The effective anti-migraine drugs triptans, all bind with high affinity to three serotonin (5-HT) subtypes, the
5-HT1B, 5-HT1D and 5-HT1F. 5-HT1B mRNA is densely localized within smooth muscle, and less in the endothelium of
cerebral blood vessels. This vascular distribution of 5-HT1B receptor has been shown to mediate the vasoconstrictive
properties of the triptans, responsible for potential cardiac adverse events. Activation of 5-HT1D subtype, although
effective in animal models of migraine, was not enough efficient to attenuate migraine attacks in clinical trials. The
5-HT1F receptor is located both in vessels and within the trigeminal ganglion (TG) and the trigeminal nucleus caudalis
(Sp5C), but with the difference that the 5-HT1F receptor lack vasoconstrictive properties, making it an attractive target for
new anti-migraine drugs. Selective activation of 5-HT1F receptor potently inhibited markers associated with electrical
stimulation of the TG. Thus 5-HT1F receptor represents an ideal target for anti-migraine drugs. So far two selective
5-HT1F agonists have been tested in human trials for migraine: LY334370 and lasmiditan. Both molecules were efficient
in attenuating migraine attacks with efficacy in the same range as oral sumatriptan 100mg, the gold standard for triptans.
The LY334370 project withdrew because of toxicity in animals, while lasmiditan is still testing. In this review we present
all the available preclinical and clinical data on the 5-HT1F agonists as a potential new class of anti-migraine drugs
lacking vascular activity and we discuss related issues on the vascular and neuronal aspects of migraine pathogenesis.