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.
Lysergic acid diethylamide (LSD) is a hallucinogen that activates the serotonin 2A receptor and is a controlled substance in Japan. Recently, MiPLA, an N-methyl-N-isopropyl derivative of LSD, has appeared in paper-sheet products in several countries. This work describes the three-step synthesis of MiPLA starting from ergometrine maleate, which also produced the (8S)-isomer, iso-MiPLA, as a by-product. Liquid chromatography-mass spectrometry showed that LSD, MiPLA, and iso-MiPLA have different retention times. Nuclear magnetic resonance spectroscopy determined their chemical structures and revealed rotamers involving the N-methyl-N-isopropyl groups of tertiary amides in MiPLA and iso-MiPLA.