Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors.
Thompson AJ, Lochner M, Lummis SC.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: 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.
EXPERIMENTAL APPROACH: 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.
KEY 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 AND IMPLICATIONS: 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.
ARUNLAKSHANA,
Some quantitative uses of drug antagonists.
1959, Pubmed
ARUNLAKSHANA,
Some quantitative uses of drug antagonists.
1959,
Pubmed Ballestero,
Effects of quinine, quinidine, and chloroquine on alpha9alpha10 nicotinic cholinergic receptors.
2005,
Pubmed
,
Xenbase Barann,
Inhibition of 5-HT3 receptor cation channels by ifenprodil in excised patches of N1E-115 cells.
1998,
Pubmed Beene,
Tyrosine residues that control binding and gating in the 5-hydroxytryptamine3 receptor revealed by unnatural amino acid mutagenesis.
2004,
Pubmed
,
Xenbase Bray,
Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance.
2005,
Pubmed Das,
Inhibition of type A GABA receptors by L-type calcium channel blockers.
2004,
Pubmed Davies,
The 5-HT3B subunit is a major determinant of serotonin-receptor function.
1999,
Pubmed
,
Xenbase Fan,
Effect of cocaine on the 5-HT3 receptor-mediated ion current in Xenopus oocytes.
1995,
Pubmed
,
Xenbase Goldin,
Maintenance of Xenopus laevis and oocyte injection.
1992,
Pubmed
,
Xenbase Gunthorpe,
Diltiazem causes open channel block of recombinant 5-HT3 receptors.
1999,
Pubmed Hargreaves,
Direct inhibition of 5-hydroxytryptamine3 receptors by antagonists of L-type Ca2+ channels.
1996,
Pubmed Jordan,
Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation.
1996,
Pubmed Kearney,
Dose-response relations for unnatural amino acids at the agonist binding site of the nicotinic acetylcholine receptor: tests with novel side chains and with several agonists.
1996,
Pubmed
,
Xenbase Kooyman,
5-Hydroxyindole slows desensitization of the 5-HT3 receptor-mediated ion current in N1E-115 neuroblastoma cells.
1993,
Pubmed Leff,
Further concerns over Cheng-Prusoff analysis.
1993,
Pubmed Lew,
Analysis of competitive agonist-antagonist interactions by nonlinear regression.
1995,
Pubmed Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase Lobel,
Long-term malaria prophylaxis with weekly mefloquine.
1993,
Pubmed Lummis,
Characterization of [3H]meta-chlorophenylbiguanide binding to 5-HT3 receptors in N1E-115 neuroblastoma cells.
1993,
Pubmed Luzzi,
Adverse effects of antimalarials. An update.
1993,
Pubmed McCool,
Ifenprodil inhibition of the 5-hydroxytryptamine3 receptor.
1995,
Pubmed Neubig,
International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology.
2003,
Pubmed Niesler,
Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E.
2003,
Pubmed Olsen,
Docking and scoring of metallo-beta-lactamases inhibitors.
2004,
Pubmed Palmer,
Mefloquine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy.
1993,
Pubmed Papke,
The correction of alpha7 nicotinic acetylcholine receptor concentration-response relationships in Xenopus oocytes.
1998,
Pubmed
,
Xenbase Price,
The role of tyrosine residues in the extracellular domain of the 5-hydroxytryptamine3 receptor.
2004,
Pubmed
,
Xenbase Ramharter,
In vitro activity of quinolines against Plasmodium falciparum in Gabon.
2004,
Pubmed Rammes,
Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner.
2004,
Pubmed Reeves,
The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel (review).
2002,
Pubmed Reeves,
Prediction of 5-HT3 receptor agonist-binding residues using homology modeling.
2003,
Pubmed Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed Shi,
FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties.
2001,
Pubmed Sieb,
Effects of the quinoline derivatives quinine, quinidine, and chloroquine on neuromuscular transmission.
1996,
Pubmed Sullivan,
Defining the roles of Asn-128, Glu-129 and Phe-130 in loop A of the 5-HT3 receptor.
2006,
Pubmed Taylor,
Antimalarial drug toxicity: a review.
2004,
Pubmed Thompson,
Locating an antagonist in the 5-HT3 receptor binding site using modeling and radioligand binding.
2005,
Pubmed Thompson,
Mutagenesis and molecular modeling reveal the importance of the 5-HT3 receptor F-loop.
2006,
Pubmed Tikhonov,
Modeling noncompetitive antagonism of a nicotinic acetylcholine receptor.
2004,
Pubmed
