SYNTHESIS AND EVALUATION OF POTENTIAL ENAMINONE AND SPIROIMIDOOXY ANTICONVULSANTS

潜在烯胺酮和螺亚胺抗惊厥药的合成和评价

• 批准号: 5211977
• 负责人: KENNETH R SCOTT
• 金额: --
• 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/5211977
• 关键词: X ray crystallography; anticonvulsants; brain disorder chemotherapy; chemical models; chemical structure function; drug design /synthesis /production; drug screening /evaluation; epilepsy; kindling; mathematical model

The specific aims of the project are to synthesize new chemical compounds and evaluate them for anticonvulsant activity. The long-term objectives include the discovery of new classes of anticonvulsant agents and the development of better anticonvulsant compounds which will lack the adverse effects of currently used antiepileptic agents. Hitherto, no chemical entity, nor surgical intervention has offered a complete cure for all types of epilepsy. The research plan is designed to exploit, in a systematic manner two interesting, and hitherto unique, lead moieties developed in our laboratories: the cyclic enaminones; and the spiroimidooxy analogs. The experimental design comprises the synthesis of new compounds of each moiety, by procedures previously reported in our laboratory, with appropriate modifications. In addition, molecular modeling techniques will be employed and the Free-Wilson analysis, as detailed by P.N. Craig(1,2) will be used in the development of quantitative structure activity relationships for each moiety. Regression analysis equations will be developed to provide clarification on the roles of chirality, lipophilicity (pi), electronic (alpha) character of the substituents, dipole moment (mu), steric parameters (Es), and molar volume (Ut) exercise on anticonvulsant activity. The application of energy minimization (MM2 and MM3) as well as molecular dynamics analysis will also be used to determine the lowest energy conformer of each compound and compared to both phenytoin, and carbamazepine, each minimized, to assess root-mean-square (rms) deviation of the superimposed molecules. X-ray structure analysis, sodium channel binding analysis, and corneal and amygdala kindling data of the active compounds will be performed in collaborating laboratories.

该项目的具体目的是合成新的化合物 并评估它们的抗惊厥活性。 长期目标 包括发现新类抗惊厥药的类别和 开发更好的抗惊险化合物，这将缺乏不利的 当前使用的抗癫痫剂的作用。 迄今为止，没有化学物质 实体，或手术干预已为所有类型提供了完整的治疗方法 癫痫。 该研究计划旨在在系统的 方式在我们 实验室：循环启蒙酮；和Spiroimidooxy类似物。 实验设计包括每种新化合物的合成 部分，根据以前在我们的实验室中报告的程序， 适当的修改。 另外，分子建模技术将 由P.N.详细介绍，被雇用和自由威尔逊分析。克雷格（1,2） 将用于定量结构活性的发展 每个部分的关系。 回归分析方程将是 开发旨在澄清手性，亲脂性的作用 （PI），取代基的电子（alpha）特征，偶极矩（MU），， 抗惊厥药的空间参数（ES）和摩尔体积（UT）练习 活动。 能量最小化的应用（MM2和MM3）以及 分子动力学分析也将用于确定最低 每种化合物的能量构象体，并将其与苯妥英和 卡马西平，每种含量最小，以评估根平方（RMS）偏差 叠加分子。 X射线结构分析，钠通道 结合分析以及活动的角膜和杏仁核点燃数据 化合物将在协作实验室中进行。