NOVEL NON-PEPTIDE OPIOID LIGANDS FOR PAIN

描述（由申请人提供）：本研究项目的长期目标是寻找具有新型生物学特征的新型配体，这些配体将介导包括神经性疼痛在内的长期疼痛，而没有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、药理学和生化研究表明，在持续疼痛状态下，神经肽及其受体的表达和活性与正常生理状态不同。在这个涉及三个不同实验室的多学科提案中，我们将利用新设计，疼痛相关药理学，生理学和分子生物学的最新发展来开发新型配体，这些配体将测试具有阿片受体激动剂活性和神经激肽I拮抗剂活性的配体在长期疼痛状态下表现出出色的抗痛觉和抗allodyic功效而不会表现出耐受性的假设。我们的具体目标是：1)设计、合成和评估体外新型的类肽物、非肽偶联物、阿片受体激动剂活性和NK1受体选择性拮抗剂活性；2)开发综合方法，使具体目标1成为可能；3)利用生物物理方法（核磁共振，x射线，压水光谱学等）结合计算化学来确定三维药效团，以供进一步设计；4)利用大鼠脑同源物和稳定转染的含人阿片受体的细胞系检测配体的结合亲和力和GTPgammaS的结合，并利用PI水解法检测其与NK1受体的结合及其拮抗剂特性；5)验证这些化合物在几种疼痛模型中的体内生物活性和神经适应性变化；6)反复使用我们的新配体证明缺乏耐受性；7)继续寻找具有高选择性系统活性mu受体拮抗剂的新型配体，具有新型生物活性特征的新型配体和用于疼痛控制的新型作用机制将从这些研究中得到结果。

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.