Abstracts

Rationale: Tonabersat (TBR) is one of a series of novel benzoylamino benzopyran compounds initially developed for the treatment of migraine and epilepsy. This group of compounds was designed by replacing the 2-pyrrolidinone group of cromakalim with a fluorobenzoylamino group, which introduces anti-seizure activity whilst totally removing potassium channel activator activity. The binding site for these compounds has been primarily detected in the brain, with minimal binding observed in peripheral tissues (eg, liver, heart, kidney). Further, this binding site is distinct from other CNS pharmacologic agents including anti-migraine compounds and antiepileptic drugs (AEDs). Carabersat (CBS), a close analogue of TBR, with a lower affinity for the binding site, demonstrated efficacy in a clinical proof-of-concept study as an adjunctive therapy in the treatment of partial onset seizures. Therefore, TBR was submitted to the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Project (ASP) for evaluation of its anti-seizure properties. Methods: The ASP evaluated TBR for toxicity and anti-seizure properties. In vivo rodent models of generalized tonic-clonic seizures (maximal electroshock [MES]), generalized myoclonic seizures (subcutaneous administration of metrazol), generalized clonic seizures (subcutaneous picrotoxin and bicuculline), focal seizures with secondary generalization (6 Hz), audiogenic seizures (Frings), hippocampal kindled seizures and pharmacoresistant seizures with secondary generalization (lamotrigine [LTG]-resistant kindled) were employed to evaluate the anti-seizure profile of TBR. Toxicity was assessed with the minimal motor impairment scale or rotarod test. The median effective and toxic dose (ED₅₀ and TD₅₀, respectively) at the time of peak anti-seizure effect was calculated using probit analysis. In models where TBR demonstrated efficacy, therapeutic index (TI = TD₅₀/ED₅₀) was calculated. Results: TBR demonstrated a potent oral anti-seizure profile. TBR blocked tonic extension seizures in the MES model with an ED₅₀ = 2.1 mg/kg and a TI >240. This effect was consistent with data observed in the threshold tonic extension model where a dose of TBR (10 mg/kg) was found to elevate tonic hindlimb extension threshold in rats >1000%. Fully expressed seizures in hippocampal- or LTG-resistant kindled rats after supra-maximal stimulation were not inhibited by TBR. Although TBR did not protect against limbic or generalized myoclonic seizures, it was effective against audiogenic seizures with a TI of >2000. Further, TBR demonstrated low toxicity with a TD₅₀ >250 mg/kg (mice) and >500 mg/kg (rats). Conclusions: TBR displayed an anti-seizure profile similar to that of other AEDs (eg, carbamazepine and LTG) but was distinguished by a higher TI. TBR has the ability to prevent seizure spread in models of generalized epilepsy, and therefore may be effective as a treatment for generalized tonic-clonic, complex partial seizures secondarily generalized, and/or partial onset seizures.