Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors
Derivatives of methoxetamine and major methoxetamine metabolites potently block NMDA receptors
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甲氧西胺衍生物和主要甲氧西胺代谢物可有效阻断 NMDA 受体
DOI：
10.1016/j.jphs.2022.09.005
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发表时间：
2022
影响因子：
3.5
通讯作者：
Kikura-Hanajiri Ruri
中科院分区：
文献类型：
--
作者：
Irie Tomohiko;Yanase Yuta;Demizu Yosuke;Usami Makoto;Kikura-Hanajiri Ruri
脑中的N-甲基-D-天冬氨酸受体（NMDAR）受精神活性药物如2-（2-氯苯基）-2-（甲氨基）环己-1-酮（氯胺酮）及其类似物2-（乙氨基）-2-（3-甲氧基苯基）-环己酮（甲氧西他明）的影响。娱乐性使用甲氧西他胺可导致多种毒性，也有与甲氧西他胺相关的死亡报告。因此，它在许多国家被禁止。2020年以来，甲氧环丁胺衍生物2-（乙氨基）-2-（间甲苯基）环己-1-酮（脱氧甲氧环丁胺）和2-（异丙氨基）-2-（3-甲氧基苯基）环己-1-酮（甲氧异丙胺）作为设计师药物在网上销售。然而，脱氧甲氧西塔明和甲氧异丙胺如何作用于NMDAR仍然未知。在本研究中，我们首先对NMDAR、脱氧甲氧基乙胺和甲氧基异丙胺以及主要的甲氧基乙胺代谢物2-氨基-2-（3-甲氧基苯基）-环己酮（N-去乙基甲氧基乙胺）和2-（乙氨基）-2-（3-羟基苯基）-环己酮（O-去甲基甲氧基乙胺）进行了硅对接研究。对接研究表明每种化合物都与NMDAR相互作用。我们还使用表达NMDAR的小鼠侧手翻中间神经元和膜片钳记录确定了甲氧西丁胺相关化合物对NMDAR的半数最大抑制浓度（IC 50）。我们发现，甲氧乙胺、脱氧甲氧乙胺、甲氧异丙胺、N-去乙基甲氧乙胺和O-去甲基甲氧乙胺对NMDAR的IC 50分别为0.524、0.679、0.661、1.649和0.227 μM。这些结果表明，甲氧西他胺相关化合物作为有效的NMDAR阻断剂。因此，脱氧甲氧西敏和甲氧异丙胺，这两种药物都可能通过阻断NMDAR而引起损伤，是一个严重的问题。N-去乙基甲氧西敏和O-去甲基甲氧西敏在代谢甲氧西敏时可能引起几种不良反应。
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 performedin silicodocking 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, andO-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 andO-desmethyl methoxetamine may cause several adverse effects when methoxetamine is metabolized.