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In Vivo Characterisation of the Small-Conductance KCa (SK) Channel Activator 1-ethyl-2-benzimidazolinone (1-EBIO) as a Potential Anticonvulsant

In Vivo Characterisation of the Small-Conductance KCa (SK) Channel Activator 1-ethyl-2-benzimidazolinone (1-EBIO) as a Potential Anticonvulsant

Neil J Anderson, Scott Slough, William P Watson

Eur J Pharmacol. 2006 Sep 28;546(1-3):48-53.

PMID: 16925994

Abstract:

Owing to their activation by increased intracellular Ca(2+) levels following burst firing, and the resultant hyperpolarisation and dampening of neuronal excitability, the small-conductance Ca(2+)-activated K(+) (SK(Ca)) channels have been proposed as a potential target for novel antiepileptic drugs. Indeed, the channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) has been shown to reduce epileptiform activity in vitro. Accordingly, this study has investigated the therapeutic potential of 1-EBIO using a range of in vivo seizure models, and assessed the adverse effect liability with the rotarod and locomotor activity paradigms. To aid benchmarking of 1-EBIO's therapeutic and adverse effect potential, it was tested alongside two currently marketed antiepileptic drugs, phenytoin and levetiracetam. 1-EBIO was found to be effective at reducing seizure incidence in mice following maximal electroshock (ED(50) 36.0 mg/kg) as well as increasing the threshold to electrically- and pentylenetetrazole-induced seizures (TID(10)s 7.3 and 21.5 mg/kg, respectively). However, results from the mouse rotarod test revealed a strong adverse effect potential within the therapeutic dose range (ID(50) 35.6 mg/kg), implying a significantly inferior therapeutic index with respect to the comparator compounds. These results, therefore, support the in vitro data detailing 1-EBIO's reduction of epileptiform activity. However, the use of in vivo models has revealed a significant adverse effect potential within the therapeutic dose range. Nevertheless, given the multiplicity of SK(Ca) channel subunits and that 1-EBIO has been shown to enhance additional, non-SK(Ca) carried currents, these findings do not preclude the possibility that more selective enhancers of SK(Ca) function could prove to be effective as antiepileptic medications.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP10045451	1-EBIO		10045-45-1	Price

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