Design of Novel Multivalent Ligands with Unique Biological Activity Profiles for Treatment of Prolonged and Neuropathic Pain without Toxicities

具有独特生物活性特征的新型多价配体的设计，用于无毒治疗长期疼痛和神经性疼痛

• 批准号: 9073237
• 负责人: Victor J Hruby
• 金额: $ 5.65万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9073237
• 关键词: Acute; Addictive Behavior; Address; Adverse effects; Affinity; Agonist; Amino Acids; Analgesics; Animal Model; Anxiety; Binding; Bioavailable; Biochemical; Biodistribution; Biological; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Chemicals; Clinical Trials; Collaborations; Computer-Aided Design; Constipation; Cyclic AMP; Development; Dose; Environment; Evaluation; Goals; Half-Life; Hour; Human; Lead; Ligands; Maintenance; Membrane; Metabolic; Modality; Molecular Conformation; Morphine; Narcotic Antagonists; Neuromedin K Receptor; Opioid; Opioid Receptor; Pain; Pain management; Pathway interactions; Penetration; Peptide Synthesis; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Plasma; Property; Public Health; Quality of life; Rattus; Research; Research Project Grants; Rewards; Serum; Societies; Structure; Substance P; Substance P Receptor; Time; Toxic effect; Ventilatory Depression; Vomiting; Work; addiction; analog; aqueous; base; biophysical analysis; biophysical tools; chronic pain; delta opioid receptor; design; drug seeking behavior; experimental study; improved; in vivo; in vivo Model; insight; kappa opioid receptors; motor impairment; nanomolar; novel; novel strategies; novel therapeutic intervention; painful neuropathy; peptidomimetics; pharmacophore; preference; receptor; single molecule

Summary - Project A: The goals of this research project are to design and discover novel peptide and peptidomimetic ligands that are multivalent ligands that can act as agonists at the mu and delta opioid receptors and antagonists at the neurokinin-1 (NK-1) receptor, all in a single molecule. These ligands can act as potent analgesics in chronic pain states, including neuropathic pain, using new mechanisms of action, but do not have any of the toxic side effects of current opioids. For this purpose, we are developing a comprehensive approach that includes: computer aided design of novel multivalent ligands, asymmetric synthesis of novel amino acids, design and synthesis of peptides and peptidomimetics with unique conformational properties, especially in membrane environments, unique biological properties for treatment of pain without toxicities and tolerance development, and unique abilities to penetrate membrane barriers. We will pursue these goals, with the following Specific Aims: 1) to design and synthesize novel multivalent ligands that have potent mu and delta opioid receptor agonist activity neutral and (mu preferring) and potent NK-1 receptor antagonist activity; 2) in conjunction with the Biochemical Core, to evaluate the pharmacological activities of these compounds with comprehensive binding affinities and efficacies at mu, delta and NK-1 receptors (also as needed, kappa opioid receptors and NK-3 receptors); 3) to evaluate the conformational properties of the best ligands by biophysical studies (NMR, CD, etc.) in aqueous and membrane environments; 4) in conjunction with the Biochemical and Synthesis Cores, to evaluate their biological activities in vivo to demonstrate the potency and efficacy in in vivo models of acute, prolonged and neuropathic pain states, and determine their lack of toxic side effects that are found in current analgesic drugs, including inhibition of gut transit, emesis, development of addictive behaviors, lack of respiratory depression and development of tolerance. We also will evaluate their ability to cross membrane barriers and their stability and biodistribution in vivo. A major goal is to obtain two or three potent, stable and bioavailable ligands with the desired biological activity profiles for examination in human clinical trials.

摘要-项目A： 本研究计划的目标是设计和发现新的肽和拟肽配体 它们是可以作为μ和δ阿片受体的激动剂和拮抗剂的多价配体 在神经激肽-1（NK-1）受体，所有在一个单一的分子。这些配体可以作为有效的镇痛剂 在慢性疼痛状态，包括神经性疼痛，使用新的作用机制，但没有任何 阿片类药物的毒副作用为此，我们正在制定一项全面的 方法，包括：计算机辅助设计的新的多价配体，不对称合成的 新的氨基酸，具有独特构象的肽和肽模拟物的设计和合成 特性，特别是在膜环境中，用于治疗疼痛的独特生物学特性 没有毒性和耐受性发展，以及独特的穿透膜屏障的能力。我们 我们将继续致力于这些目标，具体目标如下：1）设计和合成新的多价 具有有效的μ和δ阿片样物质受体激动剂活性的配体， 有效的NK-1受体拮抗剂活性; 2）与生化核心结合，以评估 这些化合物的药理活性具有全面的结合亲和力和功效， μ、δ和NK-1受体（也根据需要，κ阿片受体和NK-3受体）; 3） 通过生物物理研究（NMR，CD等）评估最佳配体的构象特性在 水和膜环境; 4）与生物化学和合成核心结合， 评价其体内生物活性，以证明其在体内模型中的效力和功效， 急性，长期和神经性疼痛状态，并确定其缺乏毒性副作用， 在目前的镇痛药物中发现，包括抑制肠道运输，呕吐，成瘾性发展， 行为，缺乏呼吸抑制和耐受性的发展。我们也将评估他们的 通过膜屏障的能力及其在体内的稳定性和生物分布。一个主要目标是获得 两种或三种有效的、稳定的和生物可利用的配体，其具有所需的生物活性特征， 在人体临床试验中进行检测。