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.

该项目的具体目标是合成新的化合物 并评估它们的抗惊厥活性。 长期目标 包括新型抗惊厥药物的发现和 开发更好的抗惊厥化合物，该化合物将消除不良反应 目前使用的抗癫痫药物的作用。 迄今为止，还没有化学物质 实体，也没有手术干预可以完全治愈所有类型 癫痫症。 该研究计划旨在系统地探索 以我们的方法开发的两个有趣且迄今为止独特的先导部分 实验室：环状烯胺酮；和螺亚胺氧基类似物。 实验设计包括每种新化合物的合成 部分，按照我们实验室先前报告的程序， 适当的修改。 此外，分子建模技术将 被采用和 Free-Wilson 分析，如 P.N. 所详述。克雷格(1,2) 将用于定量结构活动的开发 每个部分的关系。 回归分析方程为 旨在澄清手性、亲脂性的作用 (pi)、取代基的电子(α)特征、偶极矩(mu)、 抗惊厥药物的空间参数 (Es) 和摩尔体积 (Ut) 练习 活动。 能量最小化（MM2 和 MM3）的应用以及 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异构体并与苯妥英进行比较，以及 卡马西平，每个都最小化，以评估均方根 (rms) 偏差 的叠加分子。 X射线结构分析，钠通道 结合分析以及活性物质的角膜和杏仁核点燃数据 化合物将在合作实验室进行。