Development of Novel Cannabinoid Derived Therapeutics for the Treatment of Refractory Epilepsy
Abstract number :
1.393
Submission category :
7. Anti-seizure Medications / 7E. Other
Year :
2025
Submission ID :
1012
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Luke Hodson, PhD – Emory University
Scott Myers, PhD – Emory University School of Medicine
Eva Diaz, BS – Emory University School of Medicine
Mario Rivera, PhD – Emory University
Hyungyu Lee, BS – Emory University
Paul Joseph Tholath, MS – Emory University
Ken Liu, PhD – Emory University
Aletta van der Westhuyzen, PhD – Emory University
Yanli Yang, BS – Emory University
Samantha Burton, BS – Emory University
Hongjie Yuan, MD, PhD – Emory University School of Medicine
Steve Traynelis, PhD – Emory University School of Medicine
Dennis Liotta, PhD – Emory University
Rationale: Epidiolex® reduces seizure burden in approximately 35% of patients with rare, medically refractory epilepsies, including Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex (TSC). Cannabidiol (CBD) acts on multiple neurotransmitter systems and ion channels with known antiseizure properties such as Kv7, TRPV1, and GPR55. These systems are not targeted by traditional antiseizure medications, which distinguishes CBD and suggests that it possesses a novel mechanism of action. However, despite its promising anticonvulsant effects, CBD’s clinical use is hampered by several key limitations including poor aqueous solubility, low oral bioavailability (6–19%) due to extensive first-pass metabolism by CYP450 enzymes, variable patient responses, and the significant potential for drug-drug interactions. To address these challenges, we have designed and synthesized novel CBD analogs by strategically modifying key metabolic hotspots in the cannabinoid scaffold. This approach enhances resistance to metabolic degradation while simultaneously improving critical drug properties such as solubility, CYP450 inhibition, oral bioavailability and antiseizure potency.
Methods: Advanced synthetic methodologies were employed to overcome the inherent challenges of cannabinoid synthesis. The in vitro, pharmacokinetic and anticonvulsant properties of the CBD analogs were evaluated on CF-1 and CD-1 mice using the 6 Hz and maximal electroshock models respectively.
Results: Our strategy yielded new chemical entities with several significant improvements over CBD including reduced CYP450-mediated metabolism, enhanced aqueous solubility, decreased CYP enzyme inhibition (minimizing drug-drug interactions), improved pharmacokinetic profiles and superior anticonvulsant efficacy in vivo following oral administration in multiple antiseizure models.
Conclusions: These novel CBD analogs represent a promising solution to the limitations of CBD. By offering improved efficacy, safety, and pharmacokinetics, these new drug candidates have the potential to benefit patients with refractory epilepsies who do not respond to Epidiolex®, as well as those with other challenging epileptic disorders such as developmental epileptic encephalopathy (DEE).
Funding: NA
Anti-seizure Medications