Antiepileptic potential of cannabidiol analogs.

In audiogenic seizure (AGS) susceptible rats, the acute (intraperitoneal and intravenous) dose-response effects of (--)-cannabidiol (CBD) for preventing AGS and for causing rototod neurotoxicity (ROT) were determined. Also, the anti-AGS and ROT effects of 10 CBD analogs, given in intravenous doses equivalent to the AGS-ED50 (15 mg/kg) and ROT-ID50 (31 mg/kg) of CBD, were ascertained. Compared to CBD, (--)-CBD diacetate and (--)-4-(2'-olivetyl)-alpha-pinene were equally effective whereas (--)-CBD monomethyl ether, (--)-CBD dimethyl ether, (--)-3'-acetyl-CBD monoacetate, (+)-4-(2'-olivetyl)-alpha-pinene, (--)-and (+)-4-(6'-olivetyl)-alpha-pinene, (+/-)-AF-11, and olivetol were less effective anticonvulsants. Except for (--)- and (+)-4-(2'-olivetyl)-alpha-pinene and olivetol, all analogs showed less ROT than CBD. Also, CBD and all analogs were not active in tetrahydrocannabinol seizure-susceptible rabbits, the latter a putative model of cannabinoid psychoactivity in humans. These data suggest anticonvulsant requirements of 2 free phenolic hydroxyl groups, exact positioning of the terpinoid moiety in the resorcinol system and correct stereochemistry. Moreover, findings of separation of anticonvulsant from neurotoxic and psychoactive activities, notably with CBD diacetate, suggest that additional structural modifications of CBD may yield novel antiepileptic drugs.