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: 9918390
• 负责人: Victor J Hruby
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9918390
• 关键词: Acute; Addictive Behavior; Address; 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; Drug abuse; Environment; Evaluation; Goals; Half-Life; Hour; Human; Lead; Ligands; Maintenance; Membrane; Metabolic; Modality; Molecular Conformation; Morphine; Neuromedin K Receptor; Opioid; Opioid Antagonist; Opioid Receptor; Opioid agonist; Pain; Pain management; Pathway interactions; Peptide Synthesis; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacology; 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; blood-brain barrier penetration; chronic pain; delta opioid receptor; delta receptors; 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; side effect; 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： 本研究的目标是设计和发现新的多肽和模拟多肽的配体。 它们是多价配体，可以作为u和Delta阿片受体和拮抗剂的激动剂。 在神经激肽-1(NK-1)受体上，所有这些都在一个分子中。这些配体可以作为强效镇痛剂。 在慢性疼痛状态下，包括神经病理性疼痛，使用新的作用机制，但没有 当前阿片类药物的毒副作用。为此，我们正在开发一种全面的 方法包括：计算机辅助设计新的多价配体，不对称合成 新型氨基酸、具有独特构象的多肽和多肽模拟物的设计与合成 特性，特别是在膜环境中，用于治疗疼痛的独特生物特性 没有毒性和耐受性，具有独特的穿透膜屏障的能力。我们 将追求这些目标，具体目标如下：1)设计和合成新颖的多价 具有强大的Mu和Delta阿片受体激动剂活性的配体，中性和(Mu优先)和 强大的NK-1受体拮抗剂活性；2)结合生化核心，评估 具有全面结合亲和力和药效的这些化合物的药理活性 Mu、Delta和NK-1受体(根据需要，还包括kappa阿片受体和NK-3受体)；3) 通过生物物理研究(核磁共振、CD等)评价最佳配体的构象性质在……里面 水和膜环境；4)与生化和合成核心相结合，以 在体内评价它们的生物活性，以证明其在体内模型中的效力和疗效 急性、长期和神经性疼痛状态，并确定它们没有毒性副作用 发现在目前的止痛药，包括抑制肠道传输，呕吐，发展成瘾 行为、缺乏呼吸抑制和发展耐受性。我们还将评估他们的 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 两到三个有效的、稳定的和生物可用的配体，具有所需的生物活性 人体临床试验中的检查。