SYNTHESIS OF CONFORMATIONALLY CONSTRAINED COCAINES

描述(申请人摘要)： 这项建议的目标是合理地设计和综合 与多巴胺上的可卡因识别位点结合的可卡因类似物 转运蛋白，但不能抑制或仅弱抑制再摄取 多巴胺。这种拮抗剂或部分激动剂具有很好的治疗作用。 潜在的(1)用于治疗一些不良副作用 与可卡因过量有关，或(2)用于维持吸毒者在 治疗方案。要实现这些目标，就必须有一个 增加了对可卡因的基本化学和药理的了解。 这个项目的具体目标是合成经过精心挑选的类似物 以更全面地了解可卡因的结构和活性 管理可卡因药理的关系。具体地说，这个提案 中心中心合成的硬性可卡因类似物具有“锁定” 氮孤子对的构象，以解决 可卡因与其识别部位结合的方向性。 将准备更多的类比，以进一步探讨 可卡因的氮和多巴胺转运体之间的相互作用。分子 准备好的化合物的模型和生物学数据将被用于 进一步发展药效团模型。这将通过一个 着眼于确定任何增加结合的结构修改 同时减少或消除多巴胺摄取抑制。

DESCRIPTION (Applicant's Abstract): The objective of this proposal is the rational design and synthesis of cocaine analogs that bind to the cocaine recognition site on the dopamine transporter but fail to inhibit or only weakly inhibit the reuptake of dopamine. Such antagonists or partial agonists are of great therapeutic potential (1) for the treatment of some of the adverse side effects associated with cocaine overdose, or (2) for the maintenance of addicts in treatment programs. To achieve these goals it is essential to have an increased understanding of the basic chemistry and pharmacology of cocaine. The specific aim of this program is to synthesize carefully selected analogs of cocaine to obtain a more complete understanding of the structure activity relations that govern cocaine's pharmacology. Specifically, this proposal centers around the synthesis of rigid cocaine analogs with a "locked" conformation of the nitrogen lone pair to address the importance of the directionality in the binding of cocaine to its recognition site. Additional analogs will be prepared to further probe the importance of interactions between cocaine's nitrogen and dopamine transporter. Molecular modeling and biological data on the compounds prepared will be used to further develop a pharmacophore model. This will be accomplished with an eye toward identifying any structural modifications that increase binding while decreasing or eliminating dopamine uptake inhibition.