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.

概括 重度抑郁症 (MDD) 困扰着世界约 16% 的人口。尽管有几个课程可供选择 和抗抑郁药物的类型，患者通常需要数周甚至数月的时间才能对这些药物产生反应 药物，大多数人的症状从未得到持续缓解。的显着发展 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一种有效、快速起效的抗抑郁药。 在我们之前的融资周期中，我们开始探索氯胺酮代谢物在治疗和治疗中的作用 和氯胺酮的不良反应。我们确定了 (2R,6R)- 的行为、突触和神经化学效应 羟基去甲氯胺酮（HNK）代谢物。与氯胺酮相比，(2R,6R)-HNK 对 NMDAR 的亲和力较低， 这与临床前研究中测得的其不良反应减少是一致的。我们还发现 (2R,6R)-HNK 通过浓度增强海马的兴奋性突触传递 谷氨酸释放概率依赖、NMDAR 活性独立增加。我们的长期目标是 阐明 (2R,6R)-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治疗抑郁症的新型有效化合物。中心假设 HNK 发挥一种急性的、突触选择性的突触前可塑性，从而导致持续的 加强与情绪相关的回路。在具体目标#1中，我们将使用切片电生理学来解决 (2R,6R)-HNK 的突触作用，并确定 (2R,6R)-HNK 急剧增强突触作用的机制 突触谷氨酸释放的概率。我们假设 (2R,6R)-HNK 通过突触前 cAMP-起作用 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 神经元活动的光度评估以确定 (2R,6R)-HNK 对海马的突触影响 电路，特别是海马 CA1 区域的 Schaffer 侧支突触。这些实验 将决定 (2R,6R)-HNK 在完整电路中的突触作用。最后，在具体目标 #3 中，我们将定义体外 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。 这些实验将定义突触功能水平的结构-活动关系，这将使我们能够 完善 HNK 的结构，以优化其抗抑郁和药代动力学活性。全面的， 迄今为止，我们的工作强烈暗示药物对突触前可塑性的直接影响，当 这一作用的机制得到阐明，将为新型抗抑郁药物的发现开辟新途径 基于这个机制。我们提出的实验的完成将对 了解速效抗抑郁药物的药理学，开发新颖和创新的药物 疗法，以及抑郁症的未来治疗。