PHARMACOTHERAPY OF COCAINE ABUSE

这个补助金申请是一个分子药理学部分， 研究者发起的互动研究项目旨在确定 可用于治疗可卡因的药物 成瘾这项研究倡议的战略有三个方面。 I.药物化学：一组50-75种新的苯甲酰胺衍生物， 2，3-二甲氧基-N-（对氟苄基）哌啶-4-基苯甲酰胺（MBP）和2，3-二甲氧基-N-（对氟苄基）哌啶-4-基苯甲酰胺（MBP）。 二甲氧基-N-（9-对氟苄基）-氮杂双环[3.3.1]壬-3 β-基苯甲酰胺 （MABN），其已知是针对以下的高亲和力、非选择性拮抗剂： D2和D3受体。 ll.药理学：基因工程真核细胞，表达高 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学选择性 三种D2样多巴胺受体亚型的基因 伊利诺伊州行为研究：那些表现出 将使用最大的选择性1）确定其对以下的功效： 拮抗可卡因自我给药的增强作用， 灵长类动物使用行为范例，2）调查分子 D2样神经递质结合位点的性质， 标记技术，3）探索利用受体 亚型选择性不可逆拮抗剂作为治疗工具， 戒毒康复 尽管可卡因的强化作用是通过 多巴胺的神经传递，目前尚不清楚哪种多巴胺 受体亚型在强化中起主要作用。一个障碍 确定哪些多巴胺受体亚型参与 缺乏高亲和力的选择性拮抗剂 每一种受体亚型。实验策略是 建议是1）开发一种基因工程重组体， 杆状病毒病毒，其可用于感染Sf 9细胞以表达 D2、D3和D4受体，2）使用放射性配体结合技术， 定义一组新型苯甲酰胺的药理学选择性， 在Sf 9细胞中表达的D2、D3和D4受体，和3）制备和 表征可以使用的亲和标记试剂a）协同 与Sf 9细胞中表达的多巴胺受体亚型进行比较， 神经递质中苯甲酰胺的位置和方向 D2、D3和D4多巴胺受体的结合位点，和B）探索 使用不可逆受体阻断剂作为 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.