COCAINE--A STUDY OF THE BIOCHEMICAL MECHANISM OF ACTION

可卡因是一种精神兴奋剂， “强化”属性。 药理学作用 对于奖励，因此滥用责任是一节， 多巴胺能突触 确认的活动 通过阻断多巴胺受体 机制 可卡因和可卡因类药物在自我- 给药研究与其抑制 ~ 3 H-马吲哚与大鼠多巴胺摄取部位的结合 纹状体 由于绑定到大型 可卡因的其他突触前和突触后结合位点的数量 与药物滥用相关的受体似乎是 与多巴胺摄取抑制有关。 在本研究中，设计，合成和受体结合评价 可卡因类似物的建议作为一种方法，调查 可卡因滥用倾向的生化机制。 分子 模型研究被用来调查构象 可卡因可能的药效团结合模式的能量学 并设计用于研究的可卡因类似物。 由于独特的结构和立体化学要求， 在生物系统中，是由于互补的三个- 药物与其受体位点之间的三维相互作用， 这些要求的实验测定可用于 构建受体的图像。 这些信息将提供 生物化学研究的新的和独特的工具，并可以翻译 用于治疗可卡因成瘾的新药

Cocaine is a psychomotor stimulant with rewarding or "reinforcing" property. The pharmacological effect responsible for the rewarding and hence the abuse liability is an section on the dopamenergic synapses. Cocaine prolongs the activity of dopamine in the synapse by blocking the dopamine receptor mechanism. The potency of cocaine and cocaine-like drugs in self- administration studies correlates with their potencies in inhibiting 3H-mazindol binding to the dopamine uptake site in the rat striatum. Since there is no correlation for binding to a large number of other pre-and post-synaptic binding sites the cocaine receptor related to substance abuse appears to be the one associated with dopamine uptake inhibition. In this study the design, synthesis and receptor binding evaluation of cocaine analogs are proposed as a method of investigating the biochemical mechanism of cocaine abuse liability. Molecular modeling studies were used to investigate the conformational energetics of possible pharmacophore binding modes for cocaine and to design the cocaine analogs proposed for study. Since the unique structural and stereochemical requirements seen in biological systems are due to a complementary three- dimensional interaction between a drug and its receptor site, the experimental determination of these requirements can be used to construct a picture of the receptor. This information will provide new and unique tools for biochemical studies and could translate into new agents for the treatment of cocaine addiction.