Antimalarial drugs inhibit human 5-HT3 and GABAA but not GABAC receptors

Background and purpose: Antimalarial compounds have been previously shown to inhibit rodent nicotinic acetylcholine (nACh) and 5-HT3 receptors. Here, we extend these studies to include human 5-HT3A, 5-HT3(AB), GABA(A) alpha 1 beta 2, GABAA alpha 1 beta 2 gamma 2 and GABA(C) rho 1 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-HT3A receptor responses were inhibited by mefloquine, quinine and chloroquine with IC50 values of 0.66, 1.06 and 24.3 mu M. At 5-HT3AB receptors, the potencies of mefloquine (IC50 = 2.7 mu M) and quinine (15.8 mu M), but not chloroquine (23.6 mu M), were reduced. Mefloquine, quinine and chloroquine had higher IC50 values at GABA(A) alpha 1 beta 2 (98.7, 0.40 and 0.46mM, respectively) and GABA(A) alpha 1 beta 2 gamma 2 receptors (0.38, 1.69 and 0.67mM, respectively). No effect was observed at GABA(C) rho 1 receptors. At all 5-HT3 and GABA(A) receptors, chloroquine displayed competitive behaviour and mefloquine was non-competitive. Quinine was competitive at 5-HT3A and GABA(A) receptors, but non-competitive at 5-HT3AB 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-HT3AB receptors are broadly similar to those at 5-HT3A receptors. IC50 values for chloroquine and mefloquine at 5-HT3 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-HT3 receptor-related disorders.