Neurobiology and Target Validation of Novel Therapeutic Agents in Mood Disorders

情绪障碍新型治疗药物的神经生物学和靶标验证

• 批准号: 10703939
• 负责人: Carlos Zarate
• 金额: $ 382.11万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703939
• 关键词: AMPA Receptors; Adverse event; Aftercare; Age; Antidepressive Agents; Behavioral; Binding; Biological; Biological Markers; Bipolar Disorder; Brain imaging; Clinical Trials; Data; Data Analytics; Diagnosis; Dimensions; Dizziness; Dose; Double-Blind Method; Drug Kinetics; Electroencephalogram; Electrophysiology (science); Evaluation; Exhibits; Feeling suicidal; Female; Frequencies; Genes; Genetic; Glutamates; Goals; Hour; Human; Incidence; Individual; Intervention; Intravenous; Investigation; Ketamine; Link; Major Depressive Disorder; Measures; Mediating; Mediation; Mental Depression; Metabolism; Mood Disorders; Motor Activity; Mus; Naltrexone; National Institute of Mental Health; Nature; Nausea and Vomiting; Neurobiology; Neuropsychological Tests; Opioid Antagonist; Opioid Receptor; Oral; Orchiectomy; Outcome Measure; Ovariectomy; Participant; Patient Self-Report; Patients; Pattern; Penetration; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Physiological; Placebo Control; Placebos; Plasma; Polysomnography; Pre-Clinical Model; Principal Component Analysis; Procedures; Prodrugs; Property; Proteins; Protocols documentation; Randomized; Receptor Activation; Reporting; Research; Research Domain Criteria; Resistance; Rodent; Role; Safety; Self Administration; Sex Differences; Sleep; Sleep disturbances; Suicide; Sum; Symptoms; Syndrome; System; Testosterone; Therapeutic; Therapeutic Agents; Time; Validation; Wakefulness; abuse liability; antagonist; antidepressant effect; clinical development; collected works; conditioned place preference; depressive symptoms; design; enantiomer; endogenous opioids; experience; experimental study; first-in-human; forced swim test; improved; interest; kappa opioid receptors; male; metabotropic glutamate receptor 2; mu opioid receptors; new therapeutic target; norketamine; novel; novel therapeutics; off-label use; peripheral blood; phenomenological models; preservation; receptor; recruit; screening; sex; side effect; sleep onset; suicidal; suicidal behavior; suicidal risk; symptomatology; therapy development; treatment effect; treatment response; treatment-resistant depression

This Report involves work collected under protocols 01-M-0254 (NCT00024635); 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 07-M-0021 (NCT00397111); 14-M-0041 (NCT02049385); 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983), 19-M-0107 (NCT03973268), and 000101-M (NCT04821271). Results this past year: 1. Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents. TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15-400 mg TS-161) and 10-day multiple-ascending dose (50-150 mg TS-161) study in healthy subjects. Following single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a Cmax of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC50 values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness. The mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects and is a promising candidate for further clinical development in treatment of patients with depression. 2. Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search. The off-label use of racemic ketamine and the FDA approval of (S)-ketamine are promising developments for the treatment of depression. Nevertheless, racemic ketamine and (S)-ketamine are controlled substances with known abuse potential and their use is associated with undesirable side effects. For these reasons, research efforts have focused on identifying alternatives. One candidate is (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a ketamine metabolite that in preclinical models lacks the dissociative and abuse properties of ketamine while retaining its antidepressant-like behavioral efficacy. (2R,6R)-HNK's mechanism of action however is unclear. We found that unlike (S)- or (R)-ketamine, (2R,6R)-HNK did not directly bind to any known or proposed ketamine targets. Extensive screening and target deconvolution experiments at thousands of human proteins did not identify any other direct (2R,6R)-HNK-protein interactions. (2R,6R)-HNK was inactive in conditioned place preference, open-field locomotor activity, and intravenous self-administration procedures. In sum, our results indicate that (2R,6R)-HNK does not share pharmacological or behavioral profile similarities with ketamine or its enantiomers. Given its pharmacological profile, we predict that (2R,6R)-HNK will exhibit a favorable safety profile in clinical trials. 3. The Dynamic Relationship Between Alpha and Beta Power and Next-Day Suicidal Ideation in Individuals With Treatment-Resistant Depression. Nocturnal wakefulness has emerged as a potential predictor of short-term suicide risk. This analysis used dynamic temporal patterns in alpha and beta power and global sleep metrics to explore the possible link between next-day suicidal ideation (NDSI) and wakefulness measures in unmedicated participants with treatment-resistant depression. Thirty-three medication-free participants with treatment-resistant depression completed overnight polysomnography. A functional data analytic approach (multilevel functional principal component analysis MFPCA) was used to preserve the oscillatory nature of the data; MFPCA PC scores were then associated with NDSI. NDSI had the strongest relationship with the second beta PC score (slope = 0.09 90% credible interval, 0.03 to 0.14), which represented an oscillating pattern that reflected disturbed sleep. Results were equivocal for wakefulness after sleep onset with NDSI and did not support a relationship between NDSI and either sleep efficiency or total sleep time, highlighting the value of information contained in oscillating electroencephalogram patterns for identifying physiological links between nocturnal wakefulness and NDSI. This study leveraged the dynamic nature of wakefulness-related electroencephalogram frequencies and provides a potential electrophysiological link between suicidal ideation and wakefulness during sleep in individuals with treatment-resistant depression. 4. Mediation of the behavioral effects of ketamine and (2R,6R)-hydroxynorketamine in mice by kappa opioid receptors. Emerging evidence has implicated the endogenous opioid system in mediating ketamine's antidepressant activity in subjects with major depressive disorder. To date, mu opioid receptors have been suggested as the primary opioid receptor of interest. However, this hypothesis relies primarily on observations that the opioid antagonist naltrexone blocked the effects of ketamine in humans and rodents. This report confirms previous findings that pretreatment with naltrexone (1 mg/kg) just prior to ketamine (10 mg/kg) administration effectively blocks the behavioral effect of ketamine in the mouse forced swim test 24 h post-treatment. Furthermore, pharmacological blockade of kappa opioid receptors prior to ketamine administration with the selective, short-acting antagonist LY2444296 successfully blocked ketamine's effects in the forced swim test. Likewise, the ability of the ketamine metabolite (2R,6R)-hydroxynorketamine to reduce immobility scores in the forced swim test was also blocked following pretreatment with either naltrexone or LY2444296. These data support a potential role of kappa opioid receptors in mediating the behavioral activity of ketamine and its non-dissociate metabolite (2R,6R)-hydroxynorketamine. 5. Sex-dependent metabolism of ketamine and ( 2R,6R)-hydroxynorketamine in mice and humans. Ketamine is rapidly metabolized to norketamine and hydroxynorketamine (HNK) metabolites. In female mice, when compared to males, higher levels of (2R,6R;2S,6S)-HNK have been observed following ketamine treatment, and higher levels of (2R,6R)-HNK following the direct administration of (2R,6R)-HNK. In humans, plasma levels of ketamine and norketamine were higher in males than females, while (2R,6R;2S,6S)-HNK levels were not different. Following ketamine administration to mice (10 mg/kg i.p.), Cmax and total plasma concentrations of ketamine and norketamine were higher, and those of (2R,6R;2S,6S)-HNK were lower, in intact males compared to females. Direct (2R,6R)-HNK administration (10 mg/kg i.p.) resulted in higher levels of (2R,6R)-HNK in female mice. Ovariectomy did not alter ketamine metabolism in female mice, whereas orchidectomy recapitulated female pharmacokinetic differences in male mice, which was reversed with testosterone replacement. Sex is an important biological variable that influences the metabolism of ketamine and the HNKs, which may contribute to sex differences in therapeutic antidepressant efficacy or side effects.

该报告涉及根据协议01-M-0254（NCT00024635）收集的工作； 08-M-0196（NCT00759395）; 08-M-0150（NCT00697268）; 14-m-0085（NCT02122562）; 07-m-0021（NCT00397111）; 14-m-0041（NCT02049385）; 07-M-0152（NCT00472576），09-m-N230; 15-M-0151（NCT 02484456），15-M-0188（NCT02543983），19-M-0107（NCT03973268）和000101-M（NCT04821271）。 过去一年的结果： 1。对TP0473292（TS-161）的安全性，耐受性和药代动力学特征的评估，这是一种新型的正常人MGLU2/3受体拮抗剂TP0178894的前药，在健康的受试者及其健康的受试者及其抗抑郁药中的抗抑郁剂。 TP0473292（TS-161的活性成分）是一种新型代谢型谷氨酸（MGLU）2/3受体拮抗剂的前药，以治疗抑郁症患者。这是第一个人类，第1阶段，随机，双盲，安慰剂对照，单次抗剂量（15-400 mg TS-161）和10天的多余剂量（50-150 mg TS-161）研究。在单剂量和多剂量之后，将TP0473292广泛转换为其活性代谢物TP0178894。 TP0178894的血浆浓度在剂量后5小时内达到峰值（CMAX），并以T1/2 <13小时下降。 TP0178894的血浆暴露随剂量增加而增加。 TP0178894渗透到CSF中，并以100 mg的单剂量达到9.892 ng/ml的CMAX，与MGLU2/3受体的IC50拮抗剂活性值可比。在研究期间显示出与暴露有关的发病率的最常观察到的不良事件是恶心，呕吐和头晕。 MGLU2/3受体拮抗剂Prodrug TP0473292是安全且耐受性良好的，在人类中可以口服生物利用，并广泛转化为主动代谢物TP0178894，具有足够的CSF渗透，可在预期的药理学效果中施加足够的渗透，可以进一步抑郁症患者，在抑郁症患者方面具有良好的候选患者。 2。（2R，6R） - 羟基苯丙胺的目标反卷积研究：难以捉摸的搜索。标签外的氯胺酮的使用以及（S）酮胺的FDA批准是抑郁症的有希望的发展。然而，外消旋氯胺酮和（S）酮胺是具有已知滥用潜力的受控物质，其使用与不良的副作用有关。由于这些原因，研究工作集中在识别替代方案上。一个候选者是（2R，6R） - 羟基诺甲胺（（（2R，6R）-HNK），氯胺酮代谢物在临床前模型中缺乏氯胺酮的分离和滥用性能，同时保持其抗抑郁药样的行为效果。 （2R，6R） - HHNK的作用机理尚不清楚。我们发现，与（S） - 或（R） - 酮胺不同，（2R，6R）-HHNK没有直接与任何已知或提议的氯胺酮靶标结合。在数千种人类蛋白上进行的广泛筛查和靶向反向卷积实验未识别任何其他直接（2R，6R）-HHNK-蛋白质相互作用。 （2R，6R）-HHNK在条件的位置偏好，开放式运动活动和静脉自我管理程序中无效。总而言之，我们的结果表明（2R，6R）-HHNK与氯胺酮或其对映异构体不具有药理或行为概况相似性。鉴于其药理特征，我们预测（2R，6R）-HNK将在临床试验中表现出良好的安全性。 3。α和beta功率之间的动态关系以及抗治疗抑郁症患者的第二天自杀念头。夜间的清醒已成为短期自杀风险的潜在预测指标。该分析使用了Alpha和Beta功率和全球睡眠指标中的动态时间模式，以探索次日自杀念头（NDSI）（NDSI）与具有耐药治疗抑郁症的无药参与者的觉醒度量之间的可能联系。有33名无药物抗药性抑郁症的无药物参与者完成了通宵的多个术语。使用功能数据分析方法（多级功能主成分分析MFPCA）来保留数据的振荡性质。然后，MFPCA PC分数与NDSI相关联。 NDSI与第二个Beta PC得分的关系最强（坡度= 0.09 90％可靠间隔，0.03至0.14），这代表了反映扰乱睡眠的振荡模式。结果是与NDSI睡眠发作后的清醒相等的结果，并且不支持NDSI与睡眠效率或总睡眠时间之间的关系，突出了振荡脑电图模式中所包含的信息的价值，以识别识别差异性清醒和NDSI之间的生理联系。这项研究利用了与觉醒相关的脑电图频率的动态性质，并在患有耐药性抑郁症患者的睡眠过程中提供了自杀念头和睡眠期间的潜在电生理联系。 4。氯胺酮和（2R，6R） - 羟基苯丙胺在小鼠中通过Kappa阿片受体的介导。新兴的证据暗示了内源性阿片类药物系统，介导氯胺酮在严重抑郁症患者中的抗抑郁活性。迄今为止，已经建议将MU阿片类药物作为主要感兴趣的阿片类药物受体。然而，该假设主要依赖于观察结果，即阿片类药物纳曲酮阻止氯胺酮在人类和啮齿动物中的作用。该报告证实了先前的发现，在氯胺酮（10 mg/kg）给药之前，用纳曲酮（1 mg/kg）进行了预处理，有效地阻止了氯胺酮在治疗后24小时的小鼠强制游泳测试中的行为效应。此外，在氯胺酮给药之前，具有选择性的，短作用的拮抗剂LY2444296在氯胺酮给药之前的药理学封锁成功阻止了氯胺酮在强制游泳测试中的作用。同样，在用纳曲酮或LY2444296预处理后，氯胺酮代谢物（2R，6R） - 羟基诺摩甲胺在强迫游泳试验中的固定得分也被阻塞。这些数据支持Kappa阿片受体在介导氯胺酮及其非解离代谢产物（2R，6R） - 羟基诺甲苯胺的行为活性中的潜在作用。 5。氯胺酮和（2R，6R） - 小鼠和人类中的羟基苯丙胺的代谢。氯胺酮迅速代谢为北苯丙胺和羟基苯丙胺（HNK）代谢产物。在雌性小鼠中，与雄性相比，氯胺酮治疗后已经观察到更高水平的（2R，6R； 2s，6s）-HNK，并且直接给予（2R，6R）-HNK后，（2R，6R）-HHNK水平较高（2R，6R）-HNK。在人类中，男性的血浆水平高于女性，而（2R，6R； 2s，6s）-HHNK水平没有差异。在对小鼠（10 mg/kg i.p.）施用氯胺酮后，氯胺酮和甲苯丙胺的总血浆浓度更高，与女性相比，在完整雄性中，（2R，6R; 2s; 2s; 2s; 2s; 2s; 2s; 2s; 2s，6s）较低。直接（2R，6R）-HHNK给药（10 mg/kg I.P.）导致雌性小鼠的较高水平（2R，6R）-HHNK。卵巢切除术并未改变雌性小鼠的氯胺酮代谢，而乳切除术概括了雄性小鼠的雌性药代动力学差异，后者被睾丸激素替代逆转。性是一个重要的生物学变量，影响氯胺酮和HNK的代谢，这可能导致治疗性抗抑郁疗效或副作用的性别差异。