Novel Non-Peptide Opioid Ligands for Pain

描述（由申请人提供）：治疗疼痛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，但其严重的副作用会降低生活质量。众所周知，疼痛传递和调节通路中的神经元具有可塑性，导致组织损伤（即使用止痛药物的情况）下疼痛信号的放大。出乎意料的是，这种先觉性适应也会作为反复接触鸦片剂的结果而发生。通过P-NK1物质通路增加的信号强烈促进外周和中枢致敏，从而增强疼痛。这项涉及5个不同实验室的多学科提案，旨在验证这样一种假设，即缓解疼痛的药物可以预先考虑放大机制，从而减少所需的镇痛，即针对疾病的药物设计。我们假设在单个分子中具有阿片受体激动剂（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，特别是在副作用减少的慢性疼痛条件下，允许更大的耐受性和提高生活质量。因此，我们建议利用我们在从头设计和疼痛相关药理学，生理学和分子生物学方面的最新进展来开发具有mu/ δ阿片受体激动剂活性和神经激肽1拮抗剂活性的新型肽类配体。我们的具体目标是：目标1：设计、合成和表征基于TY027（目前的先导化合物）的具有NK-1拮抗剂活性的新型代谢稳定和系统活性的双功能阿片受体拮抗剂配体（δ阿片受体拮抗剂）。生物物理研究（NMR， CD， PWR等）结合计算化学将用于评估对生物活性至关重要的3-D构象。目的2将描述这些化合物在体外和体内的药理学(a)镇痛/抗痛觉功效；(b)产生抗痛觉耐受性和阿片类药物引起的痛觉过敏的倾向；(c)镇静;(d)胃肠道副作用；(f)成瘾性。Aim 3将评估(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)评估血脑屏障渗透以及这些化合物是否为P-糖蛋白的底物，(d)对可能的脱靶活性进行广泛筛选。我们的目标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提出。

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.