DEVELOPMENT OF ISOFORM-SELECTIVE INHIBITORS OF NITRIC OXIDE SYNTHASES (NOS)

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 开发具有异构体选择性的一氧化氮合酶抑制剂仍然是该提案的中心焦点。基于在前两个建议期收集的结构信息，新一代nNOS选择性抑制剂被从头设计(参见。1)。通过体外抑制试验对新化合物进行筛选。那些被证明具有良好的效力和选择性的化合物随后被用于结构研究。在临床前动物实验中，也发现了最好的抑制剂对脑缺氧所致的脑性瘫痪有保护作用(参考文献2)。酶-抑制剂复合体结构是进一步修饰和改进新型抑制剂的关键。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Development of isoform selective NOS inhibitors continues to be the central focus of this proposal. Based on structural information gathered during the two previous proposal periods, a new generation of nNOS selective inhibitors were designed de novo (ref. 1). The new compounds were screened through in vitro inhibitory assays. Those shown to have good potency and selectivity were then used for structural studies. The best inhibitors were also found to protect against cerebral palsy induced by brain hypoxia in pre-clinical animal tests (ref.2). The enzyme-inhibitor complex structures are critical for further modification and improvement of new inhibitors.