Discovering the pharmacodynamics of conolidine and cannabidiol using a cultured neuronal network based workflow
AuthorMendis, GDC; Berecki, G; Morrisroe, E; Pachernegg, S; Li, M; Varney, M; Osborne, PB; Reid, CA; Halgamuge, S; Petrou, S
Source TitleSCIENTIFIC REPORTS
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sPetrou, Steven; Reid, Christopher; Halgamuge, Saman; Osborne, Peregrine; Berecki, Geza; Morrisroe, Emma; Li, Melody
AffiliationFlorey Department of Neuroscience and Mental Health
Medicine and Radiology
Melbourne School of Population and Global Health
Anatomy and Neuroscience
Document TypeJournal Article
CitationsMendis, G. D. C., Berecki, G., Morrisroe, E., Pachernegg, S., Li, M., Varney, M., Osborne, P. B., Reid, C. A., Halgamuge, S. & Petrou, S. (2019). Discovering the pharmacodynamics of conolidine and cannabidiol using a cultured neuronal network based workflow. SCIENTIFIC REPORTS, 9 (1), https://doi.org/10.1038/s41598-018-37138-w.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333801
Determining the mechanism of action (MOA) of novel or naturally occurring compounds mostly relies on assays tailored for individual target proteins. Here we explore an alternative approach based on pattern matching response profiles obtained using cultured neuronal networks. Conolidine and cannabidiol are plant-derivatives with known antinociceptive activity but unknown MOA. Application of conolidine/cannabidiol to cultured neuronal networks altered network firing in a highly reproducible manner and created similar impact on network properties suggesting engagement with a common biological target. We used principal component analysis (PCA) and multi-dimensional scaling (MDS) to compare network activity profiles of conolidine/cannabidiol to a series of well-studied compounds with known MOA. Network activity profiles evoked by conolidine and cannabidiol closely matched that of ω-conotoxin CVIE, a potent and selective Cav2.2 calcium channel blocker with proposed antinociceptive action suggesting that they too would block this channel. To verify this, Cav2.2 channels were heterologously expressed, recorded with whole-cell patch clamp and conolidine/cannabidiol was applied. Remarkably, conolidine and cannabidiol both inhibited Cav2.2, providing a glimpse into the MOA that could underlie their antinociceptive action. These data highlight the utility of cultured neuronal network-based workflows to efficiently identify MOA of drugs in a highly scalable assay.
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