Ketamine is analgesic at anesthetic and subanesthetic doses, and it has been used recently to treat depression. Biotransformation mediates ketamine effects, influencing both systemic elimination and bioactivation. CYP2B6 is the major catalyst of hepatic ketamine N-demethylation and metabolism at clinically relevant concentrations. Numerous CYP2B6 substrates contain halogens. CYP2B6 readily forms halogen-protein (particularly Cl-π) bonds, which influence substrate selectivity and active site orientation. Ketamine is chlorinated, but little is known about the metabolism of halogenated analogs. This investigation evaluated halogen substitution effects on CYP2B6-catalyzed ketamine analogs N-demethylation in vitro and modeled interactions with CYP2B6 using various computational approaches. Ortho phenyl ring halogen substituent changes caused substantial (18-fold) differences in K_m, on the order of Br (bromoketamine, 10 μM) < Cl < F < H (deschloroketamine, 184 μM). In contrast, V_max varied minimally (83–103 pmol/min/pmol CYP). Thus, apparent substrate binding affinity was the major consequence of halogen substitution and the major determinant of N-demethylation. Docking poses of ketamine and analogs were similar, sharing a π-stack with F297. Libdock scores were deschloroketamine < bromoketamine < ketamine < fluoroketamine. A Bayesian log K_m model generated with Assay Central had a ROC of 0.86. The probability of activity at 15 μM for ketamine and analogs was predicted with this model. Deschloroketamine scores corresponded to the experimental K_m, but the model was unable to predict activity with fluoroketamine. The binding pocket of CYP2B6 also suggested a hydrophobic component to substrate docking, on the basis of a strong linear correlation (R² = 0.92) between lipophilicity (AlogP) and metabolism (log K_m) of ketamine and analogs. This property may be the simplest design criteria to use when considering similar compounds and CYP2B6 affinity.

中文翻译：

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卤素取代通过细胞色素 P450 2B6 影响氯胺酮代谢：体外和计算方法

氯胺酮在麻醉剂和亚麻醉剂剂量下具有镇痛作用，最近被用于治疗抑郁症。生物转化介导氯胺酮效应，影响全身消除和生物活化。CYP2B6 是临床相关浓度下肝脏氯胺酮N-去甲基化和代谢的主要催化剂。许多 CYP2B6 底物都含有卤素。CYP2B6 容易形成卤素-蛋白质（尤其是 Cl-π）键，从而影响底物选择性和活性位点方向。氯胺酮是氯化的，但对卤代类似物的代谢知之甚少。本研究评估了卤素取代对 CYP2B6 催化的氯胺酮类似物N的影响-体外去甲基化并使用各种计算方法模拟与 CYP2B6 的相互作用。邻苯环卤素取代基的变化导致K _m的显着（18 倍）差异，数量级为 Br（溴氯胺酮，10 μM）< Cl < F < H（去氯氯胺酮，184 μM）。相反，V _max变化很小（83-103 pmol/min/pmol CYP）。因此，表观底物结合亲和力是卤素取代的主要结果，也是N-去甲基化的主要决定因素。氯胺酮和类似物的对接姿势相似，与 F297 共享一个 π 堆栈。Libdock 评分为去氯氯胺酮 < 溴氯胺酮 < 氯胺酮 < 氟氯胺酮。贝叶斯对数K _m使用 Assay Central 生成的模型的 ROC 为 0.86。使用该模型预测氯胺酮和类似物在 15 μM 时的活性概率。去氯氯胺酮分数对应于实验K _m，但该模型无法预测氟氯胺酮的活性。基于氯胺酮和类似物的亲脂性 ( A log P ) 和代谢 (log K _{m ) 之间的强线性相关性 (} R ² = 0.92) ，CYP2B6 的结合口袋也暗示了与底物对接的疏水成分。在考虑相似化合物和 CYP2B6 亲和力时，此属性可能是最简单的设计标准。