BIOLOGICAL STUDIES OF PIPERIDINE ANALOGS OF COCAINE

描述：（申请人摘要） 需要立即治疗全世界的可卡因滥用。 在这个方向上，我们最近发现了一种基于哌啶的类似物， 可卡因（特别是1-甲基-4-（4-氯苯基）的反式异构体） 哌啶-3-羧酸甲酯）结合可卡因 与可卡因具有可比亲和力的识别位点;此外， 化合物作为多巴胺摄取的抑制剂。 尽管有 化合物的效力，已经观察到，在区分研究中， 在大鼠中，该化合物仅表现出弱的可卡因-安非他明样作用。 与可卡因不同，这种化合物具有较弱的运动兴奋作用， 由大鼠自行给药。 这些结果似乎是有希望的， 发现一种可能的药物用于药物滥用治疗的观点。 为了对这些令人鼓舞的初步成果采取适当的后续行动， 研究人员计划在体外进行进一步的化学类似物合成， 药理学研究和体内动物实验 4-苯基哌啶类似物，其目的是改善生物活性， 这个化合物的特征 在这一建议的范围内，我们打算继续努力， 具体目标如下： 1. 进行额外的构效关系研究， 以确定他们正在推进尽可能好的化合物 药物治疗 这些研究将包括准备铅结构 光学纯的形式，以及相关类似物的设计和合成 包括以下结构变化：a）性质的改变 和苯环上取代基的位置; B）取代 N-甲基被其他烷基和磺酰基取代，以及 NMe被CH 2和O等排置换; c）酯基的取代 烷基和烯基。 2. 为了表征所有新合成的类似物， 体外结合实验，以及对5 HT、NE和DA的抑制 摄取。 3. 对于选定的化合物，为了评价药物的静脉内安全性， 候选化合物，对于符合安全性标准的化合物， 进行运动活性测定。 4. 对于符合既定标准的化合物，进一步评估其行为 使用静脉注射药物的动物药理学特征 自我管理和药物歧视程序。

DESCRIPTION: (Applicant's Abstract) Immediate therapies are needed for the treatment of cocaine abuse worldwide. In this direction, we recently identified a piperidne-based analog of cocaine (specifically, the trans isomer of 1-methyl-4-(4-chlorophenyl) piperdine-3-carboxylic acid methyl ester) that binds to the cocaine recognition site with comparable affinity to cocaine; additionally, this compound acts as an inhibitor of dopamine uptake. In spite of the compound's potency, it has been observed that in discrimination studies in rats, the compound exhibits only weak cocaine-amphetamine-like effects. Unlike cocaine, this compound has weak motor stimulant effects and is not self administered by rats. These results appear to be promising from the standpoint of discovering a possible medication for drug abuse treatment. In order to properly follow up on these encouraging preliminary results, the investigators plan to conduct further chemical analog synthesis, in vitro pharmacological studies, and in vivo animal experiments on the 4-phenylpiperidine analogs with the objective to improve upon the biological profile of this compound. Within the context of this proposal, it is our intention to pursue the following specific aims: 1. To conduct additional structure-activity relationship studies in order to establish that they are advancing the best compound(s) as possible medications. These studies would include preparation of the lead structure in optically pure form, and the design and synthesis of related analogs embodying a the following structural changes: a) modification of the nature and position of the substituent borne by phenyl ring; b) replacement of the N-methyl group by other alkyl groups and sulfonyl groups, as well as isosteric replacement of NMe by CH2 and O; c) replacemnt of the ester group by alkyl and alkenyl groups. 2. To characterize all newly synthesized analogs pahamacologically in in vitro binding experiments, and for the inhibition of the 5HT, NE, and DA uptake. 3. For selected compounds, to evaluate the intravenous safety of the candidate compounds, and for compounds meeting the saftey critieria, to carry out locomotion activity assays. 4. For compounds meeting set criteria, to further evaluate their behavioral pharmacological profile in animals using intravenous drug self-administration and drug discrimination procedures.