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CNS 7056X, an ultra-short acting benzodiazepine: sedation profile in the rodent

Gavin J Kilpatrick¹, Robert P Wiard², Jeffrey A Stafford², Paul L Feldman² and Gary S Tilbrook¹. ¹CeNeS Limited, Compass House, Vision Park, Histon, Cambridge, Cambs, United Kingdom CB4 9ZR. ²GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA .

Introduction: Midazolam is a widely used benzodiazepine to induce conscious sedation for surgical and non-surgical procedures. However the variability in duration of action (due to the formation of active metabolites) is a highly undesirable feature of the compound. In order to address this deficiency a new benzodiazepine derivative, CNS 7056X, has been developed to permit a more predictable fast-onset, short duration of action and faster recovery time profile. This has been achieved by rendering the new compound susceptible to enzymatic hydrolysis via widespread non-specific tissue esterases to limit the action of the compound. This approach has been clinically proven with the short-acting opioid analgesic, remifentanil. We now report the present data on the sedative/anaesthetic profile of CNS 7056X in rat and mouse.

Methods: Male Wistar rats (300-400g) or male Rj:NMRIU mice (20-30g) were used. For loss of righting reflex (LRR) the test compound was administered intravenously via the tail vein. The times to onset of LRR and recovery of LRR were recorded. Some mice were pre-treated with flumazenil (20mg/kg i.p.) 15min prior to administration of CNS 7056X

Results: Intravenous administration of both midazolam (25mg/kg) and CNS 7056X (25mg/kg) brought about an immediate loss of the righting reflex in rats. Recovery from the LRR was observed after 9.61±0.53min (mean±s.e.m., n=6) for rats treated with CNS 7056X and after 24.62±2.46min (mean±s.e.m., n=6) for rats treated with midazolam. Intravenous administration of CNS 7056X (15-30 mg/kg; n=8) brought about a rapid LRR in mice (Table 1). The duration of LRR was short. Pre-treatment with flumazenil (20 mg/kg) significantly reduced the LRR duration (0.7±0.7 min) induced by CNS 7056X (30mg/kg; 8.4±2.6 min; p=0.013) in mice.

Conclusions: CNS 7056X induced LRR in rodents. The onset of action was rapid and the duration of LRR short. The duration of LRR in rats was shorter than that seen after administration of the same dose of midazolam. Pre-treatment of mice with flumazenil blocked the LRR induced by CNS 7056X.

Results are mean ± s.e.m. (n=8).