A potential of methoxpropamine to be a widespread recreational drug: it blocks NMDA receptors and inhibits NMDA receptor-mediated synaptic transmission in a brain preparation of mice

Abstract

The activity of N-methyl-d-aspartate (NMDA) receptors in the central nervous system is affected by many psychoactive drugs, such as 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (ketamine) and its analog 2-(3-methoxyphenyl)-2-(amino)cyclohexan-1-one (methoxetamine, MXE). Recreational use of MXE can cause acute toxicity, such as dissociative state and tachycardia. After MXE use, confusion, agitation, ataxia, and nystagmus are induced. Moreover, MXE-related deaths have been reported, and this compound is banned in many countries. Recently, MXE’s derivative, 2-(3-methoxyphenyl)-2-(propylamino)cyclohexan-1-one (methoxpropamine, MXPr), was reported as a new psychoactive substance and sold online as a designer drug. The aims were to determine how MXPr affects NMDA receptors in neurons and to compare the potency with MXE. Cartwheel cells in the dorsal cochlear nucleus of mice were used as a model of NMDA receptor-expressing neurons, and patch-clamp method was performed for the recordings. NMDA-induced inward current was initially evoked by microiontophoresis application of NMDA onto the cartwheel cells, and the effects of MXPr, MXE, and (5R,10S)-(\u2009+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801, as a positive control substance) on NMDA-induced response were examined. Moreover, the effects of MXPr on NMDA receptor-mediated excitatory postsynaptic currents were also investigated. The IC50 of MXPr, MXE, and MK-801 on NMDA-induced response decreased in the following order: MXPr (1.647 μM)\u2009>\u2009MXE (0.841 μM)\u2009>\u2009MK-801 (0.060 μM), indicating that MXPr and MXE act as potent antagonists of NMDA receptors. MXPr suppressed NMDA receptor-mediated excitatory synaptic transmission in a dose-dependent manner. MXPr, which may cause health and social damages to humans by blocking NMDA receptors, is a serious concern like MXE.