The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors.
OBJECTIVE
The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys-loop receptors and have structural similarities to 5-HT(3) receptor antagonists. They may therefore act at 5-HT(3) receptors.


METHODS
The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5-HT(3A) receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site.


RESULTS
5-HT(3) responses were blocked with IC (50) values of 13.4 microM, 11.8 microM and 9.36 microM for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with pA (2) values of 4.92 (K (B)=12.0 microM) and 4.97 (K (B)=16.4 microM). Mefloquine displayed weakly voltage-dependent, non-competitive inhibition consistent with channel block. On and off rates for quinine and chloroquine indicated a simple bimolecular reaction scheme. Quinine, chloroquine and mefloquine displaced [(3)H]granisetron with K (i) values of 15.0, 24.2 and 35.7 microM. Docking of quinine into a homology model of the 5-HT(3) receptor binding site located the tertiary ammonium between W183 and Y234, and the quinoline ring towards the membrane, stabilised by a hydrogen bond with E129. For chloroquine, the quinoline ring was positioned between W183 and Y234 and the tertiary ammonium stabilised by interactions with F226.


CONCLUSIONS
This study shows that quinine and chloroquine competitively inhibit 5-HT(3) receptors, while mefloquine inhibits predominantly non-competitively. Both quinine and chloroquine can be docked into a receptor binding site model, consistent with their structural homology to 5-HT(3) receptor antagonists.
Thompson
A J
AJ
Department of Biochemistry, University of Cambridge, Cambridge, UK.
Lochner
M
M
Lummis
S C R
SC
D000465:Algorithms; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D017829:Granisetron / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D015767:Mefloquine / Q000494:pharmacology*; D008958:Models, Molecular; D009865:Oocytes; D011803:Quinine / Q000494:pharmacology*; D011869:Radioligand Assay; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists; D014982:Xenopus laevis
D000962:Antimalarials; D002738:Chloroquine; D017829:Granisetron; D015767:Mefloquine; D011803:Quinine; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists