Authors :
Presenting Author: Hongjie Yuan, MD, PhD – Emory University School of Medicine
Luke Hodson, PhD – Emory University
Scott Myers, PhD – Emory University School of Medicine
Eva Diaz, BS – Emory University School of Medicine
Aletta van der Westhuyzen, PhD – Emory University
Ken Liu, PhD – Emory University
Yanli Yang, BS – Emory University
Jennifer Wong, PhD – Emory University
Andrew Escayg, PhD – Emory University
Steve Traynelis, PhD – Emory University School of Medicine
Dennis Liotta, PhD – Emory University
Rationale:
Epilepsy has a tremendous adverse impact on quality of life and constitutes an enormous financial burden on families and society. Despite the introduction of dozens of new antiseizure medications, the fraction of patients with seizures refractory to treatment has remained constant at ~30% over the past 30 years. This likely reflects the fact that many newly approved drugs share the same mechanism as existing therapies. Recent clinical evidence supports the use of the natural product cannabidiol (CBD), a non-psychogenic component of Cannabis, as an antiseizure medication that reduces seizures in ~35% of patients with rare, medically refractory epilepsies. CBD interacts with multiple neurotransmitter systems and ion channels distinct from those targeted by existing anticonvulsants, suggesting it acts by a novel mechanism. However, CBD is highly lipophilic and virtually insoluble in aqueous media, necessitating formulation and administration in sesame oil. CBD is poorly absorbed, undergoes significant first-pass metabolism, shows a high liver/brain ratio, produces liver toxicity, can cause gastrointestinal side effects, and is not tolerated in a subset of patients who would otherwise benefit from its actions. These properties reflect a suboptimal pharmacological profile, greatly limiting its clinical utility. Therefore, we developed a strategy to rectify the shortcomings of natural products like CBD and related cannabinoids.
Methods:
We developed novel synthetic procedures to attach unique substituents onto the phenolic hydroxyl groups of CBD and other cannabinoids, building a library of over 150 CBD prodrugs which are cleaved by a variety of mechanisms. Anticonvulsant properties of a set of selected prodrugs were evaluated in vivo using the electroshock model (e.g., 22 mA for 6 Hz electroshock on CF-1 mice).
Results:
Preliminary data show CBD prodrugs enhance aqueous solubility, plasma stability, and oral absorption while reducing hepatic metabolism and liver CBD levels, achieving higher brain concentrations and seizure suppression in vivo. Our lead prodrugs outperform CBD in electroshock models post-IP administration and show greater oral potency for seizure suppression in aqueous solutions versus CBD in sesame oil.
Conclusions:
The data suggests that our lead prodrugs presented have the potential to overcome CBD's limitations and broaden patient applicability.
Funding: NA