NOVEL NON-PEPTIDE OPIOID LIGANDS FOR PAIN

描述：（申请人摘要） 该研究项目的长期目标是寻找新的配体， 新的生物学特性，将介导剧烈疼痛而无毒性副作用 临床医学中使用的电流上传的影响。最近的生理， 药理学和分子生物学证据提供了证据， 持续性疼痛状态的表达和活动的神经肽和其他 神经调质不同于正常生理状态。这将创建 开发具有强效镇痛作用的阿片配体的新范例 但没有目前上传的一些毒副作用。在 我们提议的这项多学科资助涉及三个不同的实验室 利用最近的发展，从头设计，组合化学， 阿片类药物药理学、生理学和分子生物学，以开发新类别的 非肽模拟肽配体，其将检验配体 具有μ激动剂和δ拮抗剂活性的特征，并且其可以 穿过血脑屏障将显示出出色的抗异常性疼痛和 在慢性神经性疼痛状态中的抗伤害感受功效， 表现出宽容此外，为了更清楚地研究 新的上传的作用，我们希望开发新的有效的高选择性的使用 拮抗剂和5个拮抗剂，穿过血脑屏障，不具有长期作用 当前选择性拮抗剂的毒性。我们的具体目标是：1。去设计， 用u激动剂/6合成和体外评价新型非肽配体 拮抗剂的生物活性，通过血脑屏障。2.为了检验效力 使用放射性配体结合、GTP γ S、MVD 和GPI测定。3.证明抗痛觉过敏、抗异常性疼痛和 β激动剂/β拮抗剂的抗伤害感受功效 局4.为了证明缺乏抗伤害耐受性， 反复全身给药。5.利用计算机辅助分子 建模、构象分析、生物物理方法（NIVIR、CD、X射线等） 以确定我们最好的配体的生物活性构象，然后 比较它们的地形结构， 肽药效团，因此，真正的非肽肽模拟物的方法 可以实现。6.设计和评价新的非肽配体， 全身活性δ拮抗剂;和7.设计和评估新的 作为全身活性拮抗剂的非肽配体。 具有新的疼痛控制机制的新的配体， 这些研究将产生解决疼痛控制中未满足需求的方法。

DESCRIPTION: (Applicant's Abstract) The long term goals of this research project are to find novel ligands with novel biological profiles that will mediate severe pain without the toxic side effects of current uploads used in clinical medicine. Recent physiological, pharmacological and molecular biological evidence provide evidence that in persistent pain states the expression and activity of neuropeptides and other neuromodulators are different than in normal physiological states. This creates new paradigms for development of opioid ligands with potent analgesic properties but without some of the toxic side effects of current uploads. In this muIti-disciplinary grant involving three different laboratories we propose to exploit recent developments in de novo design, combinatorial chemistry, opioid pharmacology, physiology and molecular biology to develop new classes of non-peptide peptidomimetic ligands that will test the hypothesis that ligands with a profile of mu agonist and delta antagonist activities and which can cross the blood-brain-barrier will show outstanding antiallodynic and antinociceptive efficacy in chronic neuropathic pain states and will not demonstrate tolerance. Furthermore, to more clearly examine the mechanism of action of novel uploads, we wish to develop novel potent highly selective u antagonist and 5 antagonists that cross the BBB and do not have the long term toxicity of current selective antagonists. Our Specific Aims are: 1. To design, synthesize and evaluate in vitro, novel non-peptide ligands with u agonist/6 antagonist biological activity that cross the BBB. 2. To examine the potency and efficacy of the novel ligands using radioligand binding, GTP gamma S, MVD and GPI assays. 3. To demonstrate antihyperalgesic, antiallodynic and antinociceptive efficacy of p agonist/6 antagonist following systemic administration. 4. To demonstrate a lack of antinociceptive tolerance following repeated systemic administration. 5. To utilize computer aided molecular modeling, conformational analysis, biophysical method (NIVIR, CD, X-ray, etc.) to determine the bioactive conformations of our best ligands, and then to compare their topographical structures to see their relationships to the peptide pharmacophores, so that an approach to true non-peptide peptidomimetics can be achieved. 6. To design and evaluate novel non-peptide ligands that are systemically active delta antagonists; and 7. To design and evaluate novel non-peptide ligands that are systemically active 5 antagonists. Novel new ligands with novel mechanisms of pain control that provide new approaches to unmet needs in pain control will result from these studies.