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Publication year
2003Source
European Journal of Pharmacology, 464, 2, (2003), pp. 95-100ISSN
Publication type
Article / Letter to editor

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Organization
SW OZ DCC SMN
Former Organization
SW OZ NICI BI
Journal title
European Journal of Pharmacology
Volume
vol. 464
Issue
iss. 2
Page start
p. 95
Page end
p. 100
Subject
Cognitive neuroscienceAbstract
The molecular mechanism underlying the activity of the novel antiepileptic drug retigabine is not yet fully understood. The aim of this study was to investigate whether retigabine interacts directly with the GABAA receptor complex (-aminobutyric acid). Receptor-binding assays were conducted using rat brain membranes. [3H]-t-Butyl-bicyclo-orthobenzoate ([3H]TBOB) was used as a tracer ligand. We determined the effects of GABA and retigabine in the presence of several concentrations of GABA on the binding of [3H]TBOB. GABA inhibited [3H]TBOB binding with an EC50 of 4.8 M. In the absence of GABA, retigabine inhibited [3H]TBOB with an EC50 of 124 M and an EC50 of 42 M in the presence of 2.5 M GABA. Isobolic analysis revealed that retigabine acts in synergy with GABA in displacing [3H]TBOB. This synergy could be quantified by a molecular model in which GABA and retigabine both allosterically displace [3H]TBOB, and retigabine allosterically enhances the binding of GABA and vice versa with a factor of 4. In summary, we found that retigabine does indeed interact with a site on the GABAA receptor complex, and this site is positively allosterically coupled with the GABA site. This GABA-positive effect may well contribute to the clinical anticonvulsive effects of retigabine.
This item appears in the following Collection(s)
- Academic publications [234108]
- Electronic publications [116863]
- Faculty of Social Sciences [29125]
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