Pawhuskins: Potential Treatments for Stimulant Abuse.

Pawhuskins：兴奋剂滥用的潜在治疗方法。

基本信息

批准号：
7638987
负责人：
JEFFREY D NEIGHBORS
金额：
$ 19.81万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7638987
关键词：
Accident and Emergency department Accounting Affinity Agonist American Amphetamines Attention Award Behavioral Binding Binding Sites Biological Factors Brain Categories Cell Culture System Chemistry Cocaine Data Disease Drug user Funding Human Hydrogen Bonding Libraries Ligands Malignant Neoplasms Medical Methamphetamine Methyl Ethers Morbidity - disease rate Opioid Receptor Opioid Receptor Binding Penetration Pharmaceutical Preparations Pharmacotherapy Phenols Plants Public Health Relapse Replacement Therapy Reporting Research Project Grants Resveratrol Series Stilbenes Testing Treatment outcome United States Visit Writing analog base biological adaptation to stress career cerebrovascular chemical synthesis computational chemistry delta opioid receptor depression design drug abuse prevention drug of abuse hydroxyl group improved information gathering kappa opioid receptors mortality novel novel therapeutics pawhuskin A pharmacophore programs public health relevance receptor scaffold stimulant abuse

项目摘要

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.

描述（由申请人提供）：刺激性滥用（包括可卡因和苯丙胺）是一个严重的公共卫生问题。人们认为，在美国，这些药物的现有用户超过300万，这些药物每年都有许多急诊室就诊。这些药物的滥用与高复发率有关。尽管未满足医疗需求，目前尚未批准药物治疗来治疗刺激性滥用。旨在使用替代疗法的几个计划表现出了一些希望。最近，也有报道表明，卡帕 - 阿片类受体拮抗剂可以调节应力反应，而应力反应和抑郁症已被证明是复发的重要触发因素。因此，Kappa选择性的阿片类药物受体激动剂和拮抗剂已引起人们对刺激性滥用的潜在治疗的关注。 Pawhuskins是2004年北美草原厂报道的一小群预苯甲酸，在此早期报告中显示出一些阿片类药物受体调节功能。预防药物滥用基本化学的早期职业奖旨在检验以下假设：治疗刺激性滥用的药物可以源自Pawhuskins。我们提出了三个特定的目标，旨在通过系统地修改Pawhuskin支架来检验这一假设。我们将首先通过阻止组来探测天然产物中存在的氢键供体的要求。然后，我们将合成一系列类似物，旨在增强特定的阿片受体结合，以提高Pawhuskin核心的亲和力和受体亚型的选择性。公共卫生相关性：刺激性滥用是美国的主要公共卫生问题，可卡因和甲基苯丙胺是这一类别中滥用的主要药物。这些药物的滥用与持久的行为变化和复发倾向有关。尽管与刺激性滥用相关的发病率和死亡率目前尚未批准用于治疗该疾病的药物治疗。可以有助于复发作用或以其他方式改善治疗结果的新型治疗剂应优先考虑。