Final report: Phenotypic identification of drugs derived from Traditional Chinese Medicines (TCMs) for treating migraine headache 

Summary

Currently the molecular mechanisms of migraine headache are not well understood, which makes it difficult to discover new effective drugs. Corydalis yanhusuo and Lamiophlomis rotate are traditional Chinese medicines that have been used to treat migraine for centuries in China. The Migraine Research Foundation awarded this grant to identify the active substances in these Chinese medicines to provide novel chemical entities for testing and new drug development for treating migraine.

We found the active substances in Corydalis yanhusuo to be corydaline and related alkaloids, while the active substances in Lamiophlomis rotate are iridoid glycosides. Sixteen corydaline alkaloids were chemically synthesized and the relationship between their structure and biological activity was explored. Generally, increasing the hydrophobicity of corydaline alkaloids improved their blood–brain barrier permeability in the in vitro cell culture models. Interestingly, the ability to stop the migrainous activity increased with the increase in the hydrophobicity of corydaline alkaloids. We were unable to explore the relationship between the structure and biological activity of the iridoid glycosides due to challenges in their sugar chemistry. Our findings provide lead compounds and insights for potential new migraine drug development.

Hypotheses vs. Findings

Target-based drug discovery and rational design are the basis of current drug development. However, these strategies are not suitable for migraine headache drug discovery because the molecular pathologies of migraine are still poorly understood. In this study, we tested the hypothesis that in vivo phenotypic screening might be a good strategy for drug discovery for treating migraine. Corydaline as well as related alkaloids and iridoid glycosides were found to have promising activities for reducing migraine headache by in vivo phenotypic screening of the traditional Chinese medicines Corydalis yanhusuo and Lamiophlomis rotate.

Unanswered Questions

The observed correlation of corydaline alkaloids, blood-brain barrier permeability and their activities for treating migraine were not mechanistically investigated. Due to challenges in sugar chemistry, the structure-activity relationship of iridoid glycosides could not be explored here. The toxicities of corydaline alkaloids and iridoid glycosides have not been systematically investigated and should be before further drug development based on these substances continues.

What this Research Means to You

The funding provided by the Migraine Research Foundation helped us to identify new chemical entities for treating migraine which could provide new lead compounds for future drug development.