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The clobazam metabolite N-desmethyl clobazam is an ?2 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 ?2-subtype GABAA receptors (?2GABAAR) 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 ?1GABAARs and antihyperalgesic ?2GABAARs with similar efficacies, whereas NDMC preferred ?2GABAARs over ?1GABAARs 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 ?1GABAARs. 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 ?2/?1 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.

SUBMITTER: Ralvenius WT

PROVIDER: S-EPMC4981430 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Ralvenius William T WT Acuña Mario A MA Benke Dietmar D Matthey Alain A Daali Youssef Y Rudolph Uwe U Desmeules Jules J Zeilhofer Hanns Ulrich HU Besson Marie M

Neuropharmacology 20160705

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 ...[more]

PMID: 27392635

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Dataset Information

The clobazam metabolite N-desmethyl clobazam is an ?2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia.

Publications

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

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