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

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.

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-HT_2A receptor and an antagonist at the 5-HT_2B and 5-HT_2C receptors. Methylergometrine is a potent agonist at the 5-HT_2A and 5-HT_2B receptors and a potent partial agonist at the 5-HT_2C receptor. Methysergide and methylergometrine act as agonists at the 5-HT_1A, 5-HT_1B, and 5-HT_1F receptors and as partial agonists at the 5-HT_1D 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-HT_2B and 5-HT_2C receptors is desirable for efficacy in migraine prevention, whereas agonism at the 5-HT_2A and the 5-HT_2B receptors is associated with hallucinations and fibrotic effects, respectively.  Agonism at the 5-HT_1A, 5-HT_1B, 5-HT_1D, and 5-HT_1F 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.