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

 描述（由申请方提供）：阿片类药物（如吗啡）是目前可用于治疗中度至重度急性和慢性疼痛的最强效和有效的药物。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、阿片类药物诱导的肠功能障碍、耐受性和依赖性的发展以及对成瘾倾向的重新关注，其治疗用途受到限制。对于发现和开发与吗啡一样有效但没有显著副作用的新型镇痛剂存在迫切的未满足的医学需求。δ受体基因敲除/敲低实验和使用选择性拮抗剂和双功能（μ激动剂/δ拮抗剂）化合物的研究提供了证据，即μ受体功能的激活与δ受体功能的同时抑制产生镇痛作用，同时大大减少了μ受体介导的副作用。因此，具有μ受体激动和δ受体拮抗的双重但相反的功能活性的化合物具有表现出广谱镇痛的潜力，具有宽的安全范围和治疗指数。因此，我们一直致力于发现具有μ激动/δ拮抗双重功能特性的小分子。为此，我们最近发现的化合物具有平衡的高亲和力结合在μ和δ受体和具有混合μ激动剂/δ拮抗剂功能活性。此外，这些化合物产生耐受性、依赖性和滥用倾向的倾向降低。在这个拟议的项目中，我们的目标是开发新的口服活性μ激动剂/δ拮抗剂化合物。该方法建立在为铅系列确定的结构-活性关系的基础上。药物化学铅优化策略包括利用最近可用的μ和δ受体的晶体结构信息进行合理药物设计，以及用于改善物理化学和药代动力学特性的多参数铅优化。为了实现鉴定临床前候选药物的目标，我们将（1）基于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结合和功能活性（3）确定体外和体内药代动力学特征（生物利用度、半衰期和CNS水平）以选择化合物用于（4）啮齿动物中的全面体内镇痛功效和副作用特征分析。这些目标将通过一个在药物设计、药物化学、计算化学、阿片类药物生物化学和分子生物学、药代动力学、阿片类药物药理学和药物开发方面具有丰富经验的团队的协作努力来实现。

 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.