MEDICAL CHEMISTRY OF BUTYROLACTONES AND RELATED COMPOUNDS

这项建议的长期目标是调查 烷基取代γ-丁内酯(GBLS)及其相关化合物的化学 化合物。这些化合物已被证明与 γ-氨基丁酸的苦味毒素结合部位(S) 受体/氯通道复合体，根据其结构， 他们可能有三种不同活动中的任何一种。就像印防己毒素，有些 GBL是GABA负性物质，可阻断GABA介导的电流。不像 印防己毒素，其他GBL是GABA阳性的药物，可以增强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，但通过 它们本身对GABA介导的电流几乎没有影响。这些 化合物不仅是研究络合物的有用的实验工具 GABA-A受体功能的调节，也是GABA能的作用 神经传递在神经系统中的功能正常和 疾病缠身的国家。此外，GABA阳性和GABA中性的GBL 作为治疗癫痫的新的治疗药物的潜力。 我们的具体目标是：1)通过以下方式满足核心化学要求 合成足够量的试剂已被证明具有进一步的价值 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 一些预先制备的化合物的拆分对映体；3)至 合成用于放射性配基结合分析的GBL类似物 可以了解更多关于GBL与 印防己毒素位点(S)对GABA-A受体的影响；4)制备放射性标记的 真菌毒素黄曲霉毒素的衍生物研究结合作用 该毒素与GABA-A受体的相互作用及制备 黄曲霉素有抗惊厥活性的类似物。

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.