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.

Using human-cloned receptor assay technology, Xoc Pharmaceuticals established a 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 assays at 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 and methylergometrine act as full agonists for all 5-HT₁ receptors except for 5-HT_1D, at which both are partial agonists. For all 5-HT₁ receptor subtypes, methylergometrine is the more potent compound. Methysergide is a full agonist at the 5-HT_2A receptor, a silent antagonist (both partial agonist and antagonist) at the 5-HT_2B receptor, and an antagonist at the 5-HT_2C receptor. Methylergometrine is a potent full agonist at the 5-HT_2A and 5-HT_2B receptors and a potent partial agonist at the 5-HT_2C receptor. 

Based on a literature review and the receptor profile, 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.

Agonism at the 5-HT_1A, 5-HT_1B, 5-HT_1D, and 5-HT_1F receptor subtypes is likely desirable for acute migraine treatments and potentially for migraine prevention. 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.

The comparative receptor activity assessment suggests that methysergide represents the smaller risk for hallucinogenic and fibrotic effects and is the superior migraine prevention agent.