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

Abstract

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‐HT_3A, 5‐HT_3AB, GABA_A α1β2, GABA_A α1β2γ2 and GABA_C ρ1 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 IC₅₀ values of 0.66, 1.06 and 24.3 μM. At 5‐HT_3AB receptors, the potencies of mefloquine (IC₅₀=2.7 μM) and quinine (15.8 μM), but not chloroquine (23.6 μM), were reduced. Mefloquine, quinine and chloroquine had higher IC₅₀ values at GABA_A α1β2 (98.7, 0.40 and 0.46 mM, respectively) and GABA_A α1β2γ2 receptors (0.38, 1.69 and 0.67 mM, respectively). No effect was observed at GABA_C ρ1 receptors. At all 5‐HT₃ 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. 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. British Journal of Pharmacology (2008) 153, 1686–1696; doi:10.1038/bjp.2008.34; published online 3 March 2008