Development of Mu Agonist Delta Antagonist Opioids as Analgesics for Chronic Pain

 描述(申请人提供)：吗啡等阿片类药物是目前可用于治疗中到重度急性和慢性疼痛的最有效和最有效的药物。这些药物主要通过阿片受体的Mu亚型起作用。然而，由于呼吸抑制、阿片类药物引起的肠道功能障碍、耐受性和依赖性的形成以及对成瘾易感性的重新关注，它们的治疗应用受到限制。发现和开发与吗啡一样有效但没有明显副作用的新型止痛药是一种迫切的、尚未得到满足的医学需求。Delta受体基因敲除/敲除实验和使用选择性拮抗剂和双功能化合物(Mu激动剂/Delta拮抗剂)的研究表明，激活Mu受体功能的同时抑制Delta受体功能可以产生镇痛作用，并大大减少Mu受体介导的副作用。因此，具有Mu受体激动剂和Delta受体拮抗剂双重相反功能活性的化合物具有广谱镇痛的潜力，具有较大的安全裕度和治疗指数。因此，我们一直在寻找具有Mu激动型/Delta拮抗型双重功能的小分子。为此，我们最近发现了具有高亲和力结合在Mu和Delta受体上的平衡分布的化合物，并具有混合的Mu激动剂/Delta拮抗剂的功能活性。此外，这些化合物减少了产生耐受性、依赖性和滥用责任的倾向。在这个拟议的项目中，我们的目标是开发新的口服活性MU激动剂/三角洲拮抗剂化合物。该方法建立在为铅系列确定的结构-活动关系的基础上。药物化学先导优化策略包括利用新近获得的Mu和Delta受体的晶体结构信息进行合理的药物设计，以及为改善理化和药代动力学性质而进行的多参数先导优化。为了达到确定先导临床前候选者的目标，我们将(1)根据活性和体外药代动力学性质设计和合成新化合物(2)进行体外筛选以确定阿片受体的结合和功能活性(3)测定体外和体内药代动力学(生物利用度、半衰期和中枢神经系统水平)以选择化合物(4)在啮齿动物身上综合的体内镇痛效果和副作用描述。这些目标将通过一个在药物设计、药物化学、计算化学、阿片生物化学和分子生物学、药代动力学、阿片药理学和药物开发方面具有丰富经验的团队的合作努力来实现。

 DESCRIPTION (provided by applicant): Opioids such as morphine are the most potent and efficacious agents currently available for the treatment of moderate to severe acute and chronic pain. These drugs primarily act through the mu subtype of the opioid receptors. However, their therapeutic use is limited due to respiratory depression, opioid-induced bowel dysfunction, development of tolerance and dependence, and renewed concerns around addiction liabilities. There is an urgent unmet medical need for the discovery and development of novel analgesics that are as efficacious as morphine but devoid of significant side effects. Delta receptor gene knockout/knockdown experiments and studies using selective antagonists and bifunctional (mu agonist/delta antagonist) compounds have provided evidence that activation of mu receptor function with simultaneous suppression of delta receptor function produces analgesic effects with greatly diminished mu receptor mediated side effects. Thus, compounds possessing dual but opposing functional activity of mu receptor agonism and delta receptor antagonism have the potential to exhibit broad-spectrum analgesia with a wide safety margin and therapeutic index. Therefore, we have been pursuing the discovery of small molecules possessing the dual functional profile of mu agonism/delta antagonism. To this end, we recently discovered compounds possessing a balanced profile of high-affinity binding at mu and delta receptors and possessing mixed mu agonist/delta antagonist functional activity. In addition these compounds had a diminished propensity to produce tolerance, dependence and abuse liability. In this proposed project, our goal is to develop novel orally active mu agonist/delta antagonist compounds. The approach builds upon the structure-activity relationships determined for the lead series. The medicinal chemistry lead optimization strategy includes rational drug design utilizing crystal structure information on mu and delta receptors that became recently available as well as multi- parametric lead optimization for the improvement of physicochemical and pharmacokinetic properties. To achieve the goal of identifying lead preclinical candidates we will (1) design and synthesize new compounds based upon activity and in vitro pharmacokinetic properties (2) perform in vitro screening to determine opioid receptor binding and functional activity (3) determine the in vitro and in vivo pharmacokinetic profile (bioavailability, half-lifeand CNS levels) to select compounds for (4) comprehensive in vivo analgesic efficacy and side effect profiling in rodents. These goals will be accomplished through a collaborative effort involving a team with extensive experience in drug design, medicinal chemistry, computational chemistry, opioid biochemistry and molecular biology, pharmacokinetics, opioid pharmacology, and drug development.