antagonist GR 205171 (6). Whilst negative results such as these are disappointing, they do give us more understanding about pathophysiology, and about the relevance of the animal models that we use.
Naratriptan differs from sumatriptan in preclinical experiments in its ability to gain access to the trigeminal nucleus caudalis, the site within the brain stem where trigeminal fibres arising from the cranial vasculature terminate. Naratriptan is slightly more lipophilic than sumatriptan and hence appears to cross the blood brain barrier more readily. Naratriptan can inhibit firing of neurones within the trigeminal nucleus caudalis following activation of the trigeminal nerve, as Dr Philip Bland Ward of the GlaxoWellcome Headache Research Group in Stevenage has shown in rats (Fig. 5).
Inhibition of neuronal firing induced by naratriptan in the rat trigeminal nucleus caudalis. (By courtesy of Dr Philip Bland-Ward, Headache Research Group, GlaxoWellcome).
What are the advantages and disadvantages of naratriptan's ability to gain better access to this central site? Obviously this represents a potential additional site of action, which may add to clinical efficacy in migraine seen with a more poorly CNS penetrating triptan such as sumatriptan. However, the clinical data do not provide evidence that the more lipophilic triptans have better clinical efficacy than sumatriptan, perhaps because the blood brain barrier may be more leaky during a migraine attack. This would allow sumatriptan to gain access to these central sites. The downside of activity within the central nervous system is the potential for CNS side-effects such as tiredness and dizziness.
What about the pharmacokinetic profile of naratriptan? It is excreted predominantly unchanged and is metabolically highly stable (which translates into high oral bioavailability in humans of about 70%) and has a half-life of 6–7 hours. The 2.5 mg oral dose was selected because it provides the maximal benefit risk ratio, particularly in terms of the incidence of adverse events, which for this dose were the same as those in the placebo group (Fig. 6).
Chart of efficacy and incidence of adverse effects with different doses of naratriptan, summated from the published Phase II dose-ranging study S2WB2004.
To conclude, naratriptan has good oral bioavailability, a long duration of action and a similar pharmacological profile to that of sumatriptan. The main difference is naratriptan's ability, on the basis of animal data, to gain access more easily to the trigeminal nucleus caudalis, although the clinical significance of this property is uncertain. The 2.5 mg dose was selected because dose-ranging studies showed that this dose combined clinical efficacy with excellent tolerability.
Thank you.