The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

Introduction

Novel synthetic psychoactive drugs sold via the internet have raised concerns because many lack formal toxicology profiles. Roth and colleagues describe three classes of emerging ‘‘designer’’ dissociative drugs: methoxetamine (an analogue of ketamine), 3-methoxy-eticyclidine (3-MeO-PCE, a deoxy-analogue of methoxetamine), and two methoxy-substituted phencyclidine analogues (3-MeO-PCP and 4-MeO-PCP). These compounds have been used as legal alternatives to controlled dissociatives and reportedly produce effects in humans similar to ketamine and PCP, including euphoria, dissociation, hallucinations and, in some cases, sympathomimetic toxicity and reversible cerebellar injury. Ketamine and PCP exert major actions as non-competitive antagonists at the NMDA (N-methyl-D-aspartate) subtype of glutamate receptors, and the behavioural similarity of the novel analogues has led to the hypothesis that they act at the same target(s). The introduction also notes established harms of chronic ketamine use (for example ulcerative cystitis) and emphasises the current lack of knowledge about long-term effects of the new analogues. This study set out to characterise the neurochemical profiles of methoxetamine and several methoxy-substituted PCP analogues and to compare them with ketamine, PCP and other reference compounds. Using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP), the investigators obtained receptor binding and functional data across a broad panel of central nervous system targets. Chemical identity and purity of the tested samples were confirmed prior to pharmacological screening, allowing comparison of affinity profiles and identification of additional off-target interactions that might underlie adverse effects or distinguish these analogues from their parent drugs.