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

设计具有独特生物特征的新型配体，用于治疗神经病理性疼痛和

基本信息

批准号：
8025975
负责人：
Victor J Hruby
金额：
$ 19.82万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8025975
关键词：
Address Adverse effects Affinity Agonist Amino Acids Analgesics Binding Binding Sites Biochemical Biological Biological Availability Bradykinin Bradykinin B2 Receptor Bradykinin Receptor Calcium Calcium Channel Cell Line Chimera organism Collaborations Computer Simulation Computer-Aided Design Constipation Development Drug Addiction Drug abuse Dynorphin A Dynorphins Environment Evaluation Financial cost G-Protein-Coupled Receptors GTP-Binding Proteins Goals Human Hyperalgesia Hypersensitivity Illicit Drugs In Vitro Injury Intrathecal Injections Investigation Kallidin Kinetics Kininogens Label Lead Ligands Link Lipids Maintenance Mediating Medicine Membrane Methods Modality Modeling Molecular Molecular Conformation Opiates Opioid Opioid Receptor Pain Pain Threshold Pain management Peptide Fragments Peptides Pharmaceutical Preparations Physicians Physiological Process Production Property Protein Binding Proteolipids Public Health Radioactive Reporting Research Roentgen Rays Safety Scientist Side Signal Pathway Signal Transduction Signal Transduction Pathway Site Societies Spectrum Analysis Spinal Spinal Cord Structure Sum Tactile Technology Therapeutic Thermal Hyperalgesias Thermodynamics Time Ventilatory Depression Vertebral column Withdrawal Withdrawal Symptom Work base biphalin brain tissue chronic pain design drug of abuse drug seeking behavior in vivo insight mimetics novel novel strategies painful neuropathy peptidomimetics planetary Atmosphere professor programs receptor response success tool voltage

项目摘要

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.

这项研究的长期目标是发现和设计新颖的肽和肽合子配体包括可以充当慢性疼痛状态（例如神经性疼痛等）中有效镇痛药的二价配体使用新的作用机理，并且没有当前阿片类药物的基本毒性副作用，例如呼吸抑郁和耐受性。为此，我们正在开发一种全面的方法包括新颖配体的计算机辅助设计；新型氨基酸和p转弯的不对称合成模拟物；具有独特构象和地形特性的肽和肽仪；肽具有独特生物学特性的配体；并使用多种构象生物物理研究，这些配体的地形和动态特性，以帮助了解其独特的生物学特性并提供进一步设计的见解。为了实现这些目标，我们具有以下具体目标：1）确定可能具有相互作用的片段肽的非阿片类药物的结构特征带有布拉迪基蛋白2受体的假定新颖位点，并激活它以进行新的信号传导途径，并将其激活为这个新颖的结合位点发展拮抗剂； 2）在单个结构中设计和开发二价配体它充当MU/Delta阿片类药物激动剂和Bradykinin受体拮抗剂，以获得可以治疗的配体神经性疼痛状态，阿片类药物的副作用最小； 3）优化与双脑相关的结构具有MU/DELTA阿片类药物活性但没有最小或没有不良的有毒副作用的化合物阿片类药物配体，例如耐受性和戒断症状； 4）探索新颖的设计和综合受约束的氨基酸，氨基酸嵌合体和P-Turn Mimetics可以在X1处偏置侧链基团和x2扭转角度和/或在首选的主链构象中掺入新的配体中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 NMR，CD和等离子体波导共振（PWR）光谱法获得了对构象和地形结构与关系关系的新见解生物活性，并通过我们的新型配体对信号转导的见解。