Structure-activity Studies with Ginkgo biloba Extract Constituents as Receptor-gated Chloride Channel Blockers and Modulators

Abstract

The constituents of Ginkgo biloba leaf extract, ginkgolides A, B, C and J are known as effective antagonists of platelet-activating factor (PAF). Here, we will demonstrate that these substances are also effective blockers of glycine-activated chloride channels in the hippocampal neurons of rat. As examined in several other voltage- and ligand-operated channels, this ginkgolide action is selective. The blocking action of all tested ginkgolides is use-dependent - they block open glycine-activated channels. The IC₅₀ values for saturating blocking action of ginkgolides B and C are 0.273 μM and 0.267 μM, respectively, while ginkgolides A and J are less effective - IC₅₀ values are 1.97 μM and 2.0 μM. Corresponding dose-response relationships are close to single-site binding isotherms. Another constituent of EGb 761®, bilobalide, is a weak inhibitor of NMDA receptor-activated current. Its synthetic analogue, NV-31, demonstrates a weak facilitatory action on Gly-activated conductance. Novel findings have indicated the possibility that the unique modulating activity profiles of the EGb 761® (definition see editorial) constituents examined are due to their effects on the anion homeostasis of central neurons.