Cannabinoid‐like compounds found in non‐cannabis plants exhibit antiseizure activity in genetic mouse models of drug‐resistant epilepsy.

Objective: The cannabinoid cannabidiol has established antiseizure effects in drug‐resistant epilepsies such as Dravet syndrome and Lennox–Gastaut syndrome. Amorfrutin 2, honokiol, and magnolol are structurally similar to cannabinoids (cannabis‐like drugs) but derive from non‐cannabis plants. We aimed to study the antiseizure potential of these compounds in various mouse seizure models. In addition, we aimed to characterize their molecular pharmacology at cannabinoid CB1 and CB2 receptors and at T‐type calcium channels, which are known targets of the cannabinoids. Methods: Brain and plasma pharmacokinetic profiles were determined. Antiseizure activity was assessed against hyperthermia‐induced seizures in a Scn1a+/− mouse model of Dravet syndrome. We then elaborated on the most promising compounds in the maximal electroshock (MES) test in mice and the Gabrb3+/D120N mouse model of Lennox–Gastaut syndrome. Fluorescence‐based assays were used to examine modulatory activity at cannabinoid CB1 and CB2 receptors and T‐type calcium channel subtypes CaV3.1, CaV3.2, and CaV3.3 overexpressed in mammalian cells. Automated patch‐clamp electrophysiology was then used to confirm inhibitory activity on CaV3.1, CaV3.2, and CaV3.3 channels. Results: Magnolol and honokiol had high brain‐to‐plasma ratios (3.55 and 7.56, respectively), unlike amorfrutin 2 (0.06). Amorfrutin 2 and magnolol but not honokiol significantly increased the body temperature threshold at which Scn1a+/− mice had a generalized tonic–clonic seizure. Both amorfrutin 2 and magnolol significantly decreased the proportion of mice exhibiting hindlimb extension in the MES test. Furthermore, magnolol reduced the number and duration of atypical absence seizures in Gabrb3+/D120N mice. The three compounds inhibited all T‐type calcium channel subtypes but were without specific activity at cannabinoid receptors. Significance: We show for the first time that amorfrutin 2 and magnolol display novel antiseizure activity in mouse drug‐resistant epilepsy models. Our results justify future drug discovery campaigns around these structural scaffolds that aim to develop novel antiseizure drugs for intractable epilepsies. [ABSTRACT FROM AUTHOR]