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用于治疗药物滥用的药物疗法。既然压力可以增加吸毒行为，我们会发展出强效和选择性？阿片受体拮抗剂作为潜在的新药物治疗，以帮助成瘾者不再复吸。重要的是，开发的化合物也将作为生物化学和药理学探针，用于更好地了解可卡因，甲基苯丙胺，尼古丁，酒精和阿片类药物成瘾的生物化学和分子机制。 实现了针对当前赠款具体目标的重要研究成果。迄今为止，我们的进展已导致几种化合物，是有效的和选择性的鉴定：阿片受体拮抗剂在体外疗效测定。这些化合物是小分子，预期可穿透CNS并具有高稳定性。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）和动物行为研究中进一步开发，然后才能确定它们作为治疗物质滥用的潜在药物疗法的优点。 拟议的研究继续基于原始假设，即通过阿片受体研究领域的新型化合物的先导优化，可以发现和开发治疗药物滥用的药物疗法。我们的一般方法将是设计和合成基于（a）反式-3，4-二甲基-4-甲基-2，4-二氧戊环的化合物。（3-羟基苯基）哌啶，（B）42-和92-甲基-5-（3-羟基-苯基）吗啉，（3-羟基苯基）-8a-甲基十氢异喹啉，（取代的哌嗪-1-基）]苯酚，和（e）N-取代的4-（3-羟基苯基）-4-甲基氮杂双环[3.1.0]己烷类阿片拮抗剂。化合物的优点是有效和选择性？阿片样物质拮抗剂将通过监测测试化合物抑制由选择性β、β和β产生的刺激的[35S] GTP 3S结合的能力来获得。使用在CHO细胞中表达的克隆的人阿片样物质受体的激动剂。类似物是否符合设定的标准？将在体内PK研究中评价效力和选择性，以确定化合物穿过血脑屏障（BBB）和具有适当半衰期（t1/2）的能力。具有高效力和选择性的化合物？将评价阿片受体和在PK研究中具有适当脑水平和t1/2值的阿片受体拮抗剂的能力？选择性激动剂U50，488诱导大鼠利尿，以建立他们的？阿片受体拮抗剂特征（相对于JDTic的效力和作用持续时间）。生成的信息将用于选择化合物，用于在足电击诱导的可卡因复吸试验应答恢复中进行评价。化合物显示AD50值在本试验中可比的AD50的？处于临床前开发阶段的阿片类拮抗剂JDTic将保证进一步开发。 公共卫生相关性：药物滥用、成瘾和依赖仍然是公共卫生的主要威胁。开发新的药物疗法来治疗可卡因、甲基苯丙胺、尼古丁、海洛因和乙醇成瘾将是医学和社会的重大突破。这个应用程序解决了这些问题，提出确定和发展选择性？阿片受体拮抗剂作为治疗药物滥用成瘾患者的新药物疗法。

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.