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Effects of Quinine, Quinidine, and Chloroquine on 910 Nicotinic Cholinergic Receptors

Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (J.A.B., P.V.P., M.E.G.-C., J.T., C.V.R., E.K., A.B.E.), and Departamento de Fisiología, Biología Molecular y Celular, FCEyN, Universidad de Buenos Aires, Buenos Aires, Argentina (E.K.); and Department of Pharmacology, University College London, London, United Kingdom (S.K., N.S.M.)

In this study, we report the effects of the quinoline derivatives quinine, its optical isomer quinidine, and chloroquine on 910-containing nicotinic acetylcholine receptors (nAChRs). The compounds blocked acetylcholine (ACh)-evoked responses in 910-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 910 nAChRs. The present results add to the pharmacological characterization of 910-containing nicotinic receptors and indicate that the efferent olivocochlear system that innervates the cochlear hair cells is a target of these ototoxic antimalarial compounds.

Address correspondence to: Dr. Ana Belén Elgoyhen, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, (CONICET-UBA), Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina. E-mail: elgoyhen{at}dna.uba.ar