MEPIRAPIM-derived compounds potently inhibited T-type calcium channels and were brain-penetrant, but showed divergent effects across different epilepsy models.
Epilepsy researchers, ion channel pharmacologists, and medicinal chemists developing Cav3 inhibitors.
2.7 brain/plasma ratiofor SB2193, showing excellent brain penetration, but divergent seizure effects across epilepsy models
What the researchers found
SB2193 and SB2193F potently inhibited Cav3 channels with minimal CB1 activity. SB2193 protected against 6-Hz seizures but did not reduce seizures in Dravet syndrome or absence epilepsy models, and unexpectedly increased absence seizure activity.
Why it matters
T-type calcium channels are promising drug targets for epilepsy and pain, and these findings show that cannabinoid scaffolds can be modified to selectively target these channels, though clinical application requires careful seizure-type matching.
The numbers in context
SB2193 brain/plasma ratio: 2.7 (brain-penetrant). Acutely protected against 6-Hz induced seizures. Increased spike-and-wave discharge incidence and duration in GAERS absence epilepsy model over 4 hours.
How the study worked
In vitro calcium flux assay and patch-clamp electrophysiology, in silico docking, in vivo pharmacokinetics in mice, and anticonvulsant testing in 6-Hz, Scn1a+/- Dravet, and GAERS absence epilepsy models.
Who was studied
In vitro cell systems, mouse pharmacokinetic studies, and three rodent epilepsy models (6-Hz mice, Scn1a+/- Dravet mice, GAERS rats).
What this study cannot tell us
Divergent effects across seizure models complicate clinical development. Mechanism of increased absence seizures unclear. Limited to two compounds tested. Long-term safety not assessed.
How to read the evidence
Comprehensive preclinical characterization across multiple models, revealing both promise and important limitations.
When this study was published
Recent preclinical research in cannabinoid-derived ion channel pharmacology.
The bigger picture
This study demonstrates that cannabinoid chemical scaffolds can be repurposed to create selective calcium channel blockers, but the divergent seizure effects highlight the complexity of developing broad-spectrum anti-seizure medications.
Replication
Novel compounds; further optimization and testing needed.
Funding
Not specified in abstract
Conflicts of interest
Not specified in abstract
Questions still open
- Why did T-type channel inhibition worsen absence seizures despite the accepted role of these channels in absence epilepsy?
- Can further structural modifications eliminate the pro-seizure effects while retaining anti-seizure activity?
Read the original research
MEPIRAPIM-derived synthetic cannabinoids inhibit T-type calcium channels with divergent effects on seizures in rodent models of epilepsy.
Frontiers in physiology, 14, 1086243
Citation
Harman, Thomas; Udoh, Michael; McElroy, Dan L; Anderson, Lyndsey L; Kevin, Richard C; Banister, Samuel D; Ametovski, Adam; Markham, Jack; Bladen, Chris; Doohan, Peter T; Greba, Quentin; Laprairie, Robert B; Snutch, Terrance P; McGregor, Iain S; Howland, John G; Arnold, Jonathon C. (2023). MEPIRAPIM-derived synthetic cannabinoids inhibit T-type calcium channels with divergent effects on seizures in rodent models of epilepsy.. Frontiers in physiology, 14, 1086243. https://doi.org/10.3389/fphys.2023.1086243