Carvone derived cannabidiol enantiomers as novel anticonvulsants

Developmental epilepsy syndromes are characterized by recurrent seizures and developmental delays. Current anticonvulsants target γ-aminobutyric acid type A receptor signaling to decrease neuronal excitability, however, there are adverse effects for the developing brain, and many patients are refractory. The major non-psychotropic phytocannabinoid cannabidiol (CBD) has emerged as an anti-seizure medication effective in select developmental epilepsy syndromes, but its overall applicability in treating seizure disorders is limited. In the present study, we characterize a small library of non-Cannabis carvone derived CBD (+) enantiomers, with the larger goal of identifying novel therapeutics for developmental epilepsy syndromes. EEG based structure activity relationship assessment supports that elongated alkyl chains increase the potency of the congeners, with (+)-CBD-oct displaying effects on both δ and θ frequency bands. Pre-treatment with (+)-CBD-oct promotes seizure resilience in both wildtype mice and the Gabra2-1 model of developmental epilepsy by influencing seizure characteristics, and reduces mortality. 5 days of (+)-CBD-oct oral gavage in wildtype and Gabra2-1 mice during postnatal development normalizes the aberrant dendritic spine phenotype of Gabra2-1 mice. These findings advance the development of novel anticonvulsants by validating an influence of alkyl chain length of synthetic CBD congeners.