Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors.

Methoxetamine and its derivatives deoxymethoxetamine and methoxisopropamine, sold online as designer drugs, block N-methyl-D-aspartate receptors (NMDARs) in the brain. Computer docking simulations suggested these compounds interact with NMDARs. Using patch-clamp recordings from mouse neurons expressing NMDARs, the half-maximal inhibitory concentrations (IC50s) were determined: methoxetamine 0.524 μM, deoxymethoxetamine 0.679 μM, methoxisopropamine 0.661 μM, and the methoxetamine metabolites N-desethyl methoxetamine 1.649 μM and O-desmethyl methoxetamine 0.227 μM. All acted as potent NMDAR blockers, indicating that deoxymethoxetamine and methoxisopropamine may cause harm by blocking these receptors, and the metabolites may contribute to adverse effects when methoxetamine is metabolized.

Study at a glance

Abstract

N-Methyl-D-aspartate receptors (NMDARs) in the brain are influenced by psychoactive drugs such as 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (ketamine) and its analog 2-(ethylamino)-2-(3-methoxyphenyl)-cyclohexanone (methoxetamine). The recreational methoxetamine use can cause several toxicities and methoxetamine-related deaths have also been reported. Therefore, it has been banned in many countries. Since 2020, methoxetamine derivatives, 2-(ethylamino)-2-(m-tolyl)cyclohexan-1-one (deoxymethoxetamine) and 2-(isopropylamino)-2-(3-methoxyphenyl)cyclohexan-1-one (methoxisopropamine), have been sold online as designer drugs. However, how deoxymethoxetamine and methoxisopropamine act on NMDARs remains unknown. In this study, we first performed in silico docking studies of NMDARs, and deoxymethoxetamine and methoxisopropamine in addition to the major methoxetamine metabolites, 2-amino-2-(3-methoxyphenyl)-cyclohexanone (N-desethyl methoxetamine) and 2-(ethylamino)-2-(3-hydroxyphenyl)-cyclohexanone (O-desmethyl methoxetamine). The docking study suggested each compound interacts with NMDARs. We also determined the half-maximal inhibitory concentration (IC50s) of the methoxetamine-related compounds for NMDARs using NMDAR-expressing cartwheel interneurons of mice and patch-clamp recordings. We found that the IC50s of methoxetamine, deoxymethoxetamine, methoxisopropamine, N-desethyl methoxetamine, and O-desmethyl methoxetamine for NMDARs were 0.524, 0.679, 0.661, 1.649, and 0.227 μM, respectively. These results indicate that the methoxetamine-related compounds act as potent NMDAR blockers. Thus, deoxymethoxetamine and methoxisopropamine, both of which may cause damage by blocking NMDARs, are serious concerns. N-Desethyl methoxetamine and O-desmethyl methoxetamine may cause several adverse effects when methoxetamine is metabolized.