Reversing the toxic effects of drugs of abuse

扭转滥用药物的毒性作用

• 批准号: 7616804
• 负责人: ANDREW COOP
• 金额: $ 11.4万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616804
• 关键词: 4-hydroxybutyric acid receptor; Absence of pain sensation; Accident and Emergency department; Adverse effects; Agonist; Analgesics; Antidotes; Attenuated; Award; Chemistry; Clinic; Cocaine; Collaborations; Constipation; Coupled; Data; Dependence; Development; Dose; Drug Kinetics; Drug abuse; Educational process of instructing; France; Funding; Future; Goals; Independent Scientist Award; Investigation; Lead; Life; Morphine; Opioid; Opioid Analgesics; Opioid Receptor; Overdose; P-Glycoprotein; P-Glycoproteins; Pain; Pain-Free; Patients; Pharmaceutical Preparations; Problem Solving; Relative (related person); Research; Research Project Grants; Tern; Testing; Time; Toxic effect; Translating; Up-Regulation; base; career; club drug; cocaine overdose; design; drug of abuse; gamma hydroxybutyrate; in vivo; programs; receptor; sexual assault; sigma receptors; therapeutic development

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.

描述（由申请人提供）： 该提案代表了研究职业奖（K02）的申请，重点关注候选人开发减轻滥用药物毒性作用的药物的长期目标。实现这一目标的方法是制定一个研究计划，旨在通过使用基于化学的方法检验假设来解决与药物滥用和依赖性相关的问题。拟议的研究计划由三个项目组成，其共同主题是开发药物以减轻滥用药物的潜在致命影响。就阿片类药物而言，目标是开发吗啡类镇痛药，不会引起现有药物所见的严重便秘；对于可卡因，目标是开发基于西格玛受体的药物作为可卡因过量的潜在治疗方法；对于 GHB，我们的目标是基于 GHB 和 GABA-B 拮抗作用的混合特性，开发一种针对 GHB 过量的治疗方法。我实现后两个目标的短期方法是发展与博士目前的合作。 France 和 Matsumoto 达到了这样的程度，我能够作为 PI 领导新的 R01 提交。我对阿片类药物的计划是开发一个基于耐受药代动力学机制的新研究计划，并首先提交 R21 申请以获得有价值的初步数据。这种方法基于这样的假设：随着耐受性降低，将不需要不断增加吗啡剂量（导致便秘）。我的长期职业目标是开发这些项目和我的合作，直到我能够将这些药物转化为诊所或急诊室。候选人将花费 75% 的时间进行 NIH 资助的研究。该奖项将使候选人摆脱许多教学和行政职责，从而使他能够专注于当前和未来的研究项目。

项目成果

Effects of combining ethanol (EtOH) with gamma-hydroxybutyrate (GHB) on the discriminative stimulus, locomotor, and motor-impairing functions of GHB in mice.

乙醇 (EtOH) 与 γ-羟基丁酸酯 (GHB) 组合对小鼠 GHB 的辨别刺激、运动和运动损伤功能的影响。

• 发表时间: 2006-03
• 影响因子: 3.4
• 作者: Cook, Charles D;Biddlestone, Laura;Coop, Andrew;Beardsley, Patrick M
• 通讯作者: Beardsley, Patrick M

Cataleptic effects of gamma-hydroxybutyrate (GHB), its precursor gamma-butyrolactone (GBL), and GABAB receptor agonists in mice: differential antagonism by the GABAB receptor antagonist CGP35348.

γ-羟基丁酸 (GHB)、其前体 γ-丁内酯 (GBL) 和 GABAB 受体激动剂对小鼠的强直作用：GABAB 受体拮抗剂 CGP35348 的差异拮抗作用。

• 发表时间: 2007-06
• 影响因子: 3.4
• 作者: Koek, Wouter;Mercer, Susan L;Coop, Andrew
• 通讯作者: Coop, Andrew

Effect of a 6-cyano substituent in 14-oxygenated N-methylmorphinans on opioid receptor binding and antinociceptive potency.

14-氧化 N-甲基吗啡喃中的 6-氰基取代基对阿片受体结合和镇痛效力的影响。

• 发表时间: 2005-07-28
• 影响因子: 7.3
• 作者: Spetea, Mariana;Greiner, Elisabeth;Aceto, Mario D;Harris, Louis S;Coop, Andrew;Schmidhammer, Helmut
• 通讯作者: Schmidhammer, Helmut

Influence of charge and steric bulk in the C-24 region on the interaction of bile acids with human apical sodium-dependent bile acid transporter.

C-24 区域电荷和空间体积对胆汁酸与人顶端钠依赖性胆汁酸转运蛋白相互作用的影响。

• 发表时间: 2006-05
• 影响因子: 4.9
• 作者: Balakrishnan, Anand;Wring, Stephen A;Coop, Andrew;Polli, James E
• 通讯作者: Polli, James E

Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a micro-agonist delta-antagonist and delta-inverse agonists.

具有混合特性的阿片类配体，来自取代的对映体 N-苯乙基-5-苯基吗啡烷。

• 发表时间: 2007-04-21
• 影响因子: 3.2
• 作者: Cheng, Kejun;Kim, In Jong;Lee, Mei;Adah, Steven A;Raymond, Tyler J;Bilsky, Edward J;Aceto, Mario D;May, Everette L;Harris, Louis S;Coop, Andrew;Dersch, Christina M;Rothman, Richard B;Jacobson, Arthur E;Rice, Kenner C
• 通讯作者: Rice, Kenner C