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Front Pharmacol
2018 Jul 19;9:1339. doi: 10.3389/fphar.2018.01339.
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Effects of Quinine, Quinidine and Chloroquine on Human Muscle Nicotinic Acetylcholine Receptors.
Gisselmann G
,
Alisch D
,
Welbers-Joop B
,
Hatt H
.
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The genus Cinchona is known for a range of alkaloids, such as quinine, quinidine, cinchonine, and cinchonidine. Cinchona bark has been used as an antimalarial agent for more than 400 years. Quinine was first isolated in 1820 and is still acknowledged in the therapy of chloroquine-resistant falciparum malaria; in lower dosage quinine has been used as treatment for leg cramps since the 1940s. Here we report the effects of the quinoline derivatives quinine, quinidine, and chloroquine on human adult and fetal muscle nicotinic acetylcholine receptors (nAChRs). It could be demonstrated that the compounds blocked acetylcholine (ACh)-evoked responses in Xenopus laevis oocytes expressing the adult nAChR composed of αβ��δ subunits in a concentration-dependent manner, with a ranked potency of quinine (IC50 = 1.70 μM), chloroquine (IC50 = 2.22 μM) and quinidine (IC50 = 3.96 μM). At the fetal nAChR composed of αβγδ subunits, the IC50 for quinine was found to be 2.30 μM. The efficacy of the block by quinine was independent of the ACh concentration. Therefore, quinine is proposed to inhibit ACh-evoked currents in a non-competitive manner. The present results add to the pharmacological characterization of muscle nAChRs and indicate that quinine is effective at the muscular nAChRs close to therapeutic blood concentrations required for the therapy and prophylaxis of nocturnal leg cramps, suggesting that the clinically proven efficacy of quinine could be based on targeting nAChRs.
FIGURE 1. Left: Cinchona calisaya and Cinchona bark as the source for quinine. Right: Molecular structures of quinine, quinidine, and chloroquine.
FIGURE 2. Concentration-dependent activating effect of ACh on the adult human nicotinic acetylcholine receptor αβ𝜀δ measured in Xenopus oocytes. (A) Representative membrane currents evoked by ACh measured by two-electrode voltage-clamp. The mean current evoked by 10 μM at the third application was 95% +-. (B) Concentration–response curve of the receptor activated by different concentrations of acetylcholine (n = 6). Holding potential: –60 mV, error bars represent S.E.M.
FIGURE 3. Block of adult muscle nicotinic acetylcholine receptor by quinidine and derivatives in Xenopus oocytes. (A) Representative membrane currents measured by two-electrode voltage-clamp. Currents were elicited by 10 μM ACh in presence of quinine. (B) Concentration–inhibition curves for quinine (inverted triangles), quinidine (squares), or chloroquine (circles) at ACh mediated currents elicited by 10 μM ACh in the presence of different concentrations of the blockers (n = 6). Holding potential: –60 mV, error bars represent S.E.M.
FIGURE 4. ACh concentration–response relationship at human adult muscle nAChRs in the presence and absence of 1.8 μM quinine measured in Xenopus oocytes. Currents were elicited by various ACh concentrations. (A) Concentration-response curves for human adult muscle nAChRs in the presence (open circles) and the absence (filled circles) of 1.8 μM quinine (n = 6). (B) Relative current blocked by 1.8 μM quinine at 10, 30, and 100 μM ACh. Holding potential: -60 mV, error bars represent S.E.M.
FIGURE 5. Concentration-dependent activating effect of ACh on the fetal human nicotinic acetylcholine receptor αβγδ measured in Xenopus oocytes. (A) Concentration–response curve of the receptor activated by different concentrations of acetylcholine (n = 6). (B) Block of human fetal muscle nAChRs by quinidine in a concentration-dependent manner. Concentration–inhibition curves for quinine (circles) at ACh mediated currents elicited by 10 μM ACh in the presence of different concentrations of the blocker (n = 3). Holding potential: -60 mV, error bars represent S.E.M.
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