DRUG SYNTHESIS % TREATMENT FOR COCAINE ADDICTION

在过去的几年中，我们已经合成了超过500种3-苯基tropane类似物，这些类似物已被评估与多巴胺，五羟色胺和去甲肾上腺素转运体（分别为DAT， 5-HTT和NET）结合。这些研究确定了47个类似物，它们对DAT具有高亲和力，而对5-HTT和NET具有低亲和力。初步的动物研究表明，一些选择性的3-苯tropanes进入大脑的速度比可卡因慢得多，在大脑中的半衰期比可卡因长得多，在药物管理研究中被动物识别为可卡因，并且通过训练能够自我使用可卡因的动物减少可卡因的摄入量。因此，这些具有dat选择性的3-苯tropanes具有一些被认为是药物所必需的特性。这项SPIRCAP的目标是开发一种安全有效的药物来治疗可卡因成瘾患者。在三角研究所的F. Ivy Carroll博士的指导下，该项目将为该应用的其他SPIRCAP项目提供所需的3-苯基tropane类似物的合成。选择用于合成的化合物对DAT具有高亲和力，而对5-HTT和NET具有低亲和力（即它们具有DAT选择性）。该项目将包括合成项目2中提出的大体观察、运动活动和药物鉴别研究所需的每种500 mg的dat选择性3-苯tropanes。预计项目2的研究将导致鉴定六种类似物，这些类似物将在项目3的大鼠中进行自我给药研究。其中四种化合物将以50立方米的量制备，用于项目4中的猴子自我给药研究、初步毒理学研究（由NIDA提供）、一般受体特异性研究（Novascreen）和一般药理学研究（MDS Panlabs），以及额外的大鼠和猴子临床前评估（项目3和4）。该信息将用于选择用于1期临床评价的3-苯tropane。NIDA-MDD将安排该化合物cGMP材料的合成。该项目还包括cGMP材料起始化合物的合成，ADME研究所需的[2H]-和[14C]标记类似物，制剂开发和成品剂型的制造（根据与OREAD的合同），以及制剂前后cGMP材料的稳定性研究。

Over the past few years, we have synthesized over 500 3-phenyltropane analogs that have been evaluated for binding at the dopamine, serotine, and norepinephrine transporters (DAT, 5-HTT, and NET, respectively). These studies identified 47 analogs that showed high affinity at the DAT with low affinity at the 5-HTT and NET. Preliminary animal studies have shown that some of the DAT-selective 3-phenyltropanes enter the brain much more slowly than cocaine, have half-lives in the brain much longer than cocaine, are recognized by animals as cocaine in drug administration studies, and reduce the intake of cocaine by animals trained to self- administer cocaine. Thus, these DAT-selective 3-phenyltropanes possess several properties that are believed to be required for a medication. The goal of this SPIRCAP is to develop a safe and effective medication for treating patients addicted to cocaine. Under the direction of Dr. F. Ivy Carroll of the Research Triangle Institute, This project will provide the synthesis of the 3-phenyltropane analogs needed for study in other SPIRCAP projects of this application. The compounds selected for synthesis have high affinity for the DAT and much lower affinity for the 5-HTT and NET (i.e., they are DAT-selective). The project will involve the synthesis of 500 mg each of the DAT-selective 3-phenyltropanes needed in the gross observation, locomoter activity, and drug discrimination studies proposed in Project 2. It is expected that the studies in Project 2 will lead to the identification of six analogs which will undergo self-administration studies in rats in Project 3. Four of these compounds will be prepared in 50-m quantities for self-administration studies in monkeys in Project 4, preliminary toxicology studies (to be provided by NIDA), general receptor specificity (Novascreen), and general pharmacology (MDS Panlabs), and additional rat and monkey pre-clinical evaluation (projects 3 and 4). This information will be used to select the 3-phenyltropane for Phase 1 clinical evaluation. NIDA-MDD will arrange the synthesis of the cGMP material of this compound. This project also encompasses the synthesis the starting compound for the cGMP material, the [2H]- and [14C]-labeled analogs required for the ADME studies, and the formulation development and manufacture of the finished dosage form (under a contract with OREAD) as well as the stability studies of the cGMP material before and after formulation.