Modifications of aliphatic side chain of 20(S)-ginsenoside Rg(3) cause an enhancement or loss of brain Na+ channel current inhibitions

Abstract

A line of evidence has shown that ginsenoside Rg(3) (Rg(3)) could be one of bioactive ligands in brain Na+ channel regulations. Rg(3) exists as stereoisomer of 20(R)- or 20(S)-form. Rg(3) consists of three different parts; steroid-like backbone structure, carbohydrate portion, and aliphatic side chain [-CH2CH2CH=C(CH3)(2)], which is coupled to the carbon-20 of backbone structure. In the previous report, we demonstrated that 20(S)- but not 20(R)-Rg(3) and carbohydrate portion of Rg(3) play important roles in rat brain Na(v)1.2 channel regulations. However, little is known about the role of aliphatic side chain coupled to the carbon-20 in brain Na+ channel regulations. In the present study, we prepared Rg(3) derivatives by modifying the aliphatic side chain of Rg(3), remaining with backbone structure and carbohydrate portion intact, and examined the effects of Rg(3) derivatives on Na+ channel activity. We found that reduction of double bond in aliphatic side chain of Rg(3) exhibited agonistic actions in Na+ channel current inhibitions by shifting concentration-response curve to leftward by three-fold, whereas deletion, hydroxylation, or oxygenation of aliphatic side chain caused an attenuation or loss of Na+ channel current inhibitions. These results provide evidences that the aliphatic side chain of Rg(3) is also involved in Na+ channel regulations and further show a possibility that the aliphatic side chain of Rg(3) could be the target of chemical modifications for abolishment or potentiation of Rg(3) actions in Na+ channel regulations.