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Abstract Details

Novel Receptor Activity Mapping of Methysergide and its Metabolite, Methylergometrine, Provides a Mechanistic Rationale for both the Clinically Observed Efficacy and Risk of Fibrosis in Patients with Migraine
Headache
Headache Posters (7:00 AM-5:00 PM)
063

Methysergide was developed as the first migraine preventive therapy. However, its use as a long-term treatment diminished due to fibrotic complications. Xoc Pharmaceuticals established an accurate 5-HT receptor activity profile for methysergide and its primary metabolite, methylergometrine.

To establish a receptor activity profile for methysergide and assess the findings relative to documented clinical observations.

Methysergide and methylergometrine were tested on 13 human recombinant G-protein coupled receptors using various intracellular assays (Euroscreen laboratory, Belgium). Sample dose response curves were generated over the range of 0.01 to 20,000 nM to determine effective concentration (EC50), inhibitory concentration (IC50) and relative agonistic and antagonistic responses.

Methysergide is an agonist at the 5-HT2A receptor and an antagonist at the 5-HT2B and 5-HT2C receptors. Methylergometrine is a potent agonist at the 5-HT2A and 5-HT2B receptors and a potent partial agonist at the 5-HT2C receptor. Methysergide and methylergometrine act as agonists at the 5-HT1A, 5-HT1B, and 5-HT1F receptors and as partial agonists at the 5-HT1D receptor. For all 5-HT1 receptor subtypes, methylergometrine is the more potent compound.

Based on literature review and Xoc’s receptor data, the activity at the 5-HT1 and 5-HT2 receptors is the most significant factor with respect to the efficacy and side effects of methysergide treatment.

Antagonism at the 5-HT2B and 5-HT2C receptors is desirable for efficacy in migraine prevention, whereas agonism at the 5-HT2A and the 5-HT2B receptors is associated with hallucinations and fibrotic effects, respectively.  Agonism at the 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1F receptors may be useful secondarily in migraine prevention but is primarily desirable for acute migraine treatments.

The comparative receptor activity assessment suggests that methysergide represents the smaller risk for hallucinogenic and fibrotic effects and is the superior migraine prevention agent, which is consistent with the historical experience with the two compounds.

Authors/Disclosures
Scott Borland (Xoc Pharmaceuticals, Inc.)
PRESENTER
Scott Borland has received personal compensation for serving as an employee of Xoc Pharmaceuticals, Inc.. Scott Borland has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Xoc Pharmaceuticals, Inc.. Scott Borland has received stock or an ownership interest from Xoc Pharmaceuticals, Inc..
Miguel Guzman (Xoc Pharmaceuticals) Miguel Guzman has received personal compensation for serving as an employee of Xoc Pharmaceuticals. Miguel Guzman has received stock or an ownership interest from Xoc Pharmaceuticals. Miguel Guzman has received personal compensation in the range of $100,000-$499,999 for serving as a VP, Product Development with Xoc Pharmaceuticals.
Robert Fishman, MD (Butler Hospital ) Dr. Fishman has nothing to disclose.
Thomas Armer (Xoc Pharmaceuticals) Thomas Armer has received personal compensation for serving as an employee of Xoc Pharmaceuticals. Thomas Armer has received stock or an ownership interest from Xoc Pharmaceuticals.