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.
Antimalarial drugs inhibit human 5-HT(3) and GABA(A) but not GABA(C) receptors.
Thompson AJ
,
Lummis SC
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: Antimalarial compounds have been previously shown to inhibit rodent nicotinic acetylcholine (nACh) and 5-HT(3) receptors. Here, we extend these studies to include human 5-HT(3A), 5-HT(3AB), GABA(A) alpha1beta2, GABA(A) alpha1beta2gamma2 and GABA(C) rho1 receptors.
EXPERIMENTAL APPROACH: We examined the effects of quinine, chloroquine and mefloquine on the electrophysiological properties of receptors expressed in Xenopus oocytes.
KEY RESULTS: 5-HT(3A) receptor responses were inhibited by mefloquine, quinine and chloroquine with IC(50) values of 0.66, 1.06 and 24.3 microM. At 5-HT(3AB) receptors, the potencies of mefloquine (IC(50)=2.7 microM) and quinine (15.8 microM), but not chloroquine (23.6 microM), were reduced. Mefloquine, quinine and chloroquine had higher IC(50) values at GABA(A) alpha1beta2 (98.7, 0.40 and 0.46 mM, respectively) and GABA(A) alpha1beta2gamma2 receptors (0.38, 1.69 and 0.67 mM, respectively). No effect was observed at GABA(C) rho1 receptors. At all 5-HT(3) and GABA(A) receptors, chloroquine displayed competitive behaviour and mefloquine was non-competitive. Quinine was competitive at 5-HT(3A) and GABA(A) receptors, but non-competitive at 5-HT(3AB) receptors. Homology modelling in combination with automated docking suggested orientations of quinine and chloroquine at the GABA(A) receptor binding site.
CONCLUSIONS AND IMPLICATIONS: The effects of mefloquine, quinine and chloroquine are distinct at GABA(A) and GABA(C) receptors, whereas their effects on 5-HT(3AB) receptors are broadly similar to those at 5-HT(3A) receptors. IC(50) values for chloroquine and mefloquine at 5-HT(3) receptors are close to therapeutic blood concentrations required for malarial treatment, suggesting that their therapeutic use could be extended to include the treatment of 5-HT(3) receptor-related disorders.
Adelusi,
Tissue and blood concentrations of chloroquine following chronic administration in the rat.
1982, Pubmed
Adelusi,
Tissue and blood concentrations of chloroquine following chronic administration in the rat.
1982,
Pubmed
Akabas,
GABAA receptor structure-function studies: a reexamination in light of new acetylcholine receptor structures.
2004,
Pubmed
Ballestero,
Effects of quinine, quinidine, and chloroquine on alpha9alpha10 nicotinic cholinergic receptors.
2005,
Pubmed
,
Xenbase
Barann,
Inhibition of 5-HT3 receptors by propofol: equilibrium and kinetic measurements.
2000,
Pubmed
Barann,
5-HT3 receptors in outside-out patches of N1E-115 neuroblastoma cells: basic properties and effects of pentobarbital.
1997,
Pubmed
Barnard,
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
1998,
Pubmed
Baudry,
Stereoselective passage of mefloquine through the blood-brain barrier in the rat.
1997,
Pubmed
Beene,
Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine.
2002,
Pubmed
,
Xenbase
Boileau,
Mapping the agonist binding site of the GABAA receptor: evidence for a beta-strand.
1999,
Pubmed
,
Xenbase
Bountra,
Towards understanding the aetiology and pathophysiology of the emetic reflex: novel approaches to antiemetic drugs.
1996,
Pubmed
Bray,
Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance.
2005,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Cutting,
Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina.
1991,
Pubmed
,
Xenbase
Davies,
The 5-HT3B subunit is a major determinant of serotonin-receptor function.
1999,
Pubmed
,
Xenbase
Dellisanti,
Crystal structure of the extracellular domain of nAChR alpha1 bound to alpha-bungarotoxin at 1.94 A resolution.
2007,
Pubmed
Dow,
The acute neurotoxicity of mefloquine may be mediated through a disruption of calcium homeostasis and ER function in vitro.
2003,
Pubmed
Dubin,
The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit.
1999,
Pubmed
,
Xenbase
Dzierszinski,
Ligands of the peripheral benzodiazepine receptor are potent inhibitors of Plasmodium falciparum and Toxoplasma gondii in vitro.
2002,
Pubmed
Enz,
GABAC receptor rho subunits are heterogeneously expressed in the human CNS and form homo- and heterooligomers with distinct physical properties.
1999,
Pubmed
Faerber,
The neuronal 5-HT3 receptor network after 20 years of research--evolving concepts in management of pain and inflammation.
2007,
Pubmed
Fiebich,
Expression of 5-HT3A receptors in cells of the immune system.
2004,
Pubmed
Goldin,
Maintenance of Xenopus laevis and oocyte injection.
1992,
Pubmed
,
Xenbase
Harrison,
Locating the carboxylate group of GABA in the homomeric rho GABA(A) receptor ligand-binding pocket.
2006,
Pubmed
Leff,
Further concerns over Cheng-Prusoff analysis.
1993,
Pubmed
Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase
Liu,
Interactions of chloroquine with benzodiazepine, gamma-aminobutyric acid and opiate receptors.
1991,
Pubmed
Lobel,
Long-term malaria prophylaxis with weekly mefloquine.
1993,
Pubmed
Lummis,
A cation-pi binding interaction with a tyrosine in the binding site of the GABAC receptor.
2005,
Pubmed
Luzzi,
Adverse effects of antimalarials. An update.
1993,
Pubmed
Miyake,
Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species.
1995,
Pubmed
Niesler,
Characterization of the novel human serotonin receptor subunits 5-HT3C,5-HT3D, and 5-HT3E.
2007,
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
Piper,
[Dolasetron reduces pain on injection of propofol].
2002,
Pubmed
Ramharter,
In vitro activity of quinolines against Plasmodium falciparum in Gabon.
2004,
Pubmed
Rothlin,
Direct interaction of serotonin type 3 receptor ligands with recombinant and native alpha 9 alpha 10-containing nicotinic cholinergic receptors.
2003,
Pubmed
,
Xenbase
Rothlin,
The alpha9 nicotinic acetylcholine receptor shares pharmacological properties with type A gamma-aminobutyric acid, glycine, and type 3 serotonin receptors.
1999,
Pubmed
,
Xenbase
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
Taylor,
Antimalarial drug toxicity: a review.
2004,
Pubmed
Thompson,
5-HT3 receptors.
2006,
Pubmed
Thompson,
The 5-HT3 receptor as a therapeutic target.
2007,
Pubmed
Thompson,
The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors.
2007,
Pubmed
,
Xenbase
Thompson,
Locating an antagonist in the 5-HT3 receptor binding site using modeling and radioligand binding.
2005,
Pubmed
Tzvetkov,
Tissue-specific alternative promoters of the serotonin receptor gene HTR3B in human brain and intestine.
2007,
Pubmed
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
