DRUG SYNTHESIS % TREATMENT FOR COCAINE ADDICTION

在过去的几年里，我们已经合成了500多个3-苯基托烷类似物，它们已经被评估与多巴胺、5-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，它们在DAT上表现出高亲和力，而在5-HTT和NET上表现出低亲和力。初步的动物研究表明，一些对DAT具有选择性的3-苯基托烷类化合物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，在给药研究中被动物识别为可卡因，并通过训练自我给药的动物减少可卡因的摄入量。因此，这些DAT选择性的3-苯基托烷具有几种被认为是药物所需的性质。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F.Ivy Carroll博士的指导下，该项目将提供该应用的其他SPIRCAP项目研究所需的3-苯基托烷类似物的合成。选择合成的化合物对DAT有很高的亲和力，而对5-HTT和NET的亲和力要低得多(即它们是DAT选择性的)。该项目将涉及合成项目2中提出的大体观察、运动活动和药物鉴别研究中所需的每个500毫克的DAT选择性3-苯基托烷。预计项目2中的研究将导致识别6个类似物，这些类似物将在项目3中进行大鼠自我给药研究。其中4个化合物将以50-M的数量制备，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(Novascreen)和一般药理学(MDS PanLabs)，以及额外的大鼠和猴子临床前评估(项目3和4)。这一信息将被用于选择3-苯基托烷进行1期临床评估。NIDA-MDD将安排该化合物的cGMP材料的合成。该项目还包括合成cGMP材料的起始化合物、ADME研究所需的[2H]和[14C]标记类似物、成品剂型的配方开发和制造(根据与ORead的合同)以及配方前后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.