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

本研究的长期目标是发现和设计新的肽和拟肽配体 包括可以在慢性疼痛状态（例如神经性疼痛等）中作为有效镇痛剂的二价配体。 使用新的作用机制，并且不具有当前阿片类药物的基本毒副作用， 呼吸抑制和耐受性。为此，我们正在制定一项全面的办法， 包括新配体的计算机辅助设计、新氨基酸的不对称合成和p-turn 模拟物;具有独特构象和形貌特性的肽和肽模拟物;肽 具有独特生物学性质的配体;以及使用构象， 这些配体的拓扑和动力学性质，以帮助了解其独特的生物学性质 并为进一步的设计提供见解。为了实现这些目标，我们有以下具体目标：1） 确定可能具有相互作用的非阿片类强啡肽A片段肽的结构特征 与缓激肽2受体的一个推定的新位点结合，并激活它形成一个新的信号通路， 2）设计和开发单一结构的二价配体 其作为μ/δ阿片样物质激动剂和缓激肽受体拮抗剂，以获得可以治疗 阿片类药物副作用最小的神经病理性疼痛状态; 3）优化双啡肽相关的结构 具有μ/δ阿片样物质活性但显示最小或没有不希望的毒副作用的化合物 阿片类配体如耐受性、戒断症状等的研究; 4）探索设计合成新的 限制性氨基酸、氨基酸嵌合体和p-转角模拟物，其可以使侧链基团偏向x1 和X2扭转角和/或优选的骨架构象，用于结合到新的配体中， 提高体外和体内生物学特性; 5）利用计算和建模方法， 许多生物物理工具，包括2D NMR、CD和等离子体波导共振（PWR） 光谱，以获得新的见解的关系，构象和地形结构， 生物活性，并通过我们的新型配体获得信号转导的见解。

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.