“Different sites of interaction of quinoline derivatives with a9a10nAChRs”

BALLESTERO JA; PLAZAS PV; KRACUN S; GÓMEZ-CASATI ME; TARANDA J; ROTHLIN CV; KATZ E; MILLAR NS; ELGOYHEN AB

Pinamar, Buenos Aires, Argentina

Congreso; XLI Reunión anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2005

Sociedad Argentina de Investigación Bioquímica y Biología Molecular (SAIB)

In this study, we report the effects of the quinoline derivateives quinine (Qn), its optical isomer quinidine (Qd), and chloroquine (Cl) on the a9a10 nicotinic acetylcholine receptors (nAChRs). The compounds blocked acetylcholine (ACh)-evoked responses in a9a10-injected Xenopus laevis oocytes in a concentration-dependent manner, with a rank order of potency of Cl (IC50=0.39uM) > Qn (IC50=0.97uM) ~ Qd (IC50=1.37uM). Moreover, Cl blocked ACh-evoked responses on rat cochlear inner hair cells with an IC50 value of 0.13uM. Block by Cl was purely competitive, whereas Qn inhibited ACh currents in a mixed competitive/noncompetitive manner. The competitive nature of the blockage produced by the three compounds was confirmed by equilibrium binding experiments using [H3]methyllcaconitine. Block by Qn was found to be only slightly voltage-dependent, thus precluding open-channel block as the main mechanism of interaction of quinine with a9a10 nAChRs. The present results add to the pharmacological characterization of the a9a10- containing nicotinic receptors and indicate that the efferent olivocochlear system that innervates the cochlear hair cells is a target of these ototoxic antimalarial compounds.