Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy

Abstract

Slobodan M Janković,1 Miralem Dješević,2 Snežana V Janković1 1Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia; 2Cardiology Department, Private Policlinic Center Eurofarm, Sarajevo, Bosnia and HercegovinaCorrespondence: Slobodan M JankovićUniversity of Kragujevac, Faculty of Medical Sciences, Svetozara Markovića 69 Street, Kragujevac, 34000, SerbiaEmail [email protected]: GABA A receptors are ubiquitous in the central nervous system and there is a huge diversity of receptor subtypes in almost all regions of the brain. However, the expression of GABA A receptor subtypes is altered in both the gray and white matter of patients with focal epilepsy. Although there is a number of anticonvulsants with marketing authorization for the treatment of focal epilepsy which act through GABA A receptors, potentiating the inhibitory effects of GABA, it is necessary to develop more potent and more specific GABAergic anticonvulsants that are effective in drug-resistant patients with focal epilepsy. There are three orthosteric and at least seven allosteric agonist binding sites at the GABA A receptor. In experimental and clinical studies, full agonists of GABA A receptors showed a tendency to cause desensitization of the receptors, tolerance, and physical dependence; therefore, partial orthosteric agonists and positive allosteric modulators of GABA A receptors were further developed. Preclinical studies demonstrated the anticonvulsant efficacy of positive allosteric modulators with selective action on GABA A receptors with α2/α3 subunits, but only a handful of them were further tested in clinical trials. The best results were obtained for clobazam (already marketed), ganaxolone (in phase III trials), CVL-865 (in phase II trials), and padsevonil (in phase III trials). Several compounds with more selective action on GABA A receptors, perhaps only in certain brain regions, have the potential to become effective drugs against specific subtypes of focal-onset epilepsy. However, their development needs time, and in the near future we can expect only one or two new GABA A agonists to obtain marketing authorization for focal epilepsy, an advance that would be of use for just a fraction of patients with drug-resistant epilepsy.Keywords: GABA A receptors, positive allosteric modulators, focal-onset epilepsy

Keywords

• gaba a receptors
• positive allosteric modulators
• focal onset epilepsy