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药物治疗药物滥用的方法。由于压力会增加吸毒行为，我们将开发有效的和选择性的？阿片受体拮抗剂作为一种潜在的新药物疗法来帮助成瘾者不复发。重要的是，所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。针对当前资助的具体目标取得了重要的研究成果。迄今为止，我们的进展已经导致鉴定出几种有效和选择性的化合物：阿片受体拮抗剂在体外功效测定中。这些化合物是小分子，有望穿透中枢神经系统并具有高稳定性。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，即通过阿片受体研究领域的新化合物的先导优化，可以发现和开发药物治疗药物滥用的药物疗法。我们的一般方法是设计和合成基于(a)反式3,4-二甲基-4-（3-羟基苯基）哌啶，(b) 42-和92-甲基-5-（3-羟基-苯基）吗啡，(c) 4a-（3-羟基苯基）-8a-甲基十氢异喹啉，(d) 3-[4-（取代哌嗪-1-基）]苯酚和(e) n-取代4-（3-羟基苯基）-4-甲基苄基[3.1.0]己烷类阿片拮抗剂的化合物。化合物的效力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¿，d和？产生的刺激[35S]GTP3S结合的能力来获得。使用在CHO细胞中表达的克隆人类阿片受体的激动剂。模拟物是否符合设定的标准？效力和选择性将在体内PK研究中进行评估，以确定化合物通过血脑屏障（BBB）的能力和适当的半衰期（t1/2）。对？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，将评估它们的拮抗能力。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的效力和作用时间）。所产生的信息将用于选择化合物，以评估足震诱发的可卡因复发试验的恢复反应。在此测试中显示AD50值的化合物与？阿片类拮抗剂JDTic正处于临床前开发阶段，值得进一步开发。

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.