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

描述（由申请人提供）：药物成瘾，情绪和焦虑障碍需要新的和改进的具有新的作用机制的治疗方法。kappa阿片受体（KOR）最近被证实是一个非常有希望的靶点。选择性KOR拮抗剂可以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。虽然现有的选择性KOR拮抗剂（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疗效，但它们并不具有进入临床研究的最佳特性。具体来说，在啮齿类动物或非人灵长类动物中，单剂量在缓慢起效（~24小时）后可诱导长期（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，针对mu阿片受体（MOR）的药物设计的努力已经导致少量的KOR拮抗剂的鉴定，这些拮抗剂对KOR具有一定程度的选择性。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，并且大多在体外进行了表征。初步观察表明，这些药物可诱导快速的KOR阻断（给药后1小时内）。这将这类化合物与目前研究的所有典型的KOR拮抗剂区分开来，并强烈表明这些化合物将具有不同的，更类似于药物的KOR阻断时间过程。首先，我们拟合成11个联芳基/二芳基醚类似物：4个已知的和7个新设计的。结合和功能测定将用于评估体外KOR拮抗剂的效力和选择性，而不是其他阿片受体亚型。标准的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，两种最有效和选择性的联芳基/二芳基醚药物和标准的KOR拮抗剂JDTic将在大鼠颅内自我刺激试验中进行评估，以提供有关KOR阻断的体内效力和时间过程的信息。这种检测方法对大脑奖励系统的功能很敏感，这使得它与识别可能对药物成瘾和情绪障碍有影响的药物特别相关。短效KOR拮抗剂的鉴定具有重要意义。这些药物可以(1)作为进一步化学修饰的先导化合物，如果受体选择性需要增加，(2)在长期KOR阻断是一个限制的临床前研究中，(3)在药物成瘾，抑郁症和/或焦虑症患者的临床研究中。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，情绪和焦虑障碍。

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.