Stilbene Derivatives as Human 5-HT6 Receptor Antagonists from the Root of Caragana sinica

The 5-HT6 receptor (5-HT6R) is a member of the class of recently discovered 5-hydroxytryptamine (5-HT) receptors Due to the lack of selective 5-HT6R ligands, the cellular signaling mechanisms of the 5-HT6R are poorly understood We previously developed a cell-based high-throughput screening (HTS) method for the 5-HT6R and screened synthetic chemical compounds In the present study, we expanded our screening into natural products to find novel 5-HT6R ligands We found that the ethyl acetate fraction from the root of Caragana sinica (537-18BE) produced the most potent antagonistic activity After further isolation of 537-18BE, we found that three stilbene derivatives, (+)-alpha-viniferin, miyabenol C and pallidol, are active constituents of 537-18BE inhibiting the 5-HT6R Among them, (+)-alpha-viniferin showed the most potent inhibition, and miyabenol C also produced a considerable inhibition When examined effects on other neurotransmitters for selectivity, 537-18BE and three stilbene derivatives did not produce any notable effects on 5-HT4, 5-HT7, or muscarinic acetylcholine M1 (M-1) receptors Furthermore, 5-HT6R antagonistic effects of (+)-alpha-viniferin, mivabenol C and pallidol were confirmed on extracellular signal-regulated kinase 1 and 2 (ERK1/2) which exerts effects in downstream pathways of 5-HT6R activation