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: 6673844
• 负责人: ROBERT INNIS
• 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/6673844
• 关键词: Macaca mulatta; behavior test; carbon; 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 rat; ligands; neuropharmacology; nonhuman therapy evaluation; positron emission tomography; psychopharmacology; receptor binding; self medication; serotonin receptor; sheep; single photon emission computed tomography; stable isotope; tissue /cell culture

Corticotropin releasing hormone (CRH) is intimately involved in the regulation of numerous behavioral and physiological processes and plays a central role in the response to stress in mammalian systems. The CRH receptor 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. CRH is involved in regulation of a number of normal functions and in the pathogenesis of a number of disorders of primary interest to NIDDK including the development of insulin resistance. CRH and its receptors are located peripherally in sympathetic nerve terminals and function as proinflammatory mediators in the gastrointestinal system. In the gut, CRH decreases stomach contractions and inhibits gastric emptying by activation of CRH2 receptors and while increasing small intestinal and colonic motility by activating CRH1 receptors. Excessive chronic activation of the CRH system is involved in the pathogenesis of eating and gastrointestinal disorders. In a recent study of the latter, we described dramatic suppression of immobilization stress effects by the CRH1 antagonist antalarmin (see below) in a rat model of stomach ulcer, irritable bowel syndrome and inflammatory bowel disease. In some of our other studies in diverse paradigms involving the CRH system, we showed that (1) Antalarmin blocks CRH-induced hypertension in the rat, (2) Antalarmin suppresses stress-induced oxidative tissue damage in the brain and gut. Oxidative tissue damage, as indexed by lipid oxidation and protein oxidation products, has recently been recognized as a sensitive index of stress-induced neurotoxicity and visceral damage. (3) Antalarmin attenuates adjuvant-induced arthritis in the rat, (4) Antalarmin suppresses the CRH promotion of embryo implantation and maintenance of early pregnancy in the rat, and (5) Finally, we found that antalarmin lowers stress related behavior and enhances exploration during separation in the maternal deprivation stress paradigm in infant primates. We have also found that CRH is elevated and neuropeptide Y is depleted in the cerebrospinal fluid of these infants as a function of the number of weeks of separation whether the infants were raised with or without their mothers. Maternally deprived infants had additionally significantly higher concentrations of CRH that paralleled their higher scores of stress-related behaviors, namely vocalization, locomotion, self-directed behavior and withdrawal. These findings underscore the importance of CRH in encoding emotional memory and possibly consolidating fear into psychopathology in primates. Substance abuse and its consequences are also major stressors and contribute to many current societal and medical problems including a major role in the spread of acquired immune deficiency syndrome, drug-resistant tuberculosis and hepatitis. In order to gain further insight into the pathogenesis of stress-related disorders, 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 CRH receptors, cocaine receptors [DA transporter proteins] and the opioid receptors. Some of our results include: (1) a study of the lipophilicity of CRH1 receptor antagonists, (2) the development of chiral dopamine reuptake inhibitors as cocaine abuse treatment agents, (3) assessment of delta opioid receptor agonist effects in vivo, (4) chemical synthesis of double 13C labeled antalarmin (5) chemical synthesis of 5-phenylmorphan derivatives as probes of the opioid receptor system, (6) elucidation of the mechanism of action of the naturally occurring, nonnitrogenous salvinorin A as a kappa opioid receptor agonist, and (7) the identification of a new cocaine binding site in brain membranes from dopamine transporter knockout mice. We plan to further capitalize on 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 CHR and the other endogenous ligands at their recognition sites.

促肾上腺皮质激素释放激素（CRH）密切参与众多行为和生理过程的调节，并在哺乳动物系统对压力的反应中发挥核心作用。 CRH 受体系统由可饱和、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 CNS 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。 CRH 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，包括胰岛素抵抗的发展。 CRH 及其受体位于交感神经末梢的外周，在胃肠道系统中充当促炎介质。在肠道中，CRH 通过激活 CRH2 受体减少胃收缩并抑制胃排空，同时通过激活 CRH1 受体增加小肠和结肠蠕动。 CRH 系统的过度慢性激活与饮食和胃肠道疾病的发病机制有关。在最近的一项针对后者的研究中，我们描述了 CRH1 拮抗剂 antalarmin（见下文）在胃溃疡、肠易激综合征和炎症性肠病大鼠模型中对固定应激效应的显着抑制。在我们涉及 CRH 系统的不同范式的一些其他研究中，我们表明 (1) Antalarmin 可以阻断 CRH 诱导的大鼠高血压，(2) Antalarmin 可以抑制压力诱导的大脑和肠道氧化组织损伤。以脂质氧化和蛋白质氧化产物为指标的氧化组织损伤最近被认为是应激引起的神经毒性和内脏损伤的敏感指标。 (3) Antalarmin 减轻大鼠佐剂诱导的关节炎，(4) Antalarmin 抑制 CRH 对大鼠胚胎植入和维持早期妊娠的促进作用，(5) 最后，我们发现 Antalarmin 降低压力相关行为并增强探索能力在婴儿灵长类动物的母亲剥夺应激范式中分离期间。我们还发现，无论婴儿是否与母亲一起抚养长大，这些婴儿的脑脊液中 CRH 升高且神经肽 Y 耗尽，这与分离周数有关。母亲剥夺的婴儿的 CRH 浓度也显着较高，这与他们与压力相关的行为（即发声、运动、自我导向行为和退缩）得分较高相平行。这些发现强调了 CRH 在编码情绪记忆以及可能将恐惧巩固到灵长类动物精神病理学中的重要性。药物滥用及其后果也是主要的压力源，并导致许多当前的社会和医疗问题，包括在获得性免疫缺陷综合征、耐药结核病和肝炎的传播中发挥重要作用。为了进一步了解压力相关疾病的发病机制，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 CRH 受体、可卡因受体的新型非肽配体。 DA转运蛋白]和阿片受体。我们的一些结果包括：(1) CRH1 受体拮抗剂亲脂性的研究，(2) 手性多巴胺再摄取抑制剂作为可卡因滥用治疗剂的开发，(3) 体内 δ 阿片受体激动剂作用的评估，(4 ) 双 13C 标记安塔拉明的化学合成 (5) 作为阿片受体系统探针的 5-苯基吗啡烷衍生物的化学合成， (6) 阐明天然存在的非氮萨尔维诺林 A 作为 kappa 阿片受体激动剂的作用机制，以及 (7) 在多巴胺转运蛋白敲除小鼠的脑膜中鉴定出新的可卡因结合位点。我们计划通过开发模拟或拮抗 CHR 和其他内源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。