PHARMACOTHERAPY OF COCAINE ABUSE

这项资助申请是一个分子药理学部分 调查员发起的互动研究项目旨在确定 可用于治疗可卡因的药物治疗剂 上瘾。这项研究计划的战略有三个方面。 I.药物化学：由50-75种新型苯甲酰胺衍生物组成的小组 2，3-二甲氧基-N-(对氟苄基)胡椒素-4-基苯甲酰胺(MBP)和2，3-二甲氧基-N-(对氟苄基)胡椒素 Dimethoxy-N-(9-p-flurobenzyl)-azabicyclo[3.3.1]nonan-3beta-yl苯甲酰胺 (MABN)，它们是已知的高亲和力、非选择性拮抗剂 D2和D3受体，将被合成。 呃.。药理学：基因工程真核细胞，高表达 D2样多巴胺(D2、D3和D4)受体的水平将用于 表征每种苯甲酰胺衍生物的药理选择性 三种D2样多巴胺受体亚型。 生病了。行为研究：这些苯甲酰胺类化合物表现出 将使用最大的选择性1)来确定它们对 拮抗可卡因自我给药的强化作用 灵长类动物使用行为范式，2)研究分子 用亲和力研究类D2神经递质结合位点的性质 标记技术，以及3)探索使用受体的潜力 亚型选择性不可逆拮抗剂作为治疗手段 药物滥用康复。 虽然已知可卡因的增强作用是通过 多巴胺的神经传递，目前还不清楚是哪种多巴胺 受体亚型在强化中起主导作用。一个障碍 确定哪些多巴胺受体亚型(S)参与 强化效应是缺乏高亲和力、选择性的拮抗剂 对于每一种受体亚型。这方面的实验策略 建议是1)开发一种基因工程重组 杆状病毒可用于感染Sf9细胞进行表达 D2、D3和D4受体，2)使用放射性配基结合技术 确定一组新型苯甲酰胺类药物的药理选择性 D2、D3和D4受体在Sf9细胞中的表达；3)制备和 表征可配合a)使用的亲和标记试剂 以确定在Sf9细胞中表达的多巴胺受体亚型 苯甲酰胺类化合物在神经递质中的位置和方向 D2、D3和D4多巴胺受体的结合部位，以及b)探索 不可逆受体阻滞剂作为一种抗肿瘤药物的可行性 治疗可卡因滥用的治疗工具。

This grant application is the molecular pharmacology portion of an Investigator Initiated Interactive Research Project designed to identify pharmacotherapeutic agents that can be used in the treatment of cocaine addiction. The strategy of this research initiative is three-fold. I. Medicinal Chemistry: A panel of 50-75 novel benzamide derivatives of 2,3-dimethoxy-N-(p-flurobenzyl)piperdin-4-yl benzamide (MBP) and 2,3 - dimethoxy-N-(9-p-flurobenzyl)-azabicyclo[3.3.1]nonan-3beta-yl benzarnide (MABN), which are known to be high-affinity, nonselective antagonists for D2 and D3 receptors, will be synthesized. ll. Pharmacology: Genetically engineered eukayotic cells, expressing high levels of D2-like dopamine (D2, D3 and D4) receptors, will be used to characterize the pharmacologic selectivity of each benzamide derivative for the three D2-like dopamine receptor subtypes. Ill. Behavioral Studies: Those benzamide derivatives exhibiting the greatest selectivity will be used 1) to determine their efficacy for antagonizing the reinforcing effects of cocaine self-administration in primates using behavioral paradigms, 2) to investigate the molecular properties of the D2-like neurotransmitter binding sites using affinity labeling techniques, and 3) to explore the potential for using receptor subtype selective irreversible antagonists as a therapeutic tools for drug abuse rehabilitation. Although cocaine's reinforcing effects are known to be mediated through dopamine neurotransmission, it is not clear which of the dopamine receptor subtypes play a predominant role in reinforcement. One obstacle to defining which dopamine receptor subtype(s) are involved in reinforcing effects is the lack of high-affinity, selective antagonists for each of the receptor subtypes. The experimental strategy for this proposal is to 1) develop a genetically engineered recombinant baculovirus virus that can be used to infect Sf9 cells for the expression of D2, D3 and D4 receptors, 2) use radioligand binding techniques to define the pharmacologic selectivity of a panel of novel benzamides for D2, D3 and D4 receptors expressed in Sf9 cells, and 3) prepare and characterize affinity labeling reagents that can be used a) in concert with dopamine receptor subtypes expressed in Sf9 cells to determine the position and orientation of benzamides within the neurotransmitter binding sites of D2, D3 and D4 dopamine receptors, and b) to explore the feasibility of using irreversible receptor blocking agents as a therapeutic tool in the treatment in cocaine abuse.