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: 7058622
• 负责人: FRANK Ivy CARROLL
• 金额: $ 82.81万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7058622
• 关键词: clinical research; cocaine; cooperative study; drug abuse chemotherapy; drug addiction; drug addiction antagonist; drug design /synthesis /production; opioid receptor

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）： 为了回应RFA-DA-05-009，“药物成瘾药物疗法创新研究战略计划”，我们很高兴提交该应用程序，其总体目标是开发用于防止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，有效和选择性的阿片类药物受体拮抗剂，称为JDTIT。 JDTIT逆转了小鼠和松鼠猴子的kappa激动剂的抗伤害感受，并拮抗了大鼠Kappa激动剂诱导的Diuresis。它显示了使用皮下，肌肉内和口服途径的活性。据我们所知，JDTIC是第一个使用口腔给药途径显示活性的选择性Kappa阿片受体拮抗剂。重要的是，JDTIC防止了大鼠可卡因自我给药范式的应激诱导的复发，并显着降低了固定性，并增加了在大鼠强迫速度-SWIM测试（FST）中的游泳时间增加，后者表明抗抑郁活性。由于可卡因戒酒沉淀物复发期间的压力和抑郁症可以减轻两者，因此它是可卡因复发药物治疗的理想发展候选者。 该应用程序汇集了来自四个机构的一群经验丰富的研究人员，以实现将JDTIT作为治疗可卡因复发的药物治疗的目标。 F.I.博士Carroll（研究三角研究所），P.M。 Beardsley（弗吉尼亚联邦大学），T.R。博士Kosten（耶鲁大学）和Drs。 C. Johanson和C.R. Schuster（Wayne State Univ。）在有机和药物化学，动物行为药理学和临床研究方面具有丰富的经验，与可卡因滥用有关。研究计划分为四个项目 - 每个组织以实现我们的目标。项目1将合成完成临床前开发研究，准备CGMP样本所需的中间体所需的非GMP JDTIT，以及作为JDTIT的备份所需的类似物。此外，项目1将评估备用化合物的抗体能力，可以拮抗Kappa激动剂诱导的利尿和FST中FST的抗抑郁活性。项目2将评估项目1的化合物在大鼠可卡因脚击和可卡因培训的复发测试中，以优先选择备用化合物。所有研究的信息将用于优先考虑通过NIDA提交毒理学评估的化合物，并最终选择备用化合物。项目3和4将确定JDTIC是否将是可卡因依赖性的有效药物疗法。项目3的主要目的是确定在人类中可以很好地耐受JDTIT剂量，而当敏锐的反应没有明显的不良反应。具体而言，项目3将访问正常人中JDTIT的单一剂量的安全性，耐受性和口服药代动力学。当候选药物化合物和可卡因合并时，项目4将确保不良反应。尽管这项研究的主要目标是确定与可卡因结合使用测试药物的安全性，但在研究过程中可以获得其他重要信息。还可以获得可卡因和可卡因主观影响的渴望的变化。最重要的是，该研究计划将导致一个具有潜在效用可卡因复发的新化学实体。