Determination of the Hypnotic Potency in Rats of the Novel Ketamine Ester Analogue SN 35210

Background: Ketamine is a rapidly acting dissociative anaesthetic drug with additional sympathomimetic, analgesic, and antidepressant properties. Despite these advantages, clinical use is curtailed by prolonged psychomimetic effects apparent over the entire dose spectrum. In this study, we report on the hypnotic potency of SN 35210, the first ketamine ester-analogue designed for rapid offset via esterase-mediated hydrolysis. Methods: Thirty-three adult Sprague Dawley rats received intravenous racemic ketamine (n = 14), racemic SN 35210 (n = 19), S-enantiomer SN 35210 (n = 17), or R-enantiomer SN 35210 (n = 15), in crossover design. The ability to induce loss of righting reflex (LORR) at a given dose, the duration of righting reflex loss, and the time to return of normal behaviours were recorded. The ED50 for LORR was determined for all agents. Results: The ED50 for righting reflex loss was racemic ketamine 9.6 (95% CI 8.5-10.9) mg/kg, racemic SN 35210 10.4 (95% CI 9.5-11.5) mg/kg, S-enantiomer SN 35210 10.6 (95% CI 9.1-11.8), and R-enantiomer SN 35210 10.3 (95% CI 9.1-11.4) mg/kg. The duration of righting reflex loss and time to return to normal behaviours were approximately 5 times greater for racemic ketamine than all 3 SN 35210 ester analogues. Conclusions: Racemic, and R and S-enantiomer SN 35210, produced LORR in rats at similar doses to the parent compound ketamine. The duration of righting reflex loss, and duration of behavioural aberration, was significantly reduced for all SN 35210 analogues.