SYNTHESIS OF COCAINE ANALOGS

可卡因类似物的合成

• 批准号: 2120515
• 负责人: Mark L. Trudell
• 金额: $ 7.21万
• 依托单位: UNIVERSITY OF NEW ORLEANS
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-29 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2120515
• 关键词: analog; chemical structure function; cocaine; cycloheptanes; dopamine hydroxylase inhibitor; drug addiction antagonist; drug design /synthesis /production; high performance liquid chromatography; laboratory rat; neurotransmitters; opioid receptor; piperidine; pyrrolidines; receptor binding; reinforcer; serotonin inhibitor; stereochemistry

Identification of stereoselective, high affinity saturable binding sites for cocaine 1 in the mammalian central nervous system (CNS) have been described in both in vitro and in vivo systems.1-10 The CNS pharmacologic activity of cocaine has been shown to be mediated through occupation of a structure specific cocaine receptor.11,12 It is believed that the primary mechanism of action of cocaine is associated with the blockade of CNS biogenic amine uptake systems. Inhibition of the serotonin, dopamine and norepinephrine uptake mechanisms by cocaine have all been reported.13,14 However, the pharmacologic effects of cocaine associated with the inhibition of specific biogenic amine uptake systems is unknown. As part of a collaborative project affiliated with psychobiologists and psychopharmacologists at the National Institute of Drug Abuse, Addiction Research Center15 the specific aim of this research is directed toward the elucidation of the structural requirements for drug binding and drug efficacy at cocaine receptors of specific biogenic amine (serotonin, dopamine and norepinephrine) uptake sites. A multidisciplinary program consisting of chemical synthesis, pharmacologic evaluation and structural analysis will be employed to determine the structure-activity relationships (SAR) of cocaine and the cocaine receptor/biogenic amine uptake system. The specific areas of study with regard to the SAR of cocaine will include: (1) elucidation of the role of the carbomethoxy group, (2) determination of the importance of the rigid 8-aza-bicyclo[3.2.1]octane ring system and (3) evaluation of the importance of the relative proximity of the phenyl group to the cocaine nucleus (N(8) and carbomethoxy group). The initial approach for achieving the specific aims of this research will be to affect the stereoselective syntheses and the pharmacologic evaluation of compounds 3-13 (Chart I). The cocaine analogs will first be tested in in vitro paradigms for receptor affinity and for the ability of the compounds to inhibit dopamine, serotonin and norepinephrine uptake mechanisms. The pharmacologic activity of high affinity ligands will then be determined in vivo by assessment of the stimulant effects (locomotor stimulation, discriminative stimulus effects and reinforcing effects) of the drugs. This investigation should not only help to reveal the structural criteria for cocaine binding but should ultimately lead to the development of selective cocaine receptor mediated biogenic amine inhibitors. The availability of compounds of this nature should prove to be valuable tools for the resolution of the various pharmacologic effects of cocaine. Moreover, cocaine receptor mediated biogenic amine inhibitors can potentially be employed as cocaine antagonists and should prove useful for the treatment of cocaine addiction and overdose.17,18 The effects of the active compounds on cocaine overdose and toxicity will also be examined.

立体选择性，高亲和力饱和结合位点的识别 对于哺乳动物中枢神经系统（CNS）中的可卡因1 在体外和体内系统中描述。1-10CNS药理 可卡因的活性已被证明是通过占领 结构特异性可卡因受体。11,12据信主要 可卡因的作用机理与CNS的阻滞有关 生物胺摄取系统。 抑制5-羟色胺，多巴胺和 据报道可卡因的去甲肾上腺素摄取机制。13,14 但是，可卡因与 抑制特定生物胺摄取系统的抑制尚不清楚。 作为一个与心理生物学家隶属的合作项目的一部分 国家药物滥用，成瘾研究所的心理药理学家 研究中心15这项研究的具体目的是针对 阐明药物结合和药物的结构要求 特异性生物胺的可卡因受体（5-羟色胺，， 多巴胺和去甲肾上腺素）吸收位点。 多学科计划 由化学合成，药理评估和结构性组成 分析将用于确定结构活动关系 可卡因和可卡因受体/生物胺摄取系统的（SAR）。 关于可卡因SAR的特定研究领域将包括： （1）阐明了碳氧基群的作用，（2）确定 刚性8-Za-Bicyclo [3.2.1]辛烷环系统和（3）的重要性 评估苯基相对接近的重要性 到可卡因核（N（8）和碳氧基氧基）。 实现这项研究的具体目标的最初方法将 要影响立体选择性合成和药理评估 化合物3-13（图I）。 可卡因类似物将首先在 受体亲和力的体外范例和能力 抑制多巴胺，5-羟色胺和去甲肾上腺素摄取的化合物 机制。 然后，高亲和力配体的药理活性将 通过评估刺激效应（运动器）在体内确定 刺激，区分刺激效应和增强效应） 药物。 这项调查不仅应有助于揭示 可卡因结合的结构标准，但最终应导致 开发选择性可卡因受体介导的生物胺 抑制剂。 这种性质的化合物的可用性应证明 成为解决各种药理效应的宝贵工具 可卡因。 此外，可卡因受体介导的生物胺抑制剂 可能被用作可卡因拮抗剂，应该被证明有用 为了治疗可卡因成瘾和过量。17,18 可卡因过量和毒性上的活性化合物也将是 检查。