Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors
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 toxici...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Journal of Pharmacological Sciences |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S134786132200072X |
| _version_ | 1811334228902674432 |
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| author | Tomohiko Irie Yuta Yanase Yosuke Demizu Makoto Usami Ruri Kikura-Hanajiri |
| author_facet | Tomohiko Irie Yuta Yanase Yosuke Demizu Makoto Usami Ruri Kikura-Hanajiri |
| author_sort | Tomohiko Irie |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T17:05:42Z |
| format | Article |
| id | doaj.art-fc93e92edd564969b33ee9c3eb0669f2 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-04-13T17:05:42Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-fc93e92edd564969b33ee9c3eb0669f22022-12-22T02:38:30ZengElsevierJournal of Pharmacological Sciences1347-86132022-12-011504233243Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptorsTomohiko Irie0Yuta Yanase1Yosuke Demizu2Makoto Usami3Ruri Kikura-Hanajiri4Division of Pharmacology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City, Kanagawa, Japan; Corresponding author.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, JapanDivision 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, JapanGraduate School of Veterinary Medicine, Azabu University, 1-17-1, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa, JapanDivision of Pharmacognosy, Phytochemistry, and Narcotics, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City, Kanagawa, JapanN-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.http://www.sciencedirect.com/science/article/pii/S134786132200072XN-Methyl-D-aspartate receptorsmethoxetaminedeoxymethoxetaminemethoxisopropaminemethoxetamine metabolites |
| spellingShingle | Tomohiko Irie Yuta Yanase Yosuke Demizu Makoto Usami Ruri Kikura-Hanajiri Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors Journal of Pharmacological Sciences N-Methyl-D-aspartate receptors methoxetamine deoxymethoxetamine methoxisopropamine methoxetamine metabolites |
| title | Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors |
| title_full | Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors |
| title_fullStr | Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors |
| title_full_unstemmed | Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors |
| title_short | Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors |
| title_sort | derivatives of methoxetamine and major methoxetamine metabolites potently block nmda receptors |
| topic | N-Methyl-D-aspartate receptors methoxetamine deoxymethoxetamine methoxisopropamine methoxetamine metabolites |
| url | http://www.sciencedirect.com/science/article/pii/S134786132200072X |
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