DRUG SYNTHESIS % TREATMENT FOR COCAINE ADDICTION

在过去的几年中，我们已经合成了超过500个3-苯基托烷类似物，已经评估了它们在多巴胺、多巴胺和去甲肾上腺素转运蛋白（分别为DAT、5-HTT和NET）上的结合。这些研究鉴定了47种类似物，其在DAT处显示出高亲和力，而在5-HTT和NET处显示出低亲和力。初步的动物研究已经表明，一些DAT-选择性3-苯基托烷进入大脑比可卡因慢得多，在大脑中的半衰期比可卡因长得多，在药物给药研究中被动物识别为可卡因，并且减少训练自我给药可卡因的动物对可卡因的摄入。因此，这些DAT-选择性3-苯基托烷具有被认为是药物所需的几种性质。SPIRCAP的目标是开发一种安全有效的药物来治疗可卡因成瘾的患者。在F博士的指导下，Ivy卡罗尔的三角研究所，该项目将提供3-苯基托烷类似物的合成研究需要在其他SPIRCAP项目的这一应用。选择用于合成的化合物对DAT具有高亲和力，对5-HTT和NET具有低得多的亲和力（即，它们是DAT选择性的）。该项目将涉及在项目2中提议的大体观察、促排剂活性和药物辨别研究中所需的DAT-选择性3-苯基托烷各合成500 mg。预计项目2中的研究将鉴别出6种类似物，这些类似物将在项目3中进行大鼠自我给药研究。将制备其中4种化合物，数量为50 μ m，用于项目4中的猴自我给药研究、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）以及其他大鼠和猴临床前评价（项目3和4）。该信息将用于选择用于I期临床评价的3-苯基托烷。NIDA-MDD将安排合成该化合物的cGMP材料。该项目还包括cGMP材料的起始化合物、ADME研究所需的[2 H]和[14 C]标记类似物的合成、成品剂型的处方开发和生产（根据与OREAD的合同）以及cGMP材料在配制前后的稳定性研究。

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.