Antimalarial drugs inhibit human 5-HT(3) and GABA(A) but not GABA(C) receptors.
OBJECTIVE
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.


METHODS
We examined the effects of quinine, chloroquine and mefloquine on the electrophysiological properties of receptors expressed in Xenopus oocytes.


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
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.
Thompson
A J
AJ
Department of Biochemistry, University of Cambridge, Cambridge, UK.
Lummis
S C R
SC
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D001667:Binding, Competitive; D002478:Cells, Cultured; D002738:Chloroquine / Q000008:administration & dosage / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D058787:GABA-A Receptor Antagonists; D006801:Humans; D020128:Inhibitory Concentration 50; D015767:Mefloquine / Q000008:administration & dosage / Q000494:pharmacology; D009865:Oocytes; D011803:Quinine / Q000008:administration & dosage / Q000494:pharmacology; D018079:Receptors, GABA / Q000187:drug effects*; D058831:Serotonin 5-HT3 Receptor Antagonists; D014982:Xenopus laevis
D000962:Antimalarials; D058787:GABA-A Receptor Antagonists; C087200:GABA-C receptor; D018079:Receptors, GABA; D058831:Serotonin 5-HT3 Receptor Antagonists; D002738:Chloroquine; D011803:Quinine; D015767:Mefloquine