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

 描述（由申请人提供）：吗啡等阿片类药物是目前可用于治疗中度至重度急性和慢性疼痛的最有效的药物。这些药物主要通过阿片受体的 mu 亚型发挥作用。然而，由于呼吸抑制、阿片类药物引起的肠功能障碍、耐受性和依赖性的发展以及对成瘾倾向的新担忧，它们的治疗用途受到限制。对于发现和开发与吗啡一样有效但没有明显副作用的新型镇痛药，存在着迫切的未满足的医疗需求。使用选择性拮抗剂和双功能（μ激动剂/δ拮抗剂）化合物的δ受体基因敲除/敲低实验和研究提供了证据，证明μ受体功能的激活与δ受体功能的同时抑制可产生镇痛作用，并大大减少μ受体介导的副作用。因此，具有mu受体激动和δ受体拮抗双重但相反的功能活性的化合物有可能表现出具有宽安全范围和治疗指数的广谱镇痛作用。因此，我们一直致力于发现具有μ激动/δ拮抗双重功能的小分子。为此，我们最近发现了对 mu 和 δ 受体具有平衡的高亲和力结合特性并具有混合 mu 激动剂/δ 拮抗剂功能活性的化合物。此外，这些化合物产生耐受性、依赖性和滥用倾向的倾向也降低。在这个拟议项目中，我们的目标是开发新型口服活性 mu 激动剂/δ 拮抗剂化合物。该方法建立在为先导系列确定的结构-活性关系的基础上。药物化学先导物优化策略包括利用最近获得的 mu 和 δ 受体晶体结构信息进行合理的药物设计，以及用于改善理化和药代动力学特性的多参数先导物优化。为了实现识别主要临床前候选药物的目标，我们将（1）根据活性和体外药代动力学特性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、半衰期和中枢神经系统水平）以选择化合物（4）在啮齿类动物中进行全面的体内镇痛功效和副作用分析。这些目标将通过在药物设计、药物化学、计算化学、阿片类生物化学和分子生物学、药代动力学、阿片类药理学和药物开发方面拥有丰富经验的团队的共同努力来实现。

 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.