The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia

Abstract

Data from genetically modified mice suggest that benzodiazepine (BDZ)-site agonists with improved selectivity for α2-subtype GABAA receptors (α2GABAAR) are potentially useful for the treatment of neuropathic pain. Subtype-selective compounds available for preclinical tests in rodents support this concept but have not been approved for human use, hindering proof-of-concept studies in patients. We recently proposed that N-desmethyl clobazam (NDMC), the main metabolite of the licensed BDZ clobazam (CBZ), is responsible for most of the antihyperalgesia observed in mice after CBZ administration. In order to assess a potentially favorable pharmacological profile of NDMC, we analyzed differences in the GABAAR subtype specificity of CBZ, NDMC and diazepam (DZP) in recombinant receptors. DZP and CBZ potentiated sedating α1GABAARs and antihyperalgesic α2GABAARs with similar efficacies, whereas NDMC preferred α2GABAARs over α1GABAARs across a wide concentration range. In vivo, DZP and NDMC reduced neuropathic pain at doses between 3 and 30 mg/kg. At these doses, DZP had strong locomotor sedating effects while NDMC caused no or only weak sedation. Sedative effects of NDMC became apparent when the action of NDMC was restricted to α1GABAARs. However, when GABAAR point-mutated mice were studied that allow the analysis of antihyperalgesia and sedation in isolation, we found that, compared to DZP, NDMC had a significantly improved therapeutic window, consistent with its more favorable α2/α1 in vitro activity ratio. Given that NDMC should share the safety profile of its parent compound CBZ, it should be well-suited for proof-of-concept studies in human volunteers or patients.

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet syndrome

“…The commonly prescribed AED and anxiolytic medication CLB is a 1,5‐BDZ that is known to be metabolized in vivo to active N ‐desmethyl clobazam (N‐CLB) which has modest preference for α 2 /α 3 containing receptors (Ralvenius et al . ; but also see Jensen et al . ; Hammer et al .…”

“…Several PAMs selective for the α 2 /α 3 subunits have been developed including L-838,417 (α 1 -sparing PAM) (McKernan et al 2000;Knabl et al 2008), TCS1105 (Taliani et al 2009), AZD7325 (Alhambra et al 2011;Zhou et al 2012) and PF-06372865 Nickolls et al 2018), although none of these is currently in clinical use as an AED. The commonly prescribed AED and anxiolytic medication CLB is a 1,5-BDZ that is known to be metabolized in vivo to active N-desmethyl clobazam (N-CLB) which has modest preference for α 2 /α 3 containing receptors (Ralvenius et al 2016; but also see Jensen et al 2014;Hammer et al 2015).…”

Etiology and Pharmacology of Neuropathic Pain

“…It is known, however, that different subtypes of GABA A receptor localize with different cell types and terminals in the spinal dorsal horn. In particular, GABA A receptors containing the a2 subunit associate with C fibers (Paul et al, 2012), and this has led to the notion that benzodiazepines with high affinity for a2 may be effective in treating neuropathic pain (Besson et al, 2013;Paul et al, 2014;Ralvenius et al, 2016). One such agent, clobazam (Besson et al, 2013), which acts through an active metabolite (Ralvenius et al, 2016), is effective in relieving allodynia in the CCI model (Besson et al, 2013).…”

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet Syndrome

“…Several PAMs selective for the α 2 / α 3 subunits have been developed including L-838,417 (α 1 -sparing PAM) (McKernan et al, 2000;Knabl et al, 2008), TCS1105 (Taliani et al, 2009), AZD7325 (Alhambra et al, 2011;Zhou et al, 2012), and PF-06372865 (Gurrell et al, 2018;Nickolls et al, 2018), although none of these are currently in clinical use as an AED. The commonly prescribed AED and anxiolytic medication clobazam (CLB) is a 1,5-BDZ that is known to be metabolized in vivo to active N-desmethyl clobazam (N-CLB) that has modest preference for α 2 / α 3 containing receptors (Ralvenius et al, 2016) (but, also see (Jensen et al, 2014)).…”