AMINOBENZOMORPHAN: POTENTIAL COCAINE ABUSE MEDICATIONS

氨基苯并吗喃：潜在的可卡因滥用药物

• 批准号: 6378831
• 负责人: MARK P WENTLAND
• 金额: $ 28.3万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378831
• 关键词: affinity labeling; brain metabolism; chemical structure function; cocaine; cyclazocine; dopamine; drug addiction antagonist; drug design /synthesis /production; laboratory mouse; laboratory rat; microdialysis; narcotic antagonists; opioid receptor; pharmacokinetics; radiotracer; receptor binding

This application is focused on the synthesis and characterization of novel chiral 8-amino analogues of cyclazocine and ethylketocyclazocine (EKC) as new anti-cocaine and anti-heroin medications. Cyclazocine is a kappa opioid agonist and a mu opioid antagonist and is currently in a clinical trial as a possible medication for cocaine abuse. Kappa agonists and mu antagonists decrease dopamine release in the nucleus accumbens, a primary pathway involved in the reinforcing effects of drugs of abuse, and thus have the potential to treat drug abuse. Recently, EKC was shown to block cocaine self-administration in non-human primates. Therefore, derivatives of cyclazocine and EKC that do not have major side effects are potential medications for treating cocaine and heroin abuse in humans. Our earlier studies with racemic 8-aminocyclazocine analogues demonstrated that very good oral narcotic agonist and antagonist properties were seen in rodents. Recently, a small number of chiral derivatives in this series were made and characterized for binding to mu, delta, and kappa opioid receptors. Results from these studies support our hypothesis that opioid binding and in vivo efficacy can be improved relative to our lead compounds by first modifying R' of the 8-amino substituent (R'NH-) to provide probes to explore receptor space. We believe the NH (as H-bond donor) is required for binding. Emerging structure-activity relationship (SAR) data suggest that hydrophobic R' groups will be beneficial. Thus, we will make analogues with a broad spectrum of hydrophobicity to understand this aspect of SAR. After the first set of target compounds has been evaluated, we will use CoMFA to refine our refine our pharmacophore model allowing us to identify more potent analogues. Based on the excellent oral bioavailability of our lead compounds and our expectation that the desired pharmacological profile will be attained by rational medicinal chemistry design and synthesis, we have developed an extensive pre-clinical work- plan. Radioligand binding assays will be used to determine the affinity and selectivity of test compounds. Mouse antinociceptive tests, using selective agonists and antagonists, will be used to characterize the agonist and antagonist properties of the drugs. Also, microdialysis will be used to determine if selected compounds will inhibit cocaine-induced increases in dopamine levels in nucleus accumbens in rats. The characterization of novel cyclazocine derivatives will identify potential medications for treating cocaine and heroin abuse and will suggest the basic mechanisms responsible for the drug's action.

该应用集中于环孢菌素和乙基酮氯唑嗪（EKC）的新型手性8-氨基类似物（EKC）作为新的抗可卡因和抗英雄药物的合成和表征。 Cybazocine是Kappa阿片类药物激动剂和MU阿片类药物拮抗剂，目前正在临床试验中，作为可卡因滥用的可能药物。 Kappa激动剂和MU拮抗剂减少了伏隔核中多巴胺的释放，这是涉及滥用药物的增强作用的主要途径，因此具有治疗药物滥用的潜力。最近，EKC被证明可以阻止非人类灵长类动物的可卡因自我管理。 因此，没有主要副作用的环虫菌和EKC的衍生物是治疗人类可卡因和海洛因滥用的潜在药物。我们先前对8-氨基氨基clazocin类似物的研究表明，在啮齿动物中可以看到非常好的口服麻醉性激动剂和拮抗剂。 最近，该系列中的少量手性衍生物与与MU，Delta和Kappa阿片受体结合而进行了特征。 这些研究的结果支持我们的假设，即相对于我们的铅化合物，可以通过首先修改8-氨基取代基（R'NH-）的R'来提高阿片类药物结合和体内功效，以提供探索受体空间的探针。 我们认为，绑定需要NH（作为H键供体）。 新兴的结构 - 活性关系（SAR）数据表明疏水r'组将是有益的。 因此，我们将制作具有广泛疏水性的类似物，以了解SAR的这一方面。在评估了第一组靶化合物之后，我们将使用COMFA来完善我们的精炼模型，从而使我们能够识别出更多有效的类似物。基于我们的铅化合物的出色口服生物利用度，我们期望通过合理的药物化学设计和合成来实现所需的药理学特征，我们制定了广泛的临床前工作计划。放射性结合测定法将用于确定测试化合物的亲和力和选择性。 使用选择性激动剂和拮抗剂的小鼠抗伤害感受测试将用于表征药物的激动剂和拮抗剂特性。同样，微透析将用于确定选定的化合物是否会抑制可卡因诱导的大鼠伏隔核中多巴胺水平的升高。 新型环虫衍生物的表征将确定可卡因和海洛因滥用的潜在药物，并将提出负责该药物作用的基本机制。