Aminobenzomorphan: Potential Cocaine Abuse Medications

氨基苯并吗啡烷：潜在的可卡因滥用药物

• 批准号: 6911507
• 负责人: MARK P WENTLAND
• 金额: $ 31.59万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911507
• 关键词: CHO cells; behavior test; chemical structure function; cocaine; cyclazocine; drug addiction antagonist; drug design /synthesis /production; heroin; injection /infusion; laboratory mouse; molecular site; naloxone; opioid receptor; pain threshold; pharmacokinetics; radiotracer; receptor binding; stereochemistry; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): This application is focused on capitalizing on our recent discovery that a carboxamido group (CONH2) can replace the phenolic OH of opioids and ameliorate the rapid clearance of opioids (e.g., duration of action increased from 2 to 15 hours) without compromising intrinsic affinity for opioid receptors or antinociception efficacy. Specifically, we will design, synthesize and characterize novel 8-carboxamido analogues of cyclazocine and ethylketocyclazocine (EKC) as potential anti-cocaine and anti- heroin medications. Cyclazocine is a k 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 acumens, a primary pathway involved in the reinforcing effects of drugs of abuse, and thus have the potential to treat drug abuse. 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. We will also characterize novel carboxamido derivatives of other opioids (e.g., naltrindole, naltrexone) used as biochemical tools or for heroin abuse. Due to the uniqueness of this discovery, there is enormous potential to define a new SAR for opioids and we expect to identify new compounds having high affinity for opioid receptors. Taking advantage of computational techniques and our results with 8-aminocyclazocine analogues, we will probe an unexplored region of receptor space where an H-bond donor and hydrophobic group in the proper conformation are important for recognition. Based on the excellent preliminary pharmacokinetic and efficacy profile exhibited by these new carboxamides, we expect that the desired pharmacological profile will be attained by rational medicinal chemistry design and synthesis; an extensive pre-clinical work plan has been put in place. Radioligand binding, [35 S]GTP-gamma-S, and mouse antinociceptive assays will be used to characterize new targets pharmacologically.

描述（由申请人提供）：该申请的重点是利用我们最近的发现，即羧酰基小组（CONH2）可以替代阿片类药物的酚类OH，并改善阿片类药物的快速清除率（例如，行动持续时间从2个小时增加到15个小时）而不会损害阿片类药物的内在亲和力或无抗酸性的效果。具体而言，我们将设计，合成和表征cyclazocine和乙基酮氯唑氨酸（EKC）的新型8-羧酰胺类似物（EKC）作为潜在的抗可卡因和抗海洛因药物。 Cyclazocine是一种K阿片类药物激动剂和MU阿片类拮抗剂，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拮抗剂降低了尖核的多巴胺释放，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。 EKC被证明可以阻止非人类灵长类动物中可卡因自我管理。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。我们还将表征其他阿片类药物（例如Naltrindole，Naltrexone）的新型羧酰基衍生物，用作生化工具或滥用海洛因。 由于这一发现的独特性，有很大的潜力来定义阿片类药物的新SAR，我们希望确定对阿片类药物受体高亲和力的新化合物。利用计算技术和我们的8-氨基clazocin类似物的结果，我们将探测一个未开发的受体空间区域，在适当构象中，H键供体和疏水基团对于识别很重要。 基于这些新的羧酰胺所表现出的优秀初步药代动力学和功效，我们希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。已经制定了广泛的临床前工作计划。放射性结合，[35 s] GTP-GAMMA-S和小鼠抗伤害感受器测定将用于在药理学上表征新靶标。