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.