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

ABSTRACT

Introduction: Research has focused on serotonin (5-HT) 5-HT_1D and 5-HT_1F receptors to develop drugs acting through non-vasoconstrictive mechanisms for treating acute migraine and those targeting 5-HT_2B 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-HT_1B/1D receptor agonist (sumatriptan TDS), 5-HT_1D receptor agonist (PNU-142633), 5-HT_1F receptor agonists (LY334370, lasmiditan) and a combined 5-HT_1B/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-HT_1F 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_1D receptors. Antagonism at 5-HT_2B and 5-TH₇ receptors, a promising strategy to prevent migraine, is still limited to experimental migraine models.

KEYWORDS:

• Lasmiditan
• migraine
• receptor
• serotonin
• treatment

Article highlights

• 5-HT_1D, 5-HT_1F, 5-HT_2B, 5-HT₇ receptors are candidate targets for acute and preventive migraine treatment.

• An iontophoretic transdermal system for delivering sumatriptan, a selective 5-HT1_1B/1D receptor agonist, provides similar systemic exposure in adolescentsand adults.

• PNU-142633, a selective 5-HT_1D receptor agonist, is ineffective in acute migraine.

• Lasmiditan, a 5-HT_1F receptor agonist is safe and effective in acute migraine whereas LY334370 development has been stopped due to toxicity problems.

• NXN-188, a combined nNOS inhibitor and 5-HT_1B/1D receptor agonist, is probably helpful in acute migraine but needs further confirmation.

• Future studies should clarify whether 5TH₇ receptor antagonists, such as SB269970, might be fruitful in migraine prophylaxis.

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Declaration of interest

P. Barbanti has served as a consultant or scientific advisor for Merck, Bayer, Lusofarmaco, Abbott, Allergan, and electroCore. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.