Serotonin receptor targeted therapy for migraine treatment: an overview of drugs in phase I and II clinical development.

Research has focused on serotonin (5-HT) 5-HT and 5-HT receptors to develop drugs acting through non-vasoconstrictive mechanisms for treating acute migraine and those targeting 5-HT and 5-HT receptors for preventing migraine. Areas covered: This paper reviews antimigraine drugs targeting 5-HT receptors in one phase I trial (sumatriptan iontophoretic transdermal system, TDS) and five phase II clinical trials (PNU-142633, LY334370, lasmiditan, NOX-188). Expert opinion: Data from our overview on investigational drugs in phase I and II clinical trials using the 5-HT receptor agonist (sumatriptan TDS), 5-HT receptor agonist (PNU-142633), 5-HT receptor agonists (LY334370, lasmiditan) and a combined 5-HT receptor agonist with nNOS inhibition (NOX-188) provided encouraging data for sumatriptan TDS and lasmiditan, disappointing results for PNU-142633, and promising findings for NOX-188. The 5-HT receptor agonist lasmiditan, a drug acting through non-vasoconstrictive mechanisms, represents a promising safe, effective and tolerated acute migraine therapy also for patients at cardiovascular risk. Upcoming phase III trials should clarify the optimal lasmiditan dose and eventual clinical advantages over triptans. The negative results for the PNU-142633 trial prompt further studies using specific compounds more precisely targeting 5-HT receptors. Antagonism at 5-HT and 5-TH receptors, a promising strategy to prevent migraine, is still limited to experimental migraine models.