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，其将介导包括神经性疼痛在内的长时间疼痛，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、药理学和生物化学研究提供证据表明，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。在这个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，疼痛相关的药理学，生理学和分子生物学的最新进展，开发新的配体类别，将测试的假设，即配体与阿片受体激动剂活性和神经激肽I拮抗剂活性的配置文件将显示突出的抗伤害性和抗异常性疼痛的疗效在长期的疼痛状态，并不会表现出耐受性。我们的具体目标是：1）设计、合成和体外评价具有阿片受体激动剂活性和NK 1受体选择性拮抗剂活性的新型肽模拟物、非肽缀合物; 2）开发使具体目标1成为可能的合成方法; 3）利用生物物理方法（NMR、X射线、PWR光谱等）。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测配体的结合亲和力和GTP γ S结合，并使用PI水解测定检测配体与NK 1受体的结合及其拮抗剂性质; 5）证明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）证明重复施用我们的新配体缺乏耐受性; 7）为了继续寻找作为高选择性全身活性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。

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.