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The chiral molecule, methoxetamine (MXE), demonstrated promising biological effects in management of treatment-resistant depression patients. To satisfy the need for a method capable of providing gram quantities of each enantiopure stereoisomer of MXE to enable advanced biological studies of enantiomers, a protocol was developed to access gram scale quantities of (R)- and (S)-MXE in the form of pharmaceutically acceptable HCl salts employingl-(?)-DTTA andd-(+)-DTTA ((?)-O,O′-di-p-toluoyl-l-tartaric acid and (+)-O,O′-di-p-toluoyl-d-tartaric acid, respectively) as two chiral resolving agents. In contrast to ketamine, the measured specific optical rotation and conformational analysis indicated that the most abundant conformers possess a common axial-methoxyphenyl conformation responsible for the conserved direction of optical rotation in both free base and HCl salt forms of the MXE stereoisomers. Finally, the absolute configuration was unambiguously assigned through matching experimental and calculated ECD spectra. This report offers a gateway to obtain gram scale amounts of enantiopure MXE stereoisomers needed to advance the current knowledge on MXE biology.

Besides the abuse of well-known illicit drugs, consumers discovered new synthetic compounds with similar effects but minor alterations in their chemical structure. Originally, these so-called novel psychoactive substances (NPS) have been created to circumvent law of prosecution because of illicit drug abuse. During the past decade, such compounds came up in generations, the most popular compound was a synthetic cathinone derivative named mephedrone. Cathinones are structurally related to amphetamines; to date, more than 120 completely new derivatives have been synthesized and are traded via the Internet. Cathinones possess a chiral center; however, only little is known about the pharmacology of their enantiomers. However, NPS comprise further chiral compound classes such as amphetamine derivatives, ketamines, 2-(aminopropyl)benzofurans, and phenidines. In continuation of our project, a cheap and easy-to-perform chiral capillary zone electrophoresis method for enantioseparation of cathinones presented previously was extended to the aforementioned compound classes. Enantioresolution was achieved by simply adding native β-cyclodextrin, acetyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, or carboxymethyl-β-cyclodextrin as chiral selector additives to the background electrolyte. Fifty-one chiral NPS served as analytes mainly purchased from online vendors via the Internet. Using 10 mM of the aforementioned β-cyclodextrins in a 10 mM sodium phosphate buffer (pH 2.5), overall, 50 of 51 NPS were resolved. However, chiral separation ability of the selectors differed depending on the analyte. Additionally, simultaneous enantioseparations, the determination of enantiomeric migration orders of selected analytes, and a repeatability study were performed successfully. It was proven that all separated NPS were traded as racemic mixtures.

Methoxetamine, a designer drug marketed as a replacement for the dissociative anaesthetic ketamine, has been associated with significant numbers of hospital related intoxications and deaths in Europe. The fast and user-friendly identification and quantification of methoxetamine and its metabolites is a key factor for successful treatment of intoxication. Therefore, we suggested a convenient preparation method which was used for the synthesis of methoxetamine, seven methoxetamine metabolites and a deuterium labelled derivative as analytical standards. Methoxetamine and normethoxetamine were used as starting materials for the preparation of O-demethylated and N-dealkylated metabolites. The multistep synthesis starts from commercially available compounds and offers good yields. Our prepared analytical standards were used for the confirmation of the suggested structure of methoxetamine metabolites in rat urine by LCMS. Capillary electrophoresis was used for the chiral separation of MXE and its metabolites using β-cyclodextrin, carboxymethylated β-cyclodextrin, and sulphated β-cyclodextrin as chiral selectors at various concentrations. Chiral separation was successful for four analytes. A mixture of MXE and its metabolites was subsequently analyzed under optimal conditions, i.e. when using 15 mmol L-1 β-cyclodextrin in 50 mmol L-1 phosphate buffer, pH 2.5. In this case, chiral separation was achieved for three analytes and all analytes were separated from each other.