MEDICAL CHEMISTRY OF BUTYROLACTONES AND RELATED COMPOUNDS

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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.