NOVEL NON-PEPTIDE OPIOID LIGANDS FOR PAIN

描述(申请人提供)：这项研究项目的长期目标是寻找具有新的生物学特性的新的配体，这些配体将调节包括神经病理性疼痛在内的长期疼痛，而不会产生目前临床药物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，以测试以下假设：具有阿片受体激动剂活性和神经激动素I拮抗剂活性的配体在长时间的疼痛状态下将显示出出色的抗伤害和止痛效果，并且不会表现出耐受性。我们的具体目标是：1)设计、合成和体外评价阿片受体激动剂活性和NK1受体选择性拮抗剂活性的非肽类化合物；2)开发合成方法，使特定目标1成为可能；3)利用生物物理方法(核磁共振、X射线、PWR波谱等)。结合计算化学确定进一步设计的三维药效团；4)使用大鼠脑匀浆和稳定转染人阿片受体的细胞系，检测配体的结合亲和力和GTP-GammaS结合，并使用PI水解法检测与NK1受体的结合及其拮抗剂特性；5)展示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)通过重复使用我们的新配体来证明缺乏耐受性；7)继续寻找具有高度选择性、系统活性的Mu受体拮抗剂的新配体，这些研究将产生具有新的生物活性和新的止痛作用机制的新配体。

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.