Methylphenidate Analogs as Medications for Cocaine Abuse

描述(由申请人提供)：本项目的中心目标是 新型哌甲酸甲酯类似物的合成及其应用前景评价 治疗可卡因成瘾的药物和作为新型前体的药物 神经成像剂。即使有相当广泛的哌甲酸甲酯 过去已经探索过类似的方法，这是以前的 这一领域的研究是与传统方法相关的局限性 用于合成这些类似物。在开发了一种非常强大的 两步不对称合成哌酸苏甲酯，这使得 技术将用于合成一系列广泛的哌甲酸甲酯 类比。 该项目的具体合成目标如下： 苏氨酸甲酯和赤霉酸甲酯的类似物， 哌醋酸苏甲酯、哌酸苏甲酯的氧杂和碳水化合物类似物， 哌啶环修饰的类似物，以及多环衍生物。所有化合物 将对它们与多巴胺、5-羟色胺和 去甲肾上腺素转运体。表现出有趣的化合物的类别 生物特性将扩展到更广泛的系列。更远的地方 将对有前景的化合物进行体外和体内评估。 还将进行初步研究，以确定PET是否有用 放射性配体可以由下列任何有效的和选择性的类似物制成 在这些研究中发现的。

DESCRIPTION (provided by applicant): The central goal of this project is to synthesize novel methylphenidate analogs and evaluate their potential as medications for the treatment of cocaine addiction and as precursors to novel neuroimaging agents. Even though a reasonably wide range of methylphenidate analogs have been explored in the past, a major shortcoming with the previous studies in this area was the limitations associated with the traditional method used for the synthesis of these analogs. Having developed a very powerful two-step asymmetric synthesis of threo-methylphenidate, this enabling technology will be used for the synthesis of a wide array of methylphenidate analogs. The specific synthetic targets of the project are the following: naphthyl analogs of threo- and erythro-methylphenidate, heterocyclic analogs of threo-methylphenidate, oxa and carba analogs of threo-methylphenidate, piperidine ring-modified analogs, and polycyclic derivatives. All compounds will be initially screened for their binding to the dopamine, serotonin and norepinephrine transporters. Classes of compounds that display interesting biological properties will be extended into a more extensive series. Further in vitro and in vivo evaluation of promising compounds will be conducted. Initial studies will also be carried out to determine if useful PET radioligands can be made from any potent and selective analogs that are discovered during these studies.