Stilbene derivatives as human 5-HT(6) 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, (+)-α-viniferin, miyabenol C and pallidol, are active constituents of 537-18BE inhibiting the 5-HT₆R. Among them, (+)-α-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 (+)-α-viniferin, miyabenol 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.
Korea Institute of Science and Technology, Seoul, Korea.
Dong Hyuk
DH
Kim
Soon-Hee
SH
Kim
Hyoung Ja
HJ
Kim
Changbae
C
Jin
Kwang Chul
KC
Chung
Hyewhon
H
Rhim
D032602:Caragana / Q000737:chemistry*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018517:Plant Roots; D011083:Polycyclic Compounds / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013267:Stilbenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D010936:Plant Extracts; D011083:Polycyclic Compounds; D012702:Serotonin Antagonists; D013267:Stilbenes; C535072:pallidol; D012701:Serotonin; D048052:Mitogen-Activated Protein Kinase 3