New Modalities for the Treatment of Pain and Drug Abuse

描述（由申请人提供）：虽然已经了解了很多关于疼痛的神经生物学，但令人失望的是，临床实践中引入的新疗法数量不足。中度至重度疼痛仍采用阿片μ受体激动剂进行机械治疗，虽然一些新的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，存在大量未满足的医疗需求。我们申请的意义在于解决临床上对具有新作用机制的损伤或疾病引起的慢性非恶性疼痛药物的需求。我们在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。我们已经制定的建议是全面的，多学科的，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，药物设计可以考虑已知的神经适应和机制，可能与特定的疼痛条件，以开发改进的疼痛治疗。我们建议设计，合成和生物学验证多价药物，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性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，而没有或大大降低了目前可用药物中存在的降低生活质量的副作用。项目A将由Elisso维克托Hruby指导，并将专注于发现多价阿片类μ激动剂-δ激动剂和μ激动剂/NK 1拮抗剂肽分子，其具有药物样特征并穿透血脑屏障，可通过全身给药递送。项目B将由Frank Porreca教授和艾德罗伯茨教授指导，旨在发现具有药物样特征的口服和脑渗透阿片类mu/CCK拮抗剂分子。项目C将由Alex Makriyannis、托德·范德拉和弗兰克·波雷卡教授指导，并将探索多功能大麻素激动剂，以改善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，这些核心将实现最大的协同作用和进展。我们的目标是发现具有多种受体特征的单一分子，这些分子具有药物样特性，可以推进到人类试验，以改善疼痛的治疗。

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.