Novel Non-Peptide Opioid Ligands for Pain

描述（由申请人提供）：疼痛治疗仍然是一个主要的未满足的医疗需求。阿片类药物仍然是治疗中度至重度疼痛的最重要疗法，但具有降低生活质量的严重副作用。已知疼痛传递和调节途径中的神经元经历可塑性，这导致在组织损伤的情况下（即，使用疼痛缓解药物的条件）疼痛信号的放大。出乎意料的是，这种原伤害性适应也发生作为重复暴露于阿片类药物的结果。通过物质P-NK 1途径的信号传导增加强烈有助于外周和中枢致敏，以增强疼痛。这项涉及五个不同实验室的多学科提案旨在测试以下假设：可以在先验考虑减少所需镇痛的放大机制的情况下设计疼痛缓解药物，即，针对疾病的药物设计我们假设，在单个分子内具有阿片样物质激动剂（主要是mu）和NK-1拮抗剂活性的药物将提供有效的疼痛缓解，特别是在慢性疼痛的情况下，副作用减少，允许更大的耐受性和提高生活质量。因此，我们建议利用我们的从头设计和疼痛相关的药理学，生理学和分子生物学的最新进展，开发新的类肽模拟配体的配置文件的μ/δ阿片受体激动剂的活动和神经激肽1拮抗剂的活动。我们的具体目标是：目标1：基于TY 027（当前的先导化合物（δ阿片受体激动剂偏好/NK 1拮抗剂）），设计、合成和表征具有NK-1拮抗剂活性的新型代谢稳定和全身活性双功能<$1/4阿片受体激动剂配体。生物物理学研究（核磁共振、CD、PWR等）结合计算化学将用于评估生物活性的关键三维构象。目的2将在体外和体内表征这些化合物的药理学：（a）镇痛/抗痛觉过敏功效;（B）发展抗伤害性耐受和阿片类药物诱导的痛觉过敏的倾向;（c）镇静;（d）胃肠道副作用;和（f）成瘾倾向。目的3将评价（a）我们的新化合物的代谢稳定性，（B）进行药代动力学分析，（c）评价BB B渗透和化合物是否是β-糖蛋白的底物，和（d）对可能的脱靶活性进行广泛筛选。我们的目标将是发现一种高效的配体和备用配体，可以在此资助期间作为临床前候选药物。

DESCRIPTION (provided by applicant): Treatment of pain remains a major unmet medical need. Opiate drugs continue to be the most important therapies for the treatment of moderate to severe pain but suffer from severe side effects that diminish quality of life. It is known that neurons in the pain transmission and modulatory pathways undergo plasticity that results in amplification of pain signaling in settings of tissue injury (i.e. the conditions in which pain relieving drugs are used). Unexpectedly, such pronociceptive adaptations also occur as a consequence of repeated exposure to opiates. Increased signaling through the substance P-NK1 pathway strongly contributes to peripheral and central sensitization to enhance pain. This multidisciplinary proposal involving five different laboratories, is aimed at testing the hypothesis that pain relieving drugs can be designed with a priori consideration of mechanisms of amplification that diminish desired analgesia, i.e., drug design for disease. We hypothesize that drugs that have opioid agonist (mostly mu) and NK-1 antagonist activity within a single molecule would provide effective pain relief, particularly in conditions of chronic pain with diminished side effects allowing for greater tolerability and increased quality of life. Thus, we propose to exploit recent developments in our de novo design and pain-related pharmacology, physiology and molecular biology to develop new classes of peptidomimetic ligands with a profile of mu/delta opioid receptor agonist activities and neurokinin 1 antagonist activities. Our Specific Aims are: Aim 1: To design, synthesize and characterize novel metabolically stable and systemically active bifunctional ¿ preferring ¿/4 opioid agonist ligands with NK-1 antagonist activities based on TY027, a current lead compound (delta opioid agonist preferring/NK1 antagonist). Biophysical studies (NMR, CD, PWR, etc.) in conjunction with computational chemistry will be used to evaluate 3-D conformations critical to bioactivity. Aim 2 will characterize the pharmacology of these compounds in vitro and in vivo for (a) analgesic/antihyperalgesic efficacy; (b) propensity for developing antinociceptive tolerance and opioid-induced hyperalgesia; (c) sedation; (d) gastrointestinal side effects; and (f) addictive liability. Aim 3 will evaluate the (a) metabolic stability of our novel compounds, (b) perform pharmacokinetic analysis, (c) evaluate BBB penetration and whether the compounds are substrates for P- glycoproteins, and (d) perform a broad screen for possible off-target activities. Our goal will be to discover a highly efficacious ligand, and backup ligand, that can be brought forward as a preclinical drug candidate during this grant period.