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 (2663)

Objective: To establish a receptor activity profile for methysergide and assess the findings relative to documented clinical observations. Background: 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. Design/Methods: 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. Results: Methysergide and methylergometrine act as full agonists for all 5-HT1 receptors except for 5-HT1D, 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-HT2A receptor, a silent antagonist (both partial agonist and antagonist) at the 5-HT2B receptor, and an antagonist at the 5-HT2C receptor. Methylergometrine is a potent full agonist at the 5-HT2A and 5-HT2B receptors and a potent partial agonist at the 5-HT2C receptor. Conclusions: 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-HT1A, 5-HT1B, 5-HT1D, and 5-HT1F receptor subtypes is likely desirable for acute migraine treatments and potentially for migraine prevention. 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. The comparative receptor activity assessment suggests that methysergide represents the smaller risk for hallucinogenic and fibrotic effects and is the superior migraine prevention agent. Disclosure: Dr. Guzman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Xoc Pharmaceuticals, Inc. Dr. Guzman holds stock and/or stock options in Xoc Pharmaceuticals, Inc. which sponsored research in which Dr. Guzman was involved as an investigator. Dr. Guzman holds stock and/or stock options in Xoc Pharmaceuticals, Inc. Dr. Guzman has received research support from Xoc Pharmaceuticals, Inc.Dr. Armer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Xoc Pharmaceuticals, Inc. Dr. Armer holds stock and/or stock options in Xoc Pharmaceuticals, Inc. Dr. Armer has received research support from Xoc Pharmaceuticals, Inc.Dr. Borland has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Xoc Pharmaceuticals, Inc.. Dr. Borland holds stock and/or stock options in Xoc Pharmaceuticals, Inc. which sponsored research in which Dr. Borland was involved as an investigator. Dr. Borland holds stock and/or stock options in Xoc Pharmaceuticals, Inc.. Dr. Borland has received research support from Xoc Pharmaceuticals, Inc.. Dr. Fishman has nothing to disclose. Dr. Leyden has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Xoc Pharmaceuticals, Inc..