New Modalities for the Treatment of Pain and Drug Abuse

治疗疼痛和药物滥用的新方法

• 批准号: 9918285
• 负责人: Victor J Hruby
• 金额: $ 52.92万
• 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/9918285
• 关键词: Address; Affect; Agonist; Analgesics; Back; Biochemical; Biochemistry; Biological; Biological Assay; Biophysics; Blood - brain barrier anatomy; Brain; Brain Stem; CNR1 gene; CNR2 gene; Cannabinoids; Characteristics; Chemicals; Chemistry; Cholecystokinin; Chronic; Clinical; Clinical Trials; Data; Deep Brain Stimulation; Disease; Drug Addiction; Drug Design; Drug abuse; Effectiveness; Equilibrium; Formulation; Goals; HIV; Human; In Vitro; Individual; Infection; Inflammatory; Injury; Lead; Ligands; Medical; Modality; Molecular Biology; Nervous system structure; Neurobiology; Neurokinin B; Nociception; Non-Malignant; Opioid; Oral; Pain; Pain Research; Pain management; Patient Care; Patients; Penetration; Peptides; Peripheral; Peripheral Nervous System; Peripheral nerve injury; Pharmaceutical Preparations; Pharmacology; Physicians; Principal Investigator; Process; Property; Public Health; Quality of life; Research; Resistance; Risk; Signal Transduction; Skin; Societies; Spinal; Spinal Cord; Substance P Receptor; Testing; Therapeutic; Toxicology; Up-Regulation; addiction; cannabinoid drug; cannabinoid receptor; chronic pain; clinical practice; clinically relevant; delta opioid receptor; design; drug seeking behavior; economic cost; human imaging; improved; in vivo; inflammatory neuropathic pain; multidisciplinary; neuroadaptation; neuromechanism; novel; novel therapeutics; pain signal; painful neuropathy; peptidomimetics; personalized medicine; pharmacokinetics and pharmacodynamics; pre-clinical; professor; programs; public health relevance; receptor; relating to nervous system; response; side effect; single molecule; socioeconomics; success; synergism

DESCRIPTION (provided by applicant): While much has been learned about the neurobiology of pain, it is disappointing that an insufficient number of novel therapies have been introduced into clinical practice. Moderate to severe pain is still treated mechanistically with opiate mu agonists and while some new mechanisms and improved formulations have improved patient care, it is widely acknowledged that the armamentarium available to physicians for the treatment of chronic pain is inadequate and that there is a large unmet medical need. The significance of our application is to address the clinical need for medications for injury or disease-induced chronic non-malignant pain with new mechanisms of action. Our goals in this PPG proposal are driven by the need of patients for new therapies to control pain as well as issues relevant to society including addiction and drug abuse. The proposals we have developed are comprehensive, multidisciplinary, and emphasize novel research hypotheses. This application brings together state-of-the-art chemistry, pharmacology, biophysics, biochemistry, and molecular biology all of which are necessary for success. Our central hypothesis is that drug design can consider known neural adaptations and mechanisms that may be relevant to specific pain conditions in order to develop improved pain therapeutics. We propose to design, synthesize and biologically validate multivalent drugs that can act as analgesics for the prolonged treatment of chronic non-malignant pain. The multifunctional characteristics of these single molecules are hypothesized to demonstrate diminished likelihood of drug addiction, drug seeking behavior, and tolerance without, or with greatly reduced, side effects that are present in currently available drugs and that diminish quality of life. Project A will be directed by Professo Victor Hruby and will focus on the discovery of multivalent opioid mu agonist-delta agonist and mu agonist/NK1 antagonist peptidic molecules with drug like characteristics and penetration across the blood brain barrier for delivery by systemic administration. Project B will be directed by Professors Frank Porreca and Ed Roberts and will aim to discover orally available and brain penetrant opioid mu/CCK antagonist molecules with drug like characteristics. Project C will be directed by Professors Alex Makriyannis, Todd Vanderah and Frank Porreca and will explore multifunctional cannabinoid agonists for improved treatment of HIV neuropathic pain. These projects will be supported by an Administrative Core (Hruby/Porreca), a synthetic core (Hruby) and a Biochemical Core (Vanderah/Streicher) that will allow maximal synergy and progress. Our goals are to discover single molecules with multiple receptor characteristics that have drug-like properties allowing for advancement to human trials for improved treatment of pain.

描述（由申请人提供）：虽然人们对疼痛的神经生物学了解很多，但令人失望的是，没有足够数量的新疗法被引入临床实践。中度至重度疼痛仍然采用阿片μ激动剂进行机械治疗，虽然一些新机制和改进的制剂改善了患者护理，但人们普遍认为，医生可用于治疗慢性疼痛的医疗设备不足，并且存在大量未满足的医疗需求。我们应用的意义在于通过新的作用机制解决损伤或疾病引起的慢性非恶性疼痛药物的临床需求。我们在此 PPG 提案中的目标是由患者对控制疼痛的新疗法的需求以及与社会相关的问题（包括成瘾和药物滥用）驱动的。我们提出的建议是全面的、跨学科的，并强调新颖的研究假设。该应用程序汇集了最先进的化学、药理学、生物物理学、生物化学和分子生物学，所有这些都是成功所必需的。我们的中心假设是，药物设计可以考虑可能与特定疼痛状况相关的已知神经适应和机制，以开发改进的疼痛疗法。我们建议设计、合成和生物学验证多价药物，这些药物可以作为长期治疗慢性非恶性疼痛的镇痛药。这些单分子的多功能特征被假设为证明药物成瘾、药物寻求行为和耐受性的可能性降低，而没有或大大减少了目前可用药物中存在的副作用，这些副作用降低了生活质量。 A 项目将由 Victor Hruby 教授领导，重点是发现多价阿片类药物 mu 激动剂-δ 激动剂和 mu 激动剂/NK1 拮抗剂肽分子，这些分子具有类似药物的特性，能够穿透血脑屏障，通过全身给药进行递送。 B 项目将由 Frank Porreca 和 Ed Roberts 教授指导，旨在发现具有药物特性的口服且脑渗透性阿片类 mu/CCK 拮抗剂分子。 C 项目将由 Alex Makriyannis、Todd Vanderah 和 Frank Porreca 教授领导，将探索多功能大麻素激动剂，以改善 HIV 神经性疼痛的治疗。这些项目将得到行政核心（Hruby/Porreca）、合成核心（Hruby）和生化核心（Vanderah/Streicher）的支持，从而实现最大的协同作用和进步。我们的目标是发现具有多种受体特征的单分子，这些分子具有类似药物的特性，从而可以进行人体试验以改善疼痛的治疗。