Therapeutic Efficacy of Ketamine Metabolites for Depression Treatment

氯胺酮代谢物治疗抑郁症的疗效

• 批准号: 10553628
• 负责人: Todd D Gould
• 金额: $ 60万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553628
• 关键词: Acute; Adverse effects; Affinity; Anesthetics; Anhedonia; Antidepressive Agents; Behavioral; Behavioral Assay; Biological; Brain; Brain-Derived Neurotrophic Factor; Calcium; Clinical; Cyclic AMP; Data; Development; Disease remission; Drug Kinetics; Drug abuse; Electrophysiology (science); Feeling suicidal; Fiber; Funding; Future; Glutamates; Goals; Hippocampus; Human; In Vitro; Individual; Innovative Therapy; Ketamine; Knowledge; Major Depressive Disorder; Measurement; Measures; Mediating; Mental Depression; Metabolism; Moods; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Neuropharmacology; Neurosciences Research; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Photometry; Plasma; Population; Pre-Clinical Model; Preparation; Probability; Property; Publishing; Receptor Inhibition; Refractory; Research; Resistance; Role; Slice; Stereoisomer; Structure; Structure-Activity Relationship; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Synthesis Chemistry; Therapeutic Effect; Treatment Efficacy; Work; abuse liability; antagonist; antidepressant effect; depressive symptoms; drug development; drug discovery; experience; experimental study; improved; in vivo; insight; neurochemistry; next generation; norketamine; novel; novel therapeutics; pharmacologic; phase II trial; preclinical study; presynaptic; safety study; side effect; synaptic function; therapeutic development; translational neuroscience

SUMMARY Major depressive disorder (MDD) afflicts ~16% of the world population. Despite the availability of several classes and types of antidepressant medications, patients typically take many weeks, if not months, to respond to these drugs, and the majority never attain sustained remission of their symptoms. A remarkable development for the pharmacological treatment of MDD is the finding that the non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, is an effective, rapidly acting antidepressant in treatment-refractory patients. During our previous funding cycle, we began exploring the role of ketamine’s metabolites in both the therapeutic and adverse effects of ketamine. We identified behavioral, synaptic, and neurochemical effects of the (2R,6R)- hydroxynorketamine (HNK) metabolite. In contrast to ketamine, (2R,6R)-HNK has low affinity for the NMDAR, which is consistent with its reduced adverse effects as measured in preclinical studies. We have also found that (2R,6R)-HNK enhances excitatory synaptic transmission in the hippocampus through a concentration- dependent, NMDAR activity-independent increase in glutamate release probability. Our long-term goal is to elucidate the biological activities of (2R,6R)-HNK, as well as ketamine’s eleven additional HNK metabolites, and utilize our findings to develop novel, effective compounds for the treatment of depression. The central hypothesis is that HNKs exert an acute, synapse-selective form of presynaptic plasticity that leads to a sustained strengthening of mood-relevant circuits. In Specific Aim #1 we will use slice electrophysiology to resolve the synaptic actions of (2R,6R)-HNK, and identify the mechanism(s) by which (2R,6R)-HNK acutely enhances the probability of synaptic glutamate release. We hypothesize that (2R,6R)-HNK acts through a presynaptic cAMP- BDNF-dependent mechanism to promote glutamate release. In Specific Aim #2 we will use in vivo fiber photometry assessments of neuronal activity to determine the synaptic effects of (2R,6R)-HNK on hippocampal circuitry, specifically the Schaffer collateral synapses in the CA1 region of the hippocampus. These experiments will determine (2R,6R)-HNK’s synaptic action in an intact circuit. Finally, in Specific Aim #3 we will define, in vitro and in vivo, the relative synaptic and behavioral potencies for all 12 HNKs produced via ketamine metabolism. These experiments will define structure-activity relationships at the level of synaptic function, which will allow us to refine the structure of the HNKs, in order to optimize their antidepressant and pharmacokinetic activity. Overall, our work thus far strongly implicates an immediate drug effect on presynaptic plasticity, which when the mechanism underlying this action is clarified, will open up new avenues for novel antidepressant drug discovery based upon this mechanism. The completion of our proposed experiments will have implications for the understanding of rapid-acting antidepressant drug pharmacology, development of novel and innovative therapies, and the future treatment of depression.

总结 重度抑郁症（MDD）困扰着约16%的世界人口。尽管有几个班级 和类型的抗抑郁药物，患者通常需要数周，如果不是数月，以响应这些 药物，大多数从未达到持续缓解他们的症状。一个显着的发展， MDD的药物治疗是发现非竞争性N-甲基-D-天冬氨酸受体 （NMDAR）拮抗剂氯胺酮是治疗难治性患者的有效、快速起效的抗抑郁药。 在我们之前的资助周期中，我们开始探索氯胺酮的代谢物在治疗中的作用， 以及氯胺酮的副作用我们确定了（2 R，6 R）的行为，突触和神经化学作用， 羟基去甲氯胺酮（HNK）代谢产物。与氯胺酮相反，（2 R，6 R）-HNK对NMDAR具有低亲和力， 这与在临床前研究中测量的其减少的副作用一致。我们还发现 (2R，6 R）-HNK通过浓度依赖性增强海马中的兴奋性突触传递。 谷氨酸释放概率的依赖性、NMDAR活性非依赖性增加。我们的长期目标是 阐明（2 R，6 R）-HNK以及氯胺酮的11种其他HNK代谢物的生物活性，以及 利用我们的发现来开发新的，有效的化合物来治疗抑郁症。核心假设 HNK发挥了一种急性的、突触选择性的突触前可塑性， 加强与情绪相关的电路。在特定目标1中，我们将使用切片电生理学来解决 的突触作用，并确定（2 R，6 R）-HNK的机制，其中（2 R，6 R）-HNK急性增强突触的作用。 突触谷氨酸释放的概率。我们假设（2 R，6 R）-HNK通过突触前cAMP- BDNF依赖机制促进谷氨酸释放。在具体目标#2中，我们将使用体内纤维 神经元活性的光度法评估，以确定（2 R，6 R）-HNK对海马神经元的突触作用。 电路，特别是海马CA 1区的Schaffer侧支突触。这些实验 将决定（2 R，6 R）-HNK在完整回路中的突触作用。最后，在具体目标#3中，我们将定义体外 以及在体内，通过氯胺酮代谢产生的所有12种HNK的相对突触和行为效力。 这些实验将在突触功能水平上定义结构-活性关系，这将使我们能够 优化HNK的结构，以优化其抗抑郁和药代动力学活性。总的来说， 到目前为止，我们的工作强烈暗示了药物对突触前可塑性的直接影响，当 阐明了这种作用的机制，将为新型抗抑郁药物的发现开辟新的途径 基于这种机制。我们所提议的实验的完成将对 了解速效抗抑郁药物的药理学，开发新的和创新的 抑郁症的未来治疗。