DESIGN, SYNTHESIS AND DRUGS ACTING ON CENTRAL AND PERIPHERAL TISSUES

作用于中枢和外周组织的设计、合成和药物

• 批准号: 3941143
• 负责人: K 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/3941143
• 关键词: autoradiography; benzodiazepines; centrally acting drug; drug adverse effect; drug design /synthesis /production; drug metabolism; ligands; neuropharmacology; neurotransmitter metabolism; opiate alkaloid; phencyclidine; positron emission tomography; radiopharmacology; radiotracer

Formerly projects: Z01 DK 19226-08LC, Z01 DK 19202-13LC, Z01 DK 19237-05LC, Z01 AM 19239-04LC, Z01 DK 19246-04LC Z01 DK 19233-07LC, and Z01 DK 19235-05LC. Recent recognition that the effects of diverse classes of pharmacological agents are mediated by discrete cell receptors, which normally function in concert with their endogenous ligands, has presented unique opportunities for dramatic advances in the understanding of many central and peripheral regulatory systems in animals and humans. Optimal exploitation of such opportunities requires design and synthesis of highly selective drugs as probes for study of these systems and a collaborative, multidisciplinary approach in such studies. Elucidation of the exact molecular structure and mechanism of action of these endogenous ligand-receptor systems, and the molecular mechanism of action of endogenous ligand-mimetic drugs and their antagonists will provide new opportunities for therapeutic intervention in many clinical situations and for the design of superior drugs, particularly for disorders which are now little-understood. Studies in progress are currently aimed at identification, purification, and elucidation of the structure and function of opiate, benzodiazepine and phencyclidine receptor subpopulations in the overall modulation of the CNS. These studies require synthesis of new receptor ligands for several lines of investigation utilizing: (1) irreversible ligands specific for receptor subpopulations; (2) high specific activity radiolabeled ligands for autoradiographic visualization of receptors; (3) conformationally restricted analogs of potent receptor ligands as topological probes; (4) position emission transaxial tomographic visualization of receptor patterns in living brains. Studies designed to identify a clinically useful antagonist of PCP are underway. Synthesis of previously inaccessible unnatural opiate enantiomers using the recently developed NIH Opiate Total Synthesis is also in progress with the goals of identification of new pharmacological agents and effects of opiates mediated through nonclassical opiate receptors.

以前的项目：Z01 DK 19226-08LC、Z01 DK 19202-13LC、 Z01 DK 19237-05LC，Z01 AM 19239-04LC，Z01 DK 19246-04LC Z01 DK 19233-07LC 和 Z01 DK 19235-05LC。 最近的 认识到不同类别的药理作用的影响 药物是由离散的细胞受体介导的，通常 与其内源性配体协同发挥作用，已提出 理解方面取得显着进展的独特机会 动物的许多中枢和外周调节系统 人类。 最佳利用此类机会需要 设计和合成高选择性药物作为研究探针 这些系统和协作的多学科方法 在这样的研​​究中。 阐明确切的分子结构和 这些内源性配体受体的作用机制 系统和内源性作用的分子机制 配体模拟药物及其拮抗剂将提供新的 许多临床治疗干预的机会 情况和优质药物的设计，特别是 现在人们对这些疾病知之甚少。 正在进行的研究有 目前的目标是鉴定、纯化和阐明 阿片类药物、苯二氮卓类药物的结构和功能 苯环己哌啶受体亚群在整体调节中的作用 中枢神经系统。 这些研究需要合成新的受体配体 用于多种研究，利用：（1）不可逆配体 对受体亚群具有特异性； (2)比活度高 用于放射自显影可视化的放射性标记配体 受体； (3) 强效的构象限制类似物 受体配体作为拓扑探针； (4)位置发射 活体受体模式的经轴断层扫描可视化 大脑。 旨在鉴定临床有用的拮抗剂的研究 PCP 正在进行中。 以前无法访问的合成 使用最近开发的 NIH 的非天然阿片对映体 阿片全合成也正在进行中，其目标是 新药物的鉴定及其效果 通过非经典阿片受体介导的阿片类药物。