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.

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