NOVEL NON-PEPTIDE OPIOID LIGANDS FOR PAIN

用于止痛的新型非肽阿片配体

基本信息

批准号：
7255810
负责人：
Victor J Hruby
金额：
$ 45.75万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7255810
关键词：
3-Dimensional Absence of pain sensation Academy Acute Acute Pain Address Adverse effects Affinity Agonist American Analgesics Animals Binding Biochemical Biological Biological Assay Brain Cell Line Class Clinical Medicine Computer Assisted Condition Country Data Development Disease Dose Drug Design Drug usage Economics Expenditure Exposure to Fiber GTP gamma S Goals Grant Health Human Hydrolysis Hyperalgesia In Vitro Injury Laboratories Ligand Binding Ligands Light Mediating Medical Methods Modeling Molecular Molecular Biology Molecular Conformation Morphine Nerve Nervous system structure Neuronal Plasticity Neurons Neuropeptides Neurosciences Neurotransmitter Receptor Nociception Nociceptive Stimulus Numbers Opiates Opioid Opioid Peptide Opioid Receptor Pain Pain management Pathology Pathway interactions Patients Peptides Persistent pain Pharmaceutical Preparations Pharmacology Physiological Physiology Principal Investigator Process Property Rattus Relative (related person)Research Research Project Grants Resistance Resources Roentgen Rays Safety Sensory Thresholds Signal Transduction Spectrum Analysis Spinal Cord Substance P Substance P Receptor Synthesis Chemistry System Testing Therapeutic United States National Institutes of Health Up-Regulation Visit Work aging population base cancer pain chronic neuropathic pain chronic pain computational chemistry concept cost design desire improved in vivo indium arsenide member mimetics mu opioid receptors multidisciplinary neuroadaptation new technology novel novel strategies painful neuropathy peptidomimetics pharmacophore preclinical study professor receptor response success tool trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): The long term goals of this research project are to find novel ligands with novel biological profiles that will mediate prolonged pain including neuropathic pain without the toxic side effects of current opioids used in clinical medicine. Recent physiological, pharmacological, and biochemical studies provides evidence that in persistent pain states the expression and activity of neuropeptides and their receptors are different than in normal physiological states. In this multidisciplinary proposal involving three different laboratories, we will exploit recent developments in de novo design, pain-related pharmacology, physiology and molecular biology to develop new classes ligands that will test the hypotheses that ligands with a profile of opioid receptor agonist activities and neurokinin I antagonist activities will show outstanding antinociceptive and antiallodynic efficacy in prolonged pain states and will not demonstrate tolerance. Our Specific Aims are:1) To design, synthesize and evaluate in vitro novel peptidomimetics, non-peptides conjugates that opioid receptor agonist activities AND NK1 receptor selective antagonist activities; 2) To develop synthetic methods to make Specific Aim 1 possible; 3) To utilize biophysical methods (NMR, X-ray, PWR spectroscopy, etc.) in conjunction with computational chemistry to determine the 3-D pharmacophores for further design; 4) To examine the ligands for their binding affinities and GTPgammaS binding using rat brain homegenates and stably transfected cell lines containing human opioid receptors, and examine binding to NK1 receptor and their antagonist properties using PI hydrolysis assays; 5) To demonstrate the in vivo biological activity of these compounds in several pain models and the neuroadaptive changes; 6) To demonstrate lack of tolerance with repeated administration of our novel ligands; 7) To continue to search for novel ligands that are highly selective systemically active mu receptor antagonists novel ligands with novel biological activity profiles and novel mechanisms of action for pain control will result from these studies.

描述（由申请人提供）：该研究项目的长期目标是寻找具有新颖生物学特征的新颖配体，这些配体将介导长期疼痛，包括神经性疼痛，而不会产生目前临床医学中使用的阿片类药物的毒副作用。最近的生理学、药理学和生化研究提供的证据表明，在持续性疼痛状态下，神经肽及其受体的表达和活性与正常生理状态下不同。在这项涉及三个不同实验室的多学科提案中，我们将利用从头设计、疼痛相关药理学、生理学和分子生物学的最新进展来开发新类别的配体，以测试具有阿片受体激动剂活性和神经激肽特征的配体的假设I拮抗剂活性在长期疼痛状态下将表现出突出的镇痛和抗异常疼痛功效，并且不会表现出耐受性。我们的具体目标是：1) 设计、合成和评价体外新型肽模拟物、具有阿片受体激动剂活性和NK1受体选择性拮抗剂活性的非肽缀合物； 2）开发合成方法以使特定目标1成为可能； 3) 利用生物物理方法（NMR、X射线、PWR光谱等）结合计算化学来确定3-D药效团以供进一步设计； 4) 使用大鼠脑同源物和含有人阿片受体的稳定转染细胞系检查配体的结合亲和力和 GTPgammaS 结合，并使用 PI 水解测定检查与 NK1 受体的结合及其拮抗剂特性； 5) 证明这些化合物在多种疼痛模型中的体内生物活性和神经适应性变化； 6) 证明我们的新型配体重复给药缺乏耐受性； 7) 继续寻找高度选择性的全身活性μ受体拮抗剂的新型配体，这些研究将产生具有新型生物活性特征和新型疼痛控制作用机制的新型配体。