Pawhuskins: Potential Treatments for Stimulant Abuse.

描述（由申请人提供）：兴奋剂滥用（包括可卡因和安非他明）是一个严重的公共卫生问题。据认为，在美国，目前有超过300万人使用这些药物，这些药物每年都有许多急诊室就诊。滥用这些药物与高复发率有关。尽管存在显著的未满足的医疗需求，但目前尚无药物疗法被批准用于治疗兴奋剂滥用。几个旨在使用替代疗法的项目已经显示出一些希望。最近，也有报道显示κ-阿片受体拮抗剂可以调节应激反应，应激反应和抑郁已被证明是复发的重要触发因素。由于这个原因，κ-选择性阿片受体激动剂和拮抗剂作为兴奋剂滥用的潜在治疗方法获得了一些关注。Pawhuskin是2004年从北美草原植物中报道的一小组异戊二烯化芪。在这一早期报道中，它们被证明具有一些阿片受体调节功能。这个早期职业奖在药物滥用预防的基础化学的目的是测试的假设，用于治疗兴奋剂滥用的药物可以从pawhuskins。我们提出了三个具体的目标，旨在通过系统地修改pawhuskin支架来验证这一假设。我们将首先探讨天然产物中存在的氢键供体的封闭基团的要求。然后，我们将合成一系列旨在增强特异性阿片受体结合的类似物，以提高木瓜蛋白酶核心的亲和力和受体亚型选择性。公共卫生相关性：兴奋剂滥用是美国的一个主要公共卫生问题，可卡因和甲基苯丙胺是这类滥用的主要药物。这些药物的滥用与长期持续的行为变化和复发倾向有关。尽管与兴奋剂滥用相关的发病率和死亡率，但目前尚无药物治疗被批准用于治疗这种疾病。可以帮助复发效应或以其他方式改善治疗结果的新疗法应该是高度优先的。

DESCRIPTION (provided by applicant): Stimulant abuse (including both cocaine and amphetamines) is a serious public health problem. There are thought to be over 3 million current users of these drugs in the United States, and these drugs account for numerous emergency room visits each year. Abuse of these drugs is associated with a high rate of relapse. Despite significant unmet medical need no pharmacotherapies are currently approved for the treatment of stimulant abuse. Several programs aimed at using replacement therapy have shown some promise. Recently, there have also been reports showing kappa-opioid receptor antagonists can modulate stress responses, and stress response and depression have been shown to be important triggers for relapse. For this reason kappa-selective opioid receptor agonists and antagonists have gained some attention as potential treatments for stimulant abuse. The pawhuskins are a small set of prenylated stilbenes reported from a North American prairie plant in 2004. They were shown to have some opioid receptor modulating function in this early report. This early career award in the basic chemistry of drug abuse prevention is designed to test the hypothesis that drugs for the treatment of stimulant abuse can be derived from the pawhuskins. We propose three specific aims that are designed to test this hypothesis by systematically modifying the pawhuskin scaffold. We will first probe the requirements for hydrogen bond donors present in the natural products by blocking groups. We will then synthesize a series of analogs designed to enhance specific opioid receptor binding to improve the affinity and receptor subtype selectivity of the pawhuskin core. PUBLIC HEALTH RELEVANCE: Stimulant abuse is a major public health problem in the United States with cocaine and methamphetamine being the primary drugs of abuse in this category. Abuse of these drugs is associated with long lasting behavioral changes and propensity for relapse. Despite the morbidity and mortality associated with stimulant abuse no pharmacotherapies are currently approved for treatment of this disease. Novel therapeutics that could help with the relapse effect or otherwise improve treatment outcomes should be of high priority.