MEDICAL CHEMISTRY OF BUTYROLACTONES AND RELATED COMPOUNDS

本提案的长期目标是研究药物 烷基取代的γ-丁内酯化学及相关化学 化合物. 这些化合物已被证明与 γ-氨基丁酸（GABA-A）的印防己毒素结合位点 受体/氯离子通道复合物，根据其结构， 它们可以有三种不同的活动。像印防己毒素， GBL是阻断GABA介导的电流的GABA阴性剂。不像 印防己毒素，其他GBL是GABA阳性试剂，其增强GABA介导的 电流 最后，一些GBL类似物是GABA中性的，因为它们 拮抗GABA阴性和GABA阳性GBL的作用，但 它们本身对GABA介导的电流影响很小或没有影响。 这些 化合物是有用的实验工具，不仅研究复杂的 调节GABA-A受体功能，而且GABA能 神经传递在神经系统功能正常和 病态的国家此外，GABA阳性和GABA中性GBL具有 作为治疗癫痫的新治疗剂的潜力。 我们的具体目标是：1）满足核心化学要求， 合成足够量的试剂已经显示出值得进一步 研究; 2）继续表征结构-活性关系 GBL和GBL类似物，通过合成新化合物或通过制备 一些先前制备的化合物的拆分的对映异构体; 3）至 合成用于放射性配体结合测定GBL类似物， 可以了解更多关于GBL与 GABA-A受体上的印防己毒素位点，和; 4）制备放射性标记的 真菌毒素黄曲霉素的衍生物，以研究结合 该毒素与GABA-A受体的相互作用，并制备 具有抗惊厥活性的黄拉曲姆类似物。

The long term objective of this proposal is to investigate the medicinal chemistry of alkyl-substituted gamma-butyrolactones (GBLs) and related compounds. These compounds have been shown to interact with the picrotoxin binding site(s) of the gamma-aminobutyric acids (GABA-A) receptor/chloride channel complex where, depending on their structure, they may have any of three different activities. Like picrotoxin, some GBLs are GABA-negative agents that block GABA-mediated current. Unlike picrotoxin, other GBLs are GABA-positive agents that augment GABA-mediated current. Finally, some GBL analogs are GABA-neutral in that they antagonize the effects of the GABA-negative and GABA-positive GBLs, but by themselves they have little or no effect on GABA-mediated current. These compounds are useful experimental tools for studying not only the complex modulation of GABA-A receptor function, but also the role that GABAergic neurotransmission has in nervous system function in both normal and diseased states. In addition, the GABA-positive and GABA-neutral GBLs have potential as new therapeutic agents for the treatment of epilepsy. Our specific aims are: 1) to satisfy core chemistry requirements by synthesizing adequate quantities of agents already shown to merit further study; 2) to continue to characterize structure-activity relationships of GBLs and GBL analogs either by synthesizing new compounds or by preparing the resolved enantiomers of some previously prepared compounds; 3) to synthesize a GBL analog for use in a radioligand binding assay so that more can be learned about the complex interactions of GBLs with the picrotoxin site(s) on GABA-A receptors, and; 4) to prepare a radiolabeled derivative of the fungal toxin aflatrem to investigate the binding interactions of this toxin with the GABA-A receptor, and to prepare analogs of aflatrem having anticonvulsant activity.