DESIGN OF NOVEL LIGANDS WITH UNIQUE BIOLOGICAL PROFILES FOR NEUROPATHIC PAIN AND

这项研究的长期目标是发现和设计新的多肽和模拟多肽的配体 包括可在慢性疼痛状态(如神经病理性疼痛等)中起到有效止痛剂作用的二价配体。 使用新的作用机制，并且没有目前阿片类药物的基本毒副作用，如 呼吸抑制和耐受性。为此，我们正在制定一项全面的方法， 包括新型配体的计算机辅助设计；新型氨基酸和p-转角的不对称合成 模拟学；具有独特构象和地形学性质的多肽和多肽模拟学；多肽 具有独特生物特性的配体；以及对构象的各种生物物理研究的使用， 这些配体的地形和动力学性质有助于了解它们独特的生物学性质 并为进一步的设计提供了见解。为了实现这些目标，我们有以下具体目标：1) 确定可能存在相互作用的非阿片类强啡肽A片段的结构特征 与一个假定的缓激肽2受体的新位置，并激活它为一个新的信号通路，并 为这个新的结合位点开发拮抗剂；2)设计和开发单一结构的二价配体 作为Mu/Delta阿片激动剂和缓激肽受体拮抗剂，以获得可以治疗的配体 阿片类药物副作用最小的神经病理性疼痛状态；3)优化双酚类药物相关结构 具有Mu/Delta阿片活性，但表现出最小或没有不良毒副作用的化合物 阿片类配体耐受性、戒断症状等；4)探索新型阿片类配体的设计与合成 限制性氨基酸、氨基酸嵌合体和可在x1偏向侧链基团的p-转弯模拟物 和X2扭转角和/或优选主链构象，用于结合到新的配体中以 增强体外和体内生物学特性；5)利用计算和建模方法以及 生物物理工具的数量，包括2D核磁共振、CD和等离子体波导管共振(PWR) 光谱学，以获得构象和地形结构与 生物活性，并深入了解我们的新型配体的信号转导。

The long term goals of this research are to discover and design novel peptide and peptidomimetic ligands including bivalent ligands that can act as potent analgesics in chronic pain states (e.g. neuropathic pain, etc.) using new mechanisms of action, and that do not have the basic toxic side effects of current opioids such as respiratory depression and tolerance. For this purpose we are developing a comprehensive approach that includes computer assisted design of novel ligands; asymmetric synthesis of novel amino acids and p-turn mimetics; peptides and peptidomimetics with unique conformational and topographical properties; peptide ligands with unique biological properties; and use of a variety of biophysical studies of the conformational, topographical and dynamic properties of these ligands to help understand their unique biological properties and provide insights for further design. To pursue these goals we have the following Specific Aims: 1) To determine the structural features of non-opioid dynorphin A fragment peptides that may have interactions with a putative novel site of the bradykinin 2 receptor and activate it for a novel signaling pathway, and to develop antagonists for this novel binding site; 2) To design and develop bivalent ligands in a single structure that act as mu/delta opioid agonists and bradykinin receptor antagonists, to obtain ligands that can treat neuropathic pain states with minimal side effects of opiates; 3) To optimize structures of biphalin-related compounds that have mu/delta opioid activity but show minimal or none of undesirable toxic side effects of opioid ligands such as tolerance, and withdrawal symptoms; 4) To explore the design and synthesis of novel constrained amino acids, amino acid chimeras, and p-turn mimetics that can bias side chain groups at x1 and x2 torsional angles and/or in preferred backbone conformations for incorporation into novel ligands to enhance in vitro and in vivo biological properties; 5) To utilize computational and modeling methods and a number of biophysical tools including 2D NMR, CD, and plasmon waveguide resonance (PWR) spectroscopy to obtain novel insights into the relationships of conformational and topographical structure to biological activity, and to obtain insights into signal transduction by our novel ligands.