Abstract

In this study, we report the effects of the quinoline derivatives quinine, its optical isomer quinidine, and chloroquine on α9α10-containing nicotinic acetylcholine receptors (nAChRs). The compounds blocked acetylcholine (ACh)-evoked responses in α9α10-injected Xenopus laevis oocytes in a concentration-dependent manner, with a rank order of potency of chloroquine (IC₅₀ = 0.39 μM) > quinine (IC₅₀ = 0.97 μM) ∼ quinidine (IC₅₀ = 1.37 μM). Moreover, chloroquine blocked ACh-evoked responses on rat cochlear inner hair cells with an IC₅₀ value of 0.13 μM, which is within the same range as that observed for recombinant receptors. Block by chloroquine was purely competitive, whereas quinine inhibited ACh currents in a mixed competitive and noncompetitive manner. The competitive nature of the blockage produced by the three compounds was confirmed by equilibrium binding experiments using [³H]methyllycaconitine. Binding affinities (K_i values) were 2.3, 5.5, and 13.0 μM for chloroquine, quinine, and quinidine, respectively. Block by quinine was found to be only slightly voltage-dependent, thus precluding open-channel block as the main mechanism of interaction of quinine with α9α10 nAChRs. The present results add to the pharmacological characterization of α9α10-containing nicotinic receptors and indicate that the efferent olivocochlear system that innervates the cochlear hair cells is a target of these ototoxic antimalarial compounds.