GABA(A) receptor physiology and its relationship to the mechanism of action of the 1,5-benzodiazepine clobazam.

Clobazam was initially developed in the early 1970s as a nonsedative anxiolytic agent, and is currently available as adjunctive therapy for epilepsy and anxiety disorders in more than 100 countries. In October 2011, clobazam (Onfi™; Lundbeck Inc., Deerfield, IL, USA) was approved by the US FDA for use as adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome in patients aged 2 years and older. It is a long-acting 1,5-benzodiazepine whose structure distinguishes it from the classic 1,4-benzodiazepines, such as diazepam, lorazepam and clonazepam. Clobazam is well absorbed, with peak concentrations occurring linearly 1-4 hours after administration. Both clobazam and its active metabolite, N-desmethylclobazam, are metabolized in the liver via the cytochrome P450 pathway. The mean half-life of N-desmethylclobazam (67.5 hours) is nearly double the mean half-life of clobazam (37.5 hours). Clobazam was synthesized with the anticipation that its distinct chemical structure would provide greater efficacy with fewer benzodiazepine-associated adverse effects. Frequently reported adverse effects of clobazam therapy include dizziness, sedation, drowsiness and ataxia. Evidence gathered from approximately 50 epilepsy clinical trials in adults and children indicated that the sedative effects observed with clobazam treatment were less severe than those reported with 1,4-benzodiazepines. In several studies of healthy volunteers and patients with anxiety, clobazam appeared to enhance participants' performance in cognitive tests, further distinguishing it from the 1,4-benzodiazepines. The anxiolytic and anticonvulsant effects of clobazam are associated with allosteric activation of the ligand-gated GABA(A) receptor. GABA(A) receptors are found extensively throughout the CNS, occurring synaptically and extrasynaptically. GABA(A) receptors are composed of five protein subunits, two copies of a single type of α subunit, two copies of one type of β subunit and a γ subunit. This arrangement results in a diverse assortment of receptor subtypes. As benzodiazepine pharmacology is influenced by differences in affinity for particular GABA(A) subtypes, characterizing the selectivity of different benzodiazepines is a promising avenue for establishing appropriate use of these agents in neurological disorders. Molecular techniques have significantly advanced since the inception of clobazam as a clinical agent, adding to the understanding of the GABA(A) receptor, its subunits and benzodiazepine pharmacology. Transgenic mouse models have been particularly useful in this regard. Comparative studies between transgenic and wild-type mice have further defined relationships between GABA(A) receptor composition and drug effects. From such studies, we have learned that sedating and amnesic effects are mediated by the GABA(A) α(1) subunit, α(2) receptors mediate anxiolytic effects, α subunits are involved with anticonvulsant activity, α(5) may be implicated in learning and memory, and β(3) subunit deficiency decreases GABA inhibition. Despite progress in determining the role of various subunits to specific benzodiazepine pharmacological actions, the precise mechanism of action of clobazam, and more importantly, how that mechanism of action translates into clinical consequences (i.e. efficacy, tolerability and safety) remain unknown. Testing clobazam and 1,4-benzodiazepines using a range of recombinant GABA(A) receptor subtypes would hopefully elucidate the subunits involved and strengthen our understanding of clobazam and its mechanism of action.