Kappa Opioid Antagonist for Cocaine Addiction

用于治疗可卡因成瘾的 Kappa 阿片类药物拮抗剂

• 批准号: 7285566
• 负责人: FRANK Ivy CARROLL
• 金额: $ 56.67万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7285566
• 关键词: Kappa; Opioid; Antagonist; Cocaine; Addiction

DESCRIPTION (provided by applicant): In response to RFA-DA-05-009, "Strategic Program for Innovative Research on Drug Addiction Pharmacotherapy (SPIRDAP)," we are pleased to submit this application whose overall goal is developing a pharmacotherapy for use in preventing relapse to cocaine abuse. We have developed a structurally novel, potent, and selective opioid receptor antagonist referred to as JDTic. JDTic reversed antinociception of kappa agonists in mice and squirrel monkeys and antagonized kappa agonist-induced diuresis in rats. It showed activity using subcutaneous, intramuscular, and oral administration routes. To our knowledge, JDTic is the first selective kappa opioid receptor antagonist to show activity using the oral route of administration. Importantly, JDTic prevented stress-induced relapse in a rat cocaine self-administration paradigm and significantly decreased immobility and increased swimming time in the forced-swim test (FST) in rats, the latter suggesting antidepressant activity. Since stress and depression during cocaine abstinence precipitate relapse, and JDTic can attenuate both, it is an ideal development candidate for cocaine relapse pharmacotherapy. This application brings together a group of experienced investigators from four institutions to achieve the goal of developing JDTic as a pharmacotherapy to treat cocaine relapse. Dr. F.I. Carroll (Research Triangle Inst.), Dr. P.M. Beardsley (Virginia Commonwealth Univ.), Dr. T.R. Kosten (Yale Univ.), and Drs. C. Johanson and C.R. Schuster (Wayne State Univ.) have extensive experience in organic and medicinal chemistry, animal behavioral pharmacology, and clinical research, relating to cocaine abuse. The research plan is divided into four projects-one from each organization to reach our goals. Project 1 will synthesize non-GMP JDTic needed to complete preclinical development studies, intermediates needed to prepare the cGMP sample, and analogs needed as back-ups for JDTic. In addition, Project 1 will evaluate back-up compounds for their ability to antagonize kappa agonist-induced diuresis and for antidepressive activity in FST in rats. Project 2 will evaluate compounds from Project 1 in a rat cocaine foot-shocked and cocaine-primed relapse test to prioritize for selection of a back-up compound. Information from all studies will be used to prioritize compounds to be submitted for toxicological evaluation by NIDA and final selection of a backup compound. Projects 3 and 4 will determine if JDTic will be an effective pharmacotherapy for cocaine dependence. The primary purpose of Project 3 is to determine what JDTic doses can be well tolerated in humans with no significant adverse reactions when given acutely. Specifically, Project 3 will access safety, tolerance, and oral pharmacokinetics of isolating single dosages of JDTic in normal humans. Project 4 will ensure no adverse reactions when candidate medication compound and cocaine are combined. Although the primary goal of this research is to determine safety of the test medication when combined with cocaine, obtaining other important information is possible during the study's course. Changes in craving for cocaine and subjective effects of cocaine can also be obtained. Most importantly, the research program will lead to a new chemical entity with potential utility for treating cocaine relapse.

描述（由申请人提供）： 为响应RFA-DA-05-009“药物成瘾药物治疗创新研究战略计划（SPIRDAP）”，我们很高兴提交此申请，其总体目标是开发一种用于预防可卡因滥用复发的药物治疗。我们已经开发了一种结构新颖的，有效的，选择性阿片受体拮抗剂称为JDTic。JDTic在小鼠和松鼠猴中逆转kappa激动剂的抗伤害感受，并在大鼠中拮抗kappa激动剂诱导的利尿作用。其在皮下、肌内和口服给药途径中显示出活性。据我们所知，JDTic是第一个使用口服给药途径显示活性的选择性κ阿片受体拮抗剂。重要的是，JDTic在大鼠可卡因自我给药范例中预防了应激诱导的复发，并在大鼠强迫游泳试验（FST）中显著降低了不动性并增加了游泳时间，后者表明具有抗抑郁活性。由于可卡因戒断期间的压力和抑郁会导致复发，而JDTic可以减轻这两种情况，因此它是可卡因复发药物治疗的理想候选药物。 该应用程序汇集了来自四个机构的一组经验丰富的研究人员，以实现开发JDTic作为治疗可卡因复发的药物疗法的目标。菲博士卡罗尔（三角研究所），P.M.比尔兹利博士（弗吉尼亚联邦大学），T.R.医生Kosten（耶鲁大学），C博士Johanson和C.R.舒斯特（韦恩州立大学）在有机化学和药物化学、动物行为药理学以及与可卡因滥用有关的临床研究方面拥有丰富的经验。研究计划分为四个项目，每个组织一个，以达到我们的目标。项目1将合成完成临床前开发研究所需的非GMP JDTic、制备cGMP样品所需的中间体以及作为JDTic备份所需的类似物。此外，项目1将评价备用化合物拮抗κ激动剂诱导的利尿的能力和大鼠FST中的抗抑郁活性。项目2将在大鼠可卡因足电击和可卡因引发复发试验中评价项目1的化合物，以优先选择备用化合物。所有研究的信息将用于确定提交NIDA进行毒理学评价的化合物的优先顺序，并最终选择备用化合物。项目3和4将确定JDTic是否是可卡因依赖的有效药物疗法。项目3的主要目的是确定JDTic剂量在人类中可以很好地耐受，并且在急性给药时没有显著的不良反应。具体而言，项目3将评估在正常人中分离单剂量JDTic的安全性、耐受性和口服药代动力学。项目4将确保候选药物化合物和可卡因联合使用时无不良反应。虽然本研究的主要目的是确定试验药物与可卡因联合使用时的安全性，但在研究过程中可能会获得其他重要信息。还可以获得对可卡因的渴望和可卡因的主观效果的变化。最重要的是，该研究计划将导致一种新的化学实体，具有治疗可卡因复发的潜在效用。