Kappa Opioid Antagonist for Cocaine Addiction

描述(由申请人提供)： 为响应RFA-DA-05-009，“药物成瘾药物疗法创新研究战略计划(SPIRDAP)”，我们很高兴地提交这份申请，其总体目标是开发一种用于防止可卡因滥用复发的药物疗法。我们开发了一种结构新颖、有效和选择性的阿片受体拮抗剂，称为JDTic。JDTic逆转Kappa激动剂对小鼠和松鼠猴的抗伤害作用，拮抗Kappa激动剂诱导的大鼠利尿作用。它通过皮下、肌肉和口服给药途径显示出活性。据我们所知，JDTic是第一个通过口服途径显示活性的选择性kappa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防止了应激诱导的复发，并显著减少了大鼠在强迫游泳试验(FST)中的不动和增加游泳时间，后者表明了抗抑郁活性。由于在可卡因戒断过程中应激和抑郁会导致复发，而JDTic可以减轻这两种作用，因此它是可卡因复发药物治疗的理想候选药物。 这项申请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。卡罗尔博士(三角研究所)、比尔兹利博士(弗吉尼亚联邦大学)、科斯滕博士(耶鲁大学)、约翰逊博士和舒斯特博士(韦恩州立大学)在有机和药物化学、动物行为药理学和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-每个组织一个项目，以实现我们的目标。项目1将合成完成临床前开发研究所需的非GMP JDTic，制备cGMP样本所需的中间体，以及作为JDTic备份所需的类似物。此外，项目1将评估备用化合物对抗kappa激动剂诱导的利尿的能力，以及在大鼠FST中的抗抑郁活性。项目2将在大鼠可卡因足部电击和可卡因引发的复发测试中评估项目1中的化合物，以确定选择备份化合物的优先顺序。所有研究的信息将被用来确定提交给NIDA进行毒理学评估的化合物的优先顺序，并最终选择一种备用化合物。项目3和4将确定JDTic是否将成为治疗可卡因依赖的有效药物疗法。项目3的主要目的是确定什么剂量的JDTic在人类身上可以很好地耐受，而在急性给药时没有明显的不良反应。具体地说，项目3将获得在正常人身上分离单剂量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与可卡因联合使用时不会出现不良反应。虽然这项研究的主要目标是确定测试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。对可卡因的渴望和可卡因的主观影响也可以得到改变。最重要的是，该研究计划将产生一种新的化学实体，具有治疗可卡因复发的潜在用途。

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.