DESIGN AND SYNTHESIS OF DRUGS ACTING ON CENTRAL AND PERIPHERAL TISSUES

作用于中枢和外周组织的药物的设计与合成

• 批准号: 3855435
• 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/3855435
• 关键词: buprenorphine; central nervous system; chemical models; chemical structure function; drug design /synthesis /production; drug metabolism; guinea pigs; laboratory mouse; narcotic antagonists; neuropharmacology; neurotransmitters; opiate alkaloid; opioid receptor; positron emission tomography; psychoneuroimmunology; receptor binding; single photon emission computed tomography

The primary goals of this program are to gain further insight into the structure and function of neurotransmitter systems in the overall operation of the mammalian central nervous system (CNS), and the molecular mechanism of action of drugs which act on the CNS, as well as the mechanism(s) through which the immune and other peripheral systems are influenced by the CNS in normal and disease states. The multidisciplinary approach utilized in this program employs rational drug design based on structure-activity relations and molecular modeling, modern organic chemical synthesis, pharmacology, biochemistry, immunology and requires collaboration with other appropriate disciplines. Elucidation of the molecular structure and mechanism of action of the ligand-receptor systems and their antagonists provides new opportunities for the design of superior drugs and understanding disorders for which the pathogenesis is largely obscure. Synthetic programs are continuing to develop new ligands for imaging brain drug receptors by positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanning. The NIH Opiate Total Synthesis continues to be employed to provide previously inaccessible unnatural enantiomers of opiates and derivatives (e.g., (+)-buprenorphine and (+)-diprenorphine) as new pharmacological agents and research tools. (+)-Buprenorphine is a potentially valuable research tool in mechanistic studies of suppression of cocaine self-administration by (-)-buprenorphine. The role of classical opiate receptors in cocaine addiction is now being intensely studied. (-)-Buprenorphine appears to protect against the lethal effects of cocaine by a process mediated by mu-opioid receptors. Oxide-bridged 5-phenylmorphans are being studied, through synthesis and computer-assisted molecular modeling, as probes for narcotic receptor mediated phenomena. Irreversible antagonists to selective opioid receptors are also under investigation. Our recently synthesized UPHIT has been found to irreversibly inhibit binding at kappa sites and may prove useful in determining the biological function of kappa receptor subtypes.

该计划的主要目标是进一步了解 神经递质系统在整体运作中的结构和功能 哺乳动物中枢神经系统（CNS）的作用及其分子机制 作用于中枢神经系统的药物的作用及其机制 通过它，免疫系统和其他外围系统受到 正常和疾病状态下的中枢神经系统。 采用的多学科方法 在该计划中采用基于结构活性的合理药物设计 关系与分子建模、现代有机化学合成、 药理学、生物化学、免疫学，需要与 其他适当的学科。 分子结构的阐明和 配体-受体系统及其拮抗剂的作用机制 为优质药物的设计提供了新的机遇 了解发病机制很大程度上不清楚的疾病。 合成程序正在继续开发用于脑成像的新配体 通过正电子发射断层扫描 (PET) 和单光子检测药物受体 发射计算机断层扫描 (SPECT) 扫描。 NIH 阿片类药物总量 继续采用合成来提供以前无法获得的 阿片类药物及其衍生物的非天然对映体（例如，(+)-丁丙诺啡） 和(+)-二丙诺啡）作为新的药理制剂和研究工具。 (+)-丁丙诺啡是一种潜在的有价值的机械研究工具 (-)-丁丙诺啡抑制可卡因自我给药的研究。 经典阿片受体在可卡因成瘾中的作用现在正在研究 深入研究。 (-)-丁丙诺啡似乎可以预防致命的 可卡因通过 mu-阿片受体介导的过程产生作用。 正在研究氧化物桥联的 5-苯基吗啡烷，通过合成和 计算机辅助分子建模，作为麻醉受体的探针 介导的现象。 选择性阿片受体的不可逆拮抗剂 也正在接受调查。 我们最近合成的 UPHIT 已 发现不可逆地抑制 kappa 位点的结合，并且可能被证明是有用的 确定 kappa 受体亚型的生物学功能。