Targeted 5-HT_1F Therapies for Migraine

Migraine is a common neurological disease characterised by the presence of attacks of unilateral, severe head pain accompanied by other symptoms. Although it has been classified as the sixth most disabling disorder, the available therapeutic options to treat this condition have not progressed accordingly. The advance in the development of 5-HT₁ receptor agonists for migraine, including 5-HT_1B/D and 5-HT_1F receptor agonists, has meant a major step forward towards the progression of a better treatment for migraine. Triptans have a limited efficacy, and their effect on vasoconstriction makes them unsafe for patients with cardiovascular and/or cerebrovascular diseases. Therefore, novel effective antimigraine treatments without cardiovascular effects are required, such as selective 5-HT_1F receptor agonists (ditans). Lasmiditan has much higher affinity for the 5-HT_1F receptor than for the vasoconstrictor 5-HT_1B receptor. This has been confirmed in preclinical studies performed to date, where lasmiditan showed no effect on vasoconstriction, and in clinical trials, where healthy individuals and patients did not report cardiac events due to treatment with lasmiditan, although it should be confirmed in larger cohorts. Lasmiditan crosses the blood-brain barrier and may act both centrally and peripherally on 5-HT_1F receptors expressed on trigeminal neurons. It is a well-tolerated compound that does not induce major adverse events. Although ongoing phase III clinical trials are needed to confirm its efficacy and safety, lasmiditan might offer an alternative to treat acute migraine with no associated cardiovascular risk. This review will focus on the characterisation of 5-HT₁ receptor agonists and their effects as migraine therapies.