Ginkgolides and Glycine Receptors: A Structure–Activity Relationship Study

Abstract Ginkgolides from the Ginkgo biloba tree are diterpenes with a cage structure consisting of six five‐membered rings and a unique t Bu group. They exert a variety of biological properties. In addition to being antagonists of the platelet activating factor receptor (PAFR), it has recently been shown that native ginkgolides are potent and selective antagonists of the inhibitory glycine receptor. Forty new ginkgolide derivatives have been prepared in good to high yields on milligram scales and investigated for their antagonistic properties at homomeric α1 glycine receptors, thus providing the first structure–activity relationship study of ginkgolides at glycine receptors. A high‐throughput screening assay showed that native ginkgolide C was the most potent ligand, and that manipulation of any of the hydroxyl groups led to loss of activity at α1 glycine receptors.