Novel Non-Peptide Opioid Ligands for Pain

用于止痛的新型非肽阿片类配体

• 批准号: 8416276
• 负责人: Victor J Hruby
• 金额: $ 45.81万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416276
• 关键词: 3-Dimensional; Absence of pain sensation; Acute Pain; Adverse effects; Affect; Affinity; Agonist; American; Analgesics; Bioavailable; Blood - brain barrier anatomy; Cells; Characteristics; Chronic; Chronic inflammatory pain; Clinical; Data; Development; Disease; Dose; Drug Design; Drug Kinetics; Drug effect disorder; Drug usage; Effectiveness; Equilibrium; Exposure to; Freedom; G-Protein-Coupled Receptors; Goals; Grant; Human; Hyperalgesia; In Vitro; Injury; Laboratories; Lead; Ligands; Medical; Metabolic; Molecular Biology; Molecular Conformation; Nature; Nerve; Nervous system structure; Neuraxis; Neurobiology; Neuronal Plasticity; Neurons; Nociception; Nociceptors; Non-Malignant; Non-Steroidal Anti-Inflammatory Agents; Opiates; Opioid; Opioid Peptide; P-Glycoproteins; Pain; Pain management; Pain-Free; Pathology; Pathway interactions; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Principal Investigator; Process; Quality of life; Research; Sedation procedure; Signal Transduction; Substance P; Substance P Receptor; Synapses; Testing; Time; Tissues; Toxic effect; United States; base; cancer pain; central sensitization; chronic pain; computational chemistry; delta opioid receptor; design; drug candidate; drug seeking behavior; gastrointestinal; improved; in vivo; inflammatory pain; multidisciplinary; neuroadaptation; novel; novel strategies; painful neuropathy; peptidomimetics; pre-clinical; public health relevance; receptor; reuptake; single molecule; transmission process; triptans

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.

描述（由申请人提供）：疼痛的治疗仍然是一个未满足的主要医疗需求，阿片类药物仍然是治疗中度至重度疼痛的最重要的疗法，但众所周知，阿片类药物存在严重的副作用，会降低生活质量。疼痛传递和调节通路中的神经元经历可塑性，导致组织损伤情况下（即使用止痛药物的情况）疼痛信号的放大，出乎意料的是，这种促伤害性适应也会发生。由于反复接触阿片类药物，通过 P-NK1 物质途径的信号增强强烈促进外周和中枢敏化，从而增强疼痛。这项涉及五个不同实验室的多学科提案旨在检验可以设计止痛药物的假设。事先考虑了减弱所需镇痛作用的放大机制，即针对疾病的药物设计，我们利用了在单一药物中具有阿片类激动剂（主要是 mu）和 NK-1 拮抗剂活性的药物。分子将提供有效的疼痛缓解，特别是在慢性疼痛的情况下，并减少副作用，从而提高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药理学、生理学和分子生物学的最新进展。开发具有 mu/delta 阿片受体激动剂活性和神经激肽 1 拮抗剂活性的新型拟肽配体 我们的具体目标是： 目标 1：设计、合成和表征新型代谢稳定且系统性的。主动双功能更喜欢 ¿ /4 基于 TY027 的具有 NK-1 拮抗剂活性的阿片类激动剂配体，TY027 是一种当前的先导化合物（δ 阿片类激动剂优选/NK1 拮抗剂），生物物理研究（NMR、CD、PWR 等）将与计算化学结合使用。目标 2 评估对生物活性至关重要的 3-D 构象，以表征这些化合物的体外和体内药理学 (a) 镇痛/抗痛觉过敏功效；药物耐受性和阿片类药物引起的痛觉过敏的倾向；(d) 胃肠道副作用；(f) 成瘾倾向；(a) 我们的新型化合物的代谢稳定性；(b) 药代动力学。分析，(c) 评估 BBB 渗透以及化合物是否是 P-糖蛋白的底物，以及 (d) 对可能的脱靶活性进行广泛筛选。有效配体和备用配体，可以在本次资助期间作为临床前候选药物提出。