Pharmacokinetic, pharmacodynamic, and behavioural studies of deschloroketamine (DCK) in Wistar rats

Deschloroketamine (DCK), a structural analogue of ketamine, has recently emerged on the illicit drug market as a recreational drug with a modestly long duration of action. Despite it being widely used by recreational users, no systematic research on its effects has been performed to-date. For this reason, we investigated the pharmacokinetic, pharmacodynamic, and behavioural battery of test in Wistar rats to find implications for understanding the risks associated with the illicit use of deschloroketamine. The structural similarity of widely used ketamine rise the hypothesis, whether deschloroketamine may be promising candidate for an antidepressant with a rapid onset. Pharmacokinetics, acute effects and addictive potential in a series of behavioural tests in Wistar rats were performed following subcutaneous (s.c.) administration of DCK (5, 10, and 30 mg/kg) and its enantiomers S-DCK (10 mg/kg) and R-DCK (10 mg/kg). Behavioural experiments [open field test, prepulse inhibition (PPI) of acoustic startle response (ASR), conditioned place preference] have a standardised design in order to obtain comparable data, therefore female rats were not tested. DCK also served as a reference standard for pharmacokinetic analyses using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). DCK was subjected to chiral separation using a chiral amylosebased column. The enantiopurity of both enantiomers was verified (> 99% for both enantiomers) by the LC-UV system in the analytical mode. The absolute configuration was determined using a combination of ab initio calculation with circular dichroism spectral comparison and single crystal data. Analytical standards of metabolites (nordeschloroketamine, trans-dihydrodeschloroketamine, cis-dihydronordeschloroketamine, trans-dihydronordeschloroketamine and trans-dihydrodeschloroketamine-d4) have been synthetized in house. R-DCK and S-DCK were assessed on recombinant human hGluN1/hGluN2A or hGluN1/hGluN2B receptors expressed in HEK293 cells. DCK rapidly crosses the blood brain barrier, with maximum brain levels achieved at 30 min and remaining high at 2 hours after administration. Its antagonist activity at NMDA receptors is comparable to the ketamine with S-DCK being more potent. DCK had stimulatory effects on locomotion, induced place preference, and robustly disrupted PPI. Locomotor stimulant effects tended to disappear more quickly than disruptive effects on PPI. S-DCK had more pronounced stimulatory properties than its counterpart. However, the potency in disrupting PPI was comparable in both enantiomers. DCK shows similar behavioural and addictive profiles and pharmacodynamics to ketamine, with S-DCK being in general more active. It has a slightly slower pharmacokinetic profile than ketamine, which is consistent with its reported longer duration of action. The findings have implications and significance for understanding the risks associated with the illicit use of DCK.