Present and future of 5-HT receptor agonists as antimigraine drugs

Serotonin (5-hydroxytryptamine; 5-HT) is thought to play an important role in the pathogenesis of migraine. The discovery of the 5-HT1B/1D/1F agonist sumatriptan constitutes a substantial advance in the acute treatment of mig raine, though it displays a number of nonnegligible shortcomings. Today, a number of second-generation drugs derived from tryptamine are under advance d clinical development or are about to be marketed worldwide for the acute treatment of migraine. These tryptamine derivatives display partial agonist properties at 5-HT1B/1D receptors. It is not yet dearly established whethe r these agents represent a major improvement over sumatriptan in therapeuti c effectiveness. Most of them also show affinity for 5-ht(1F) binding sites and have better oral pharmacokinetics than sumatriptan. The acute antimigr aine effects of this second-generation of triptans seem to be obtained in l argely the same way as with sumatriptan: by cranial vasoconstriction and in hibition of trigeminovascular activation from both peripheral and central p rojections. Future directions in migraine therapy should focus on agents th at exhibit high intrinsic activity at 5-HT1B/1D receptors, offer a good saf ety profile, and demonstrate long-lasting action which might also be consid ered in migraine prophylaxis.