Design And Synthesis Of Drugs Acting On Central And Peri

中枢及末梢药物的设计与合成

• 批准号: 6984033
• 负责人: Kenner C Rice
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6984033
• 关键词: behavior test; chemoprevention; cocaine; corticotropin releasing factor; drug abuse chemotherapy; drug abuse prevention; drug addiction antagonist; drug design /synthesis /production; drug receptors; drug screening /evaluation; hormone receptor; laboratory mouse; ligands; neuroimaging; neuropharmacology; nonhuman therapy evaluation; positron emission tomography; psychopharmacology; receptor binding; self medication; serotonin receptor; single photon emission computed tomography

In order to gain further insight into the pathogenesis of stress-related disorders and drug abuse, to probe sites for possible intervention, and to develop potential treatments for these disorders, we have designed, synthesized and evaluated novel nonpeptide ligands which act on corticotropin releasing hormone (CRH) receptor system receptors, cocaine receptors [DA transporter proteins] and the opioid receptors. The CRH system consists of saturable, high-affinity CRH1 and CRH2 receptors and their endogenous ligands located in anatomically well-defined regions of the CNS and periphery with the CRH1 receptor mediating many CRH effects in the brain. This hormone is involved in regulation of a number of normal functions and in the pathogenesis of a number of disorders disorders of primary interest to NIDDK including the development of insulin resistance. Excessive chronic activation of the CRH system is involved in the pathogenesis of eating and gastrointestinal disorders and many other disorders including drug abuse. The treatment and prevention of the abuse of narcotic drugs and the psychomotor stimulants cocaine and methamphetamine are critical areas from a health and societal viewpoint. We have made advances in these areas and have originated a medication for treatment of psychomotor stimulant abuse that has now entered phase 2 clinical testing. We have also introduced several related drugs as later generation candidates for clinical trials that can be converted to ultra long-acting prodrugs. Earlier, we showed that one dose of one of these prodrugs virtually abolished cocaine self-administration in rhesus monkeys for about one month. We also studied the effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys and determined the relationship to transporter occupancy as measured by PET neuroimaging. Some of our other results include: (1) pharmacological characterization of the role of the 5-HT2A receptor on hyperlocomotor activity and hyperthermic effects produced by 3,4-methylenedioxymethamphetamine (Ecstasy) (2) Study of the effects of the delta-opioid receptor agonist SNC80 on learning and its antidepressant-like effects in rats (3) the development of a practical chemical synthesis of optically pure N-norbremazocine enantiomers as intermediates for a novel and facile preparation of bremazocine enantiomers (4) elucidation of the behavioral, adrenal and sympathetic responses to long term administration of an oral CRH receptor antagonist in a primate stress paradigm (5) the chemical synthesis of novel 5-phenylmorphan derivatives as probes of the opioid receptor system. A review, Analgesic research at NIH: State of the Art 1930?s to State of the Art 2002 was published. A review was also published on nonpeptide CRH type 1 receptor antagonists as medications and imaging agents. We plan to further exploit current and developing knowledge of the CRH, dopamine and cocaine receptor systems through the development of nonpeptide drugs that either mimic or antagonize the effects of drugs and endogenous ligands at their recognition sites.

为了进一步了解压力相关疾病和药物滥用的发病机制，探索可能的干预位点，并开发这些疾病的潜在治疗方法，我们设计、合成和评估了作用于促肾上腺皮质激素释放激素的新型非肽配体(CRH) 受体系统受体、可卡因受体 [DA 转运蛋白] 和阿片受体。 CRH 系统由可饱和、高亲和力的 CRH1 和 CRH2 受体及其内源性配体组成，这些配体位于中枢神经系统和外周解剖学明确的区域，CRH1 受体介导大脑中的许多 CRH 效应。该激素参与多种正常功能的调节以及 NIDDK 主要关注的多种疾病的发病机制，其中包括胰岛素抵抗的发展。 CRH 系统的过度慢性激活与饮食和胃肠道疾病以及包括药物滥用在内的许多其他疾病的发病机制有关。从健康和社会的角度来看，治疗和预防滥用麻醉药品和精神运动兴奋剂可卡因和甲基苯丙胺是关键领域。我们在这些领域取得了进展，并发明了一种治疗精神运动兴奋剂滥用的药物，现已进入二期临床测试。我们还推出了几种相关药物作为临床试验的下一代候选药物，可以转化为超长效前药。早些时候，我们发现，在恒河猴中，服用其中一种前药的一剂实际上可以在大约一个月内消除可卡因的自我给药。我们还研究了多巴胺转运蛋白抑制剂对恒河猴自我施用可卡因的影响，并通过 PET 神经影像测量确定了与转运蛋白占用率的关系。我们的其他一些结果包括：(1) 5-HT2A 受体对 3,4-亚甲二氧基甲基苯丙胺（摇头丸）产生的过度运动活性和热效应作用的药理学特征 (2) δ-阿片受体作用的研究激动剂 SNC80 对大鼠学习及其抗抑郁样作用 (3) 光学纯 N-去甲布马佐辛的实用化学合成的开发对映异构体作为新型且简便制备布马佐辛对映异构体的中间体 (4) 阐明在灵长类应激范例中长期施用口服 CRH 受体拮抗剂的行为、肾上腺和交感神经反应 (5) 新型 5-苯基吗啡烷的化学合成衍生物作为阿片受体系统的探针。发表了一篇综述，《NIH 的镇痛研究：1930 年代至 2002 年的最新技术》。还发表了一篇关于非肽 CRH 1 型受体拮抗剂作为药物和显像剂的综述。我们计划通过开发模拟或拮抗药物和内源性配体在其识别位点的作用的非肽药物，进一步利用 CRH、多巴胺和可卡因受体系统的当前和正在发展的知识。