DRUG SYNTHESIS % TREATMENT FOR COCAINE ADDICTION

药物%20合成%20%%20治疗%20用于%20可卡因%20成瘾

• 批准号: 7459046
• 负责人: FRANK Ivy CARROLL
• 金额: $ 10.84万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459046
• 关键词: ADME Study; Affinity; Animals; Binding; Brain; Cocaine; Cocaine Dependence; Contracts; Cyclic GMP; Development; Dopamine; Dosage Forms; Drug Formulations; Goals; Half-Life; Institutes; Intake; Label; Lead; Monkeys; National Institute of Drug Abuse; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Property; Rattus; Research; Self Administration; Self-Administered; Specificity; Toxicology; Training; analog; drug discrimination; drug synthesis; noradrenaline transporter; pre-clinical; receptor; research clinical testing

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.

在过去的几年中，我们已经合成了超过500个3-苯基趋烷类似物，这些类似物在多巴胺，血清素和去甲肾上腺素转运蛋白（DAT，5-HTT和NET）上进行了评估。这些研究确定了47个类似物，这些类似物表明DAT的高亲和力在5-HTT和NET时具有低亲和力。初步动物研究表明，某些DAT选择性3-苯基型的进入大脑比可卡因要慢得多，在大脑中的半衰期比可卡因更长，在药物管理中被动物视为可卡因，并减少受训练的自我管理可卡因的动物的可卡因摄入量。因此，这些DAT选择性3-苯基型具有几种被认为是药物所需的特性。该旋转的目的是开发一种安全有效的药物，以治疗沉迷于可卡因的患者。在研究三角研究所的F. ivy Carroll博士的指导下，该项目将提供在本应用程序的其他Spircap项目中进行研究的3-苯基基质类似物。选择用于合成的化合物对DAT具有很高的亲和力，并且对5-HTT和NET的亲和力较低（即它们是DAT-Selesext）。该项目将涉及500毫克的合成，每个数据选择性的3-苯基趋化型在项目2中提出的总观察，运动活性和药物歧视研究中所需的3-苯基趋化素。项目4中的猴子，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）以及其他大鼠和猴子前临床前评估（项目3和4）。此信息将用于选择3-苯基趋烷进行1期临床评估。 NIDA-MDD将安排该化合物的CGMP材料的合成。该项目还涵盖了CGMP材料，[2H] - 和[14C]标记的类似物的启动化合物的起始化合物，以及成品剂型的配方开发和制造（根据合同与OREAD）以及配方材料之前和之后的CGMP材料的稳定性研究。