Selective Opioid Antagonists as Medications for Drug Abuse

描述(由申请人提供)：本申请的广泛、长期目标是发现和开发治疗药物滥用的药物疗法。既然压力会增加吸毒行为，我们会不会养成强势和选择性？阿片受体拮抗剂作为潜在的新药物疗法，帮助吸毒者不再吸毒复发。重要的是，开发的化合物还将作为生化和药理学探针，有助于更好地了解可卡因、甲基苯丙胺、尼古丁、酒精和鸦片成瘾的生化和分子机制。实现了针对当前赠款具体目标的重大研究成果。到目前为止，我们的进展已经导致了几种有效和选择性的化合物的鉴定：阿片受体拮抗剂在体外疗效分析中。这些化合物是有望穿透中枢神经系统的小分子，具有很高的稳定性。因此，这些化合物是非常有用的先导结构，需要在药代动力学(PK)和动物行为研究方面进一步发展，才能确定它们作为治疗药物滥用的潜在药物疗法的价值。拟议的研究继续基于最初的假设，即治疗药物滥用的药物疗法可以通过阿片受体研究领域的新化合物的先导优化来发现和开发。我们的一般方法是设计和合成基于(A)trans-3，4-dimethyl-4-(3-hydroxyphenyl)piperidine，(B)42-和92-甲基-5-(3-羟基苯基)吗啡，(C)4a-(3-hydroxyphenyl)-8a-methyldecahydroisoquinoline，(D)3-[4-(取代哌嗪-1-基)]苯酚和(E)N-取代4-(3-hydroxyphenyl)-4-methylazabicyclo[3.1.0]hexane类阿片类拮抗剂的化合物。这些化合物的强效和选择性的优点是什么？阿片类拮抗剂将通过监测测试化合物抑制选择性地产生的刺激的[35S]GTP3S结合的能力来获得。使用克隆的人阿片受体的激动剂在CHO细胞中表达。符合既定标准的类似物？效力和选择性将在体内PK研究中进行评估，以确定化合物穿越血脑屏障(BBB)和具有合适的半衰期(T1/2)的能力。具有高效力和选择性的化合物？在PK研究中具有合适的脑水平和T1/2值的阿片受体将被评估其拮抗能力？选择性激动剂U50,488诱导大鼠利尿，以建立其？阿片受体拮抗剂概况(相对于JDTic的效力和持续时间)。产生的信息将被用来选择在足部电击诱导的可卡因复发反应恢复测试中进行评估的化合物。在本试验中显示AD50值的化合物与？处于临床前开发阶段的阿片类拮抗剂JDTic将有可能进一步开发。 公共卫生相关性：药物滥用、成瘾和依赖仍然是公共健康的主要威胁。开发治疗可卡因、甲基苯丙胺、尼古丁、海洛因和乙醇成瘾的新药物疗法将是医学和社会上的重大突破。这个应用程序通过提出识别和开发选择性的？阿片受体拮抗剂作为治疗药物成瘾患者滥用的新药物疗法。

DESCRIPTION (provided by applicant): The broad, long-term goal of this application is to discover and develop pharmacotherapies for the treatment of substance abuse. Since stress can increase drug-taking behavior, we will develop potent and selective ? opioid receptor antagonists as potential new pharmacotherapies to help addicts not relapse to drug taking. Importantly, compounds developed will also serve as biochemical and pharmacological probes useful in gaining a better understanding of the biochemical and molecular mechanisms of cocaine, methamphetamine, nicotine, alcohol, and opiate addictions. Significant research findings directed toward the specific aims of the current grant were achieved. Our progress to date has led to the identification of several compounds that are potent and selective : opioid receptor antagonists in in vitro efficacy assays. The compounds are small molecules that are expected to penetrate the CNS and have high stability. Thus, these compounds are highly useful lead structures that require further development in pharmacokinetic (PK) and animal behavioral studies before their merit as potential pharmacotherapies for treating substance abuse can be determined. The proposed research continues to be based on the original hypothesis that pharmacotherapies for treating substance abuse can be discovered and developed through lead optimization of novel compounds from the : opioid receptor research area. Our general approach will be to design and synthesize compounds based on the (a) trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, (b) 42- and 92-methyl-5-(3-hydroxy- phenyl)morphan, (c) 4a-(3-hydroxyphenyl)-8a-methyldecahydroisoquinoline, (d) 3-[4-(substituted piperazin-1- yl)]phenol, and (e) N-substituted 4-(3-hydroxyphenyl)-4-methylazabicyclo[3.1.0]hexane classes of opioid antagonist. The merit of the compounds as potent and selective ? opioid antagonists will be obtained by monitoring the ability of the test compounds to inhibit stimulated [35S]GTP3S binding produced by selective ¿, d, and ? agonists using cloned human opioid receptors expressed in CHO cells. Analogs meeting set criteria for ? potency and selectivity will be evaluated in an in vivo PK study to determine the ability of the compounds to cross the blood-brain barrier (BBB) and to have an appropriate half-life (t1/2). Compounds that have high potency and selectivity for ? opioid receptors and that have suitable brain levels and t1/2 values in the PK studies will be evaluated for their ability to antagonize ? selective agonist U50,488-induced diuresis in rats in order to establish their ? opioid receptor antagonist profile (potency and duration of action relative to JDTic). Information generated will be used to select compounds for evaluation in a foot-shock-induced reinstatement of responding for cocaine relapse test. Compounds that show AD50 values in this test comparable to the AD50 of the ? opioid antagonist JDTic, which is in preclinical development, will warrant further development. PUBLIC HEALTH RELEVANCE: Drug abuse, addiction, and dependence remain major threats to public health. Development of new pharmacotherapies to treat cocaine, methamphetamine, nicotine, heroin, and ethanol addictions would be a major medical and societal breakthrough. This application addresses these problems by proposing to identify and develop selective ? opioid receptor antagonists as new pharmacotherapies to treat patients addicted to drugs of abuse.