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： 该研究项目的目标是设计和发现新型的肽和肽含量配体 这是可以在MU和Delta阿片受体和拮抗剂上充当激动剂的多价配体 在单个分子中，在Neurokinin-1（NK-1）受体上。这些配体可以充当有效的镇痛药 在慢性疼痛状态中，包括神经性疼痛，使用新的作用机理，但没有任何 当前阿片类药物的有毒副作用。为此，我们正在开发一个全面的 方法包括：新型多价配体的计算机辅助设计，不对称合成 新型氨基酸，具有独特构象的肽和肽仪的设计和合成 特性，尤其是在膜环境中，用于治疗疼痛的独特生物学特性 没有毒性和耐受性的发展，也没有渗透膜屏障的独特能力。我们 将实现这些目标，并具有以下特定目的：1）设计和综合新颖的多价 具有有效MU和三角洲阿片受体激动剂活性中性和（MU更喜欢）和（MU）和 有效的NK-1受体拮抗剂活性； 2）与生化核心一起评估 这些化合物的药理活动具有全面的结合亲和力和有效性 MU，Delta和NK-1受体（也根据需要，Kappa阿片受体和NK-3受体）； 3）到 通过生物物理研究（NMR，CD等）评估最佳配体的构象性能 水和膜环境； 4）与生化和合成核的结合 评估其在体内生物学活动，以证明体内模型的效力和功效 急性，长时间和神经性疼痛状态，并确定其缺乏有毒的副作用 在当前的镇痛药中发现，包括抑制肠道过境，呕吐，成瘾性的发展 行为，缺乏呼吸道抑郁和耐受性的发展。我们还将评估他们的 能够穿越膜屏障及其在体内的稳定性和生物分布。一个主要目标是获得 两三个有效的，稳定和可生物利用的配体具有所需的生物学活性曲线 在人类临床试验中检查。