Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors

Tomohiko Irie; Yuta Yanase; Yosuke Demizu; Makoto Usami; Ruri Kikura-Hanajiri

doi:10.1016/j.jphs.2022.09.005

Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors

J Pharmacol Sci. 2022 Dec;150(4):233-243. doi: 10.1016/j.jphs.2022.09.005. Epub 2022 Sep 28.

Authors

Tomohiko Irie¹, Yuta Yanase², Yosuke Demizu², Makoto Usami³, Ruri Kikura-Hanajiri⁴

Affiliations

¹ Division of Pharmacology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City, Kanagawa, Japan. Electronic address: irie@nihs.go.jp.
² Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City, Kanagawa, Japan; Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa, Japan.
³ Graduate School of Veterinary Medicine, Azabu University, 1-17-1, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa, Japan.
⁴ Division of Pharmacognosy, Phytochemistry, and Narcotics, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City, Kanagawa, Japan.

PMID: 36344045
DOI: 10.1016/j.jphs.2022.09.005

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.

Keywords: N-Methyl-D-aspartate receptors; deoxymethoxetamine; methoxetamine; methoxetamine metabolites; methoxisopropamine.

MeSH terms

Cyclohexanones* / pharmacology
Cyclohexylamines / pharmacology
Receptors, N-Methyl-D-Aspartate* / metabolism

Substances

2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone
cyclohexanone
Cyclohexanones
Receptors, N-Methyl-D-Aspartate
Cyclohexylamines