The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors

Background and Purpose: The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys- loop receptors and have structural similarities to 5- HT3 receptor antagonists. They may therefore act at 5- HT3 receptors. Experimental Approach: The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5- HT3A receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site. Key Results: 5- HT3 responses were blocked with IC50 values of 13.4 mu M, 11.8 mu M and 9.36 mu M for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with p Alpha(2) values of 4.92 ( Kappa(B) 12.0 mu M) and 4.97 ( K-B 16.4 mu M). 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 [H-3] granisetron with K-i values of 15.0, 24.2 and 35.7 mu M. Docking of quinine into a homology model of the 5- HT3 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 and Implications: This study shows that quinine and chloroquine competitively inhibit 5- HT3 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- HT3 receptor antagonists.