NEUROPHARMACOLOGY AND METABOLISM OF PHENOTHIAZINES

吩噻嗪类药物的神经药理学和代谢

• 批准号: 3376193
• 负责人: Richard B Mailman
• 金额: $ 15.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1988-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3376193
• 关键词: acetylcholine; adenylate cyclase; amphetamines; apomorphine; brain metabolism; chlorpromazine; cytochrome P450; dopamine; drug administration routes; drug metabolism; ethology; haloperidol; high performance liquid chromatography; human tissue; neuropharmacology; neurotransmitter metabolism; oxygenases; phenothiazines; thioridazine

This proposal will investigate the relationship between metabolism and neuropharmacology of three structurally dissimilar phenothiazine antipsychotic drugs [thioridazine (Mellaril), trifluoperazine (Stelazine), and chlorpromazine (Thorazine)]. The primary goal of the neuropharmacological experiments is to compare the antidopaminergic activity of the parent phenothiazines with their major metabolites. The in vitro techniques to be used include various radioligand binding assays (e.g., with [3H]-spiperone and [3H]-dopamine), and the ability of drugs to affect dopamine-stimulated adenylate cyclase activity. Another in vitro measure to bridge the gap between data from the intact animal vs. that from brain homogenates, are effects of these drugs on pre- and post-synaptic receptors modulating the release of dopamine and acetylcholine from slices of striatum or other regions. In vitro effects on other neurotransmitter systems (e.g., [3H]-QNB or [3H]-WB-4101 binding) will also be examined. In vivo studies will determine the ability of the drug metabolites or their parent compounds to inhibit amphetamine- or apomorphine-induced behaviors (e.g., stereotyped behavior, aggression, and locomotion) and to alter biochemical estimates of the activity of dopamine neurons using neurochemical methods to evaluated DOPAC, HVA, 1-DOPA, etc., as required. Both intracerebroventricular and peripheral routes of drug administration will be used in the in vivo experiments. Finally, the effects of withdrawal from chronic drug administration will be measured to determine if behavioral and neurochemical changes observed are a function of the metabolites formed from the parent compound. These functional and biochemical data relevant to these phenothiazines and their metabolites will be compared to similar studies with a classical non-phenothiazine neuroleptic (haloperidol) and a compound, SCH 23390, purported to be a specific D1 dopamine antagonist. Mechanisms of metabolism will be determined, focusing on two distinct enzyme systems, the flavin-containing monooxygenase (EC1.14.13.8) and cytochrome P450 monooxygenases. The relative role of the P450 and FCM enzymes in the bioformation of pharmacologically active metabolites, and the effects of chronic administration of these drugs on enzyme activity, will be determined. Species differences in enzyme activity will be exploited by using a species (e.g., hamsters) that should produce patterns of metabolites in blood that are similar to humans and unlike rats.

该提议将调查新陈代谢与 三种结构上不同势噻嗪的神经药理学 抗精神病药[硫代嗪（Mellaril），三氟嗪（Stelazine），Stelazine， 和氯丙嗪（胸嗪）]。 主要目标 神经药物实验是比较抗多巴胺能 父苯二胺与主要代谢产物的活性。 in 要使用的体外技术包括各种放射性结合测定 （例如，使用[3H] - 刺酮和[3H] - 多巴胺），以及药物的能力 影响多巴胺刺激的腺苷酸环化酶活性。 另一个体外 从完整的动物与从 脑匀浆，是这些药物对前和突触后的作用 从切片中调节多巴胺和乙酰胆碱释放的受体 纹状体或其他地区。 体外对其他神经递质的影响 还将检查系统（例如[3H] -QNB或[3H] -WB-4101绑定）。 在 体内研究将确定药物代谢产物或其它们的能力 母体化合物可抑制苯丙胺或丙氨酸诱导的行为 （例如，刻板的行为，攻击性和运动）并改变 使用多巴胺神经元活性的生化估计 根据需要评估DOPAC，HVA，1-DOPA等的神经化学方法。 药物给药的脑室内和外周途径均 将用于体内实验。 最后，影响的影响 将测量从慢性药物管理中提取以确定 如果观察到的行为和神经化学变化是 由母体化合物形成的代谢产物。 这些功能和 与这些势噻嗪及其代谢产物有关的生化数据 将与经典非苯噻嗪的类似研究进行比较 神经肽（氟哌啶醇）和一个化合物SCH 23390，据称为一个 特定的D1多巴胺拮抗剂。 代谢机制将是 确定，专注于两个不同的酶系统，含黄素 单加氧酶（EC1.14.13.8）和细胞色素p450单加氧酶。 这 P450和FCM酶在生物形成中的相对作用 药理学活性代谢产物，以及慢性的影响 将确定这些药物在酶活性上的施用。 酶活性的物种差异将通过使用一个物种来利用 （例如，仓鼠）应在血液中产生代谢物的模式 与人类相似，与老鼠不同。