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

INTRODUCTION: Research has focused on serotonin (5-HT) 5-HT1D and 5-HT1F receptors to develop drugs acting through non-vasoconstrictive mechanisms for treating acute migraine and those targeting 5-HT2B and 5-HT7 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-HT1B/1D receptor agonist (sumatriptan TDS), 5-HT1D receptor agonist (PNU-142633), 5-HT1F receptor agonists (LY334370, lasmiditan) and a combined 5-HT1B/1D 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-HT1F 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-HT1D receptors. Antagonism at 5-HT2B and 5-TH7 receptors, a promising strategy to prevent migraine, is still limited to experimental migraine models.