New Modalities for the Treatment of Pain and Drug Abuse

描述(由申请人提供)：虽然关于疼痛的神经生物学已经有了很多了解，但令人失望的是，没有足够数量的新疗法被引入临床实践。中度到重度疼痛仍然使用阿片类MU激动剂进行机械治疗，虽然一些新的机制和改进的配方改善了患者的护理，但人们普遍承认，医生用于治疗慢性疼痛的医疗设备不足，还有大量未得到满足的医疗需求。我们的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的药物临床需求。我们在PPG提案中的目标是出于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。我们开发的建议是全面的、多学科的，并强调新的研究假设。这一应用将最先进的化学、药理学、生物物理学、生物化学和分子生物学结合在一起，所有这些都是成功所必需的。我们的中心假设是，药物设计可以考虑已知的神经适应和可能与特定疼痛情况相关的机制，以开发改进的疼痛疗法。我们建议设计、合成和生物验证多价药物，这些药物可以作为长期治疗慢性非恶性疼痛的镇痛剂。这些单分子的多功能特征被假设为表明药物成瘾、寻求药物行为和耐受性降低的可能性降低，没有或极大地减少了现有药物中存在的副作用，这些副作用降低了生活质量。项目A将由Victor Hruby教授指导，重点是发现多价阿片类阿片类MU激动剂-Delta激动剂和MU激动剂/NK1拮抗剂多肽分子，具有药物样特性并可穿透血脑屏障，通过全身给药给药。项目B将由Frank Porreca教授和Ed Roberts教授指导，旨在发现具有药物样特征的口服阿片类药物MU/CCK拮抗剂分子。项目C将由Alex Makriyannis、Todd Vanderah和Frank Porreca教授指导，并将探索多功能大麻类激动剂来改进艾滋病毒神经性疼痛的治疗。这些项目将得到一个行政核心(Hruby/Porreca)、一个合成核心(Hruby)和一个生化核心(Vanderah/Streicher)的支持，这些核心将发挥最大的协同作用和取得进展。我们的目标是发现具有多种受体特性的单分子，这些分子具有类似药物的特性，从而可以进入改进疼痛治疗的人体试验。

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.