Kappa opioid antagonists: synthesis, potency, selectivity, and time-course

Kappa 阿片拮抗剂：合成、效力、选择性和时程

• 批准号: 8030479
• 负责人: William A. Carlezon
• 金额: $ 7.9万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8030479
• 关键词: Affinity; Agonist; Animal Model; Anti-Anxiety Agents; Antidepressive Agents; Anxiety Disorders; Behavior; Binding; Biological Assay; Brain; Chemicals; Clinical; Clinical Drug Development; Clinical Research; Clinical Trials; Cocaine; Data; Development; Dose; Drug Addiction; Drug Delivery Systems; Drug usage; Dynorphins; Ethers; Evaluation; Human; Hybrids; In Vitro; Industry; Lead; Legal patent; Ligands; Measurement; Measures; Mental Depression; Modification; Mood Disorders; Moods; Narcotic Antagonists; Neuropeptides; Opioid Receptor; Patients; Pharmaceutical Preparations; Procedures; Property; Publishing; Rattus; Regulation; Relapse; Research; Research Personnel; Rewards; Rodent; Rodent Model; Self Stimulation; Side; Signal Transduction; Stress; Structure-Activity Relationship; Symptoms; System; Testing; Time; Work; analog; base; delta opioid receptor; depressive symptoms; design; drug development; drug discovery; drug of abuse; improved; in vivo; kappa opioid receptors; mu opioid receptors; nonhuman primate; novel; preclinical study; prevent; receptor; research study; response

DESCRIPTION (provided by applicant): New and improved treatments with novel mechanisms of action are needed for drug addiction, mood and anxiety disorders. The kappa opioid receptor (KOR) has recently been validated as a highly promising target for this purpose. Selective KOR antagonists may prevent stress-induced relapse, limit drug use, and provide antidepressant and anxiolytic effects. While available selective KOR antagonists (e.g., norBNI, JDTic) showed efficacy in rodent models used to study drug addiction, mood and anxiety disorders, they do not possess optimal properties to enter clinical studies. Specifically, a single dose in rodents or non-human primates induces long lasting (several weeks) in vivo KOR blockade after a slow onset of action (~24 h). Improved selective KOR antagonists are needed to determine if this class of compounds is effective in clinical settings. Recent efforts focusing on the design of drugs targeting the mu opioid receptor (MOR) have led to the identification of a small number of KOR antagonists with some degree of selectivity for KOR over MOR. These biaryl/diaryl ether containing compounds are structurally different from current KOR antagonists and have mostly been characterized in vitro. Preliminary observations indicate that these agents induce rapid KOR blockade (within 1 h post-administration). This distinguishes this class of compounds from all currently studied, prototypical KOR antagonists and strongly suggests that these compounds will possess a different, more drug-like, time course of KOR blockade. First, we propose to synthesize eleven biaryl/diaryl ether analogues: four known and seven newly designed agents. Binding and functional assays will then be used to assess in vitro KOR antagonist potency and selectivity for KOR over other opioid receptor subtypes. The standard KOR antagonists norBNI and JDTic will be tested under the same conditions to provide reference data. Finally, the two most potent and selective biaryl/diaryl ether agents and the standard KOR antagonist JDTic will be evaluated in the rat intracranial self stimulation test to provide information about in vivo potency and time course of KOR blockade. This assay is sensitive to the function of brain reward systems, making it specifically relevant to identifying agents that might have effects in drug addiction and mood disorders. The identification of short-acting KOR antagonists would have important implications. These agents could be used (1) as lead compounds for further chemical modification, if receptor selectivity needs to be increased, (2) in preclinical studies in which long-lasting KOR blockade is a limitation, and (3) for clinical studies in patients with drug addiction, depression and/or anxiety disorders. This work is of particular importance because it could lead to the development of clinically useful compounds with entirely new mechanisms of action for the treatment of drug addiction, mood and anxiety disorders. PUBLIC HEALTH RELEVANCE: Preclinical studies suggest that selective kappa opioid receptor antagonists have great potential to alleviate symptoms of drug addiction, mood and anxiety disorders. Using a combination of synthesis, in vitro, and in vivo evaluation, the proposed studies seek to identify a class of agents with optimal kappa opioid receptor antagonist properties for use in clinical trials. This work is of particular importance because it could lead to the development of clinically useful compounds with entirely new mechanisms of action, which might help those who respond poorly or inadequately to currently available treatments.

描述（由申请人提供）：需要具有新作用机制的新的和改进的治疗方法来治疗药物成瘾、情绪和焦虑症。κ阿片受体（KOR）最近已被证实是一个非常有前途的目标。选择性KOR拮抗剂可预防应激诱导的复发，限制药物使用，并提供抗抑郁和抗焦虑作用。 虽然可用的选择性KOR拮抗剂（例如，norBNI，JDTic）在用于研究药物成瘾、情绪和焦虑障碍的啮齿动物模型中显示出功效，但它们不具有进入临床研究的最佳性质。具体而言，啮齿动物或非人灵长类动物中的单次给药在缓慢起效（约24 h）后诱导持久（数周）的体内KOR阻断。需要改进的选择性KOR拮抗剂来确定这类化合物在临床环境中是否有效。 最近集中于设计靶向μ阿片受体（莫尔）的药物的努力已经导致鉴定出少数KOR拮抗剂，其对KOR的选择性超过对莫尔的选择性。这些含有联芳基/二芳基醚的化合物在结构上不同于目前的KOR拮抗剂，并且大多数在体外进行了表征。初步观察表明，这些药物诱导快速KOR阻断（给药后1小时内）。这将这类化合物与所有目前研究的原型KOR拮抗剂区分开来，并强烈表明这些化合物将具有不同的、更像药物的KOR阻断时程。首先，我们建议合成11联芳基/二芳基醚类似物：四个已知的和七个新设计的代理。然后将使用结合和功能测定来评估体外KOR拮抗剂效力和KOR相对于其他阿片受体亚型的选择性。标准KOR拮抗剂norBNI和JDTic将在相同条件下进行测试，以提供参考数据。最后，将在大鼠颅内自我刺激试验中评价两种最有效和选择性的联芳基/二芳基醚试剂和标准KOR拮抗剂JDTic，以提供关于KOR阻断的体内效力和时间过程的信息。该分析对大脑奖励系统的功能敏感，使其特别适用于识别可能对药物成瘾和情绪障碍有影响的药物。 短效KOR拮抗剂的鉴定将具有重要意义。这些药物可用于：（1）如果需要增加受体选择性，则可用作进一步化学修饰的先导化合物;（2）用于长期KOR阻断受限的临床前研究;以及（3）用于药物成瘾、抑郁和/或焦虑症患者的临床研究。这项工作特别重要，因为它可能导致开发具有全新作用机制的临床有用化合物，用于治疗药物成瘾，情绪和焦虑症。 公共卫生关系：临床前研究表明，选择性κ阿片受体拮抗剂具有很大的潜力，以减轻药物成瘾，情绪和焦虑障碍的症状。使用合成，体外和体内评价的组合，拟议的研究旨在确定一类具有最佳κ阿片受体拮抗剂特性的药物用于临床试验。这项工作特别重要，因为它可能导致开发具有全新作用机制的临床有用化合物，这可能有助于那些对目前可用治疗反应不佳或不充分的人。