Hydroxynorketamines (HNKs) are formed in vivo after (R,S)-ketamine (ketamine) administration. The 12 HNK stereoisomers are distinguished by the position of cyclohexyl ring hydroxylation (at the 4, 5, or 6 position) and their unique stereochemistry at two stereocenters. Although HNKs were initially classified as inactive metabolites because of their lack of anesthetic effects, more recent studies have begun to reveal their biologic activities. In particular, (2R,6R)- and (2S6)-HNK exert antidepressant-relevant behavioral and physiologic effects in preclinical models, which led to a rapid increase in studies seeking to clarify the mechanisms by which HNKs exert their pharmacological effects. To date, the majority of HNK research has focused on the actions of (2R,6R)-HNK because of its robust behavioral actions in tests of antidepressant effectiveness and its limited adverse effects. This review describes HNK pharmacokinetics and pharmacodynamics, as well as the putative cellular, molecular, and synaptic mechanisms thought to underlie their behavioral effects, both following their metabolism from ketamine and after direct administration in preclinical studies. Converging preclinical evidence indicates that HNKs modulate glutamatergic neurotransmission and downstream signaling pathways in several brain regions, including the hippocampus and prefrontal cortex. Effects on other neurotransmitter systems, as well as possible effects on neurotrophic and inflammatory processes, and energy metabolism, are also discussed. Additionally, the behavioral effects of HNKs and possible therapeutic applications are described, including the treatment of unipolar and bipolar depression, post-traumatic stress disorder, chronic pain, neuroinflammation, and other anti-inflammatory and analgesic uses.

中文翻译：

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羟基去甲氯胺酮：药理学和潜在的治疗应用

给予( R , S ) -氯胺酮（氯胺酮）后，体内会形成羟基去甲氯胺酮（HNK）。12 种 HNK 立体异构体的特征在于环己基环羟基化的位置（在 4、5 或 6 位）及其在两个立体中心的独特立体化学。尽管 HNK 最初因缺乏麻醉作用而被归类为无活性代谢物，但最近的研究已开始揭示其生物活性。特别是，( 2R , 6R )- 和 ( 2S 6 )-HNK 在临床前模型中发挥抗抑郁药相关的行为和生理作用，这导致寻求阐明 HNK 发挥药理作用机制的研究迅速增加。迄今为止，大多数 HNK 研究都集中在 ( 2R , 6R )-HNK 的作用上，因为它在抗抑郁药有效性测试中具有强大的行为作用，且副作用有限。这篇综述描述了 HNK 的药代动力学和药效学，以及假定的细胞、分子和突触机制，这些机制被认为是其行为效应的基础，无论是在氯胺酮代谢后还是在临床前研究中直接给药后。临床前证据表明，HNK 调节多个大脑区域（包括海马体和前额皮质）的谷氨酸能神经传递和下游信号通路。还讨论了对其他神经递质系统的影响，以及对神经营养和炎症过程以及能量代谢的可能影响。此外，还描述了 HNK 的行为效应和可能的治疗应用，包括治疗单相和双相抑郁症、创伤后应激障碍、慢性疼痛、神经炎症以及其他抗炎和镇痛用途。