Reversing the toxic effects of drugs of abuse

描述(由申请人提供)： 这项提案代表了一项研究事业奖(K02)的申请，该奖项的重点是候选人开发药物的长期目标，以减轻滥用药物的毒性影响。实现这一目标的方法是有一个研究计划，寻求通过用基于化学的方法测试假设来解决与药物滥用和依赖有关的问题。拟议的研究计划包括三个项目，共同的主题是开发药物以减轻滥用药物的潜在致命影响。对于阿片类药物，目标是开发不会引起目前药物所见的严重便秘的吗啡类镇痛剂；对于可卡因，目标是开发基于Sigma受体的药物，作为可卡因过量的潜在治疗方法；对于GHB，目标是基于GHB和GABA-B拮抗的混合特征，开发一种治疗GHB过量的方法。对于后两个目标，我的短期方法是发展目前与法国博士和松本博士的合作，使我能够在新的R01提交中作为PI发挥带头作用。我对阿片类药物的计划是基于耐受性的药代动力学机制开发一个新的研究计划，并初步提交R21申请，以获得有价值的初步数据。这种方法是基于这样一种假设，即随着耐受性的降低，将不需要不断增加的吗啡剂量(导致便秘)。我的长期职业目标是发展这些项目和我的合作，使我能够将这些药物转化为诊所或急诊室。候选人将把75%的时间花在NIH资助的研究上。这一奖项将使候选人从许多教学和行政责任中解脱出来，从而使他能够专注于当前和未来的研究项目。

DESCRIPTION (provided by applicant): This proposal represents an application for a Research Career Award (K02) focused on the candidate's long-term goal of developing agents, which attenuate the toxic effects of drugs of abuse. The approach to achieving this goal is to have a research program that seeks to solve problems associated with drug abuse and dependence through testing hypotheses with chemistry-based approaches. The proposed research plan comprises of three projects, sharing the common theme of developing agents to attenuate the potentially lethal effects of drugs of abuse. In the case of opioids, the goal is to develop morphine-like analgesics which do not give rise to the severe constipation seen with current agents; for cocaine, the goal is to develop sigma receptor-based agents as potential treatments for cocaine overdose; for GHB, the goal is to develop a treatment for GHB overdose based on a mixed profile of GHB and GABA-B antagonism. My short-term approach to the latter two goals is to develop the current collaborations with Drs. France and Matsumoto to a point where I am able to take the lead as PI on new R01 submissions. My plans for the opioids is to develop a new research program based on pharmacokinetic mechanisms of tolerance, and initially submit an R21 application to gain valuable preliminary data. This approach is based on the hypothesis that as tolerance is reduced, the ever-increasing doses of morphine (which leads to the constipation) will not be required. My long-tern career goal is to develop these projects and my collaborations to the point where I am able to translate these medications into the clinic or emergency room. The candidate will spend 75% of his time on NIH-funded research. This award will allow the candidate to be relieved from many teaching and administrative responsibilities, thereby allowing him to focus on current and future research projects.