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The Antimalarial Drug Proguanil Is an Antagonist at 5-HT3 Receptors

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2014
Author Lochner Martin, Thompson Andrew J. (corresponding author),
Project Synthetic Neurochemistry - Introduction of Biophysical Tools into Ion Channels Using Chemical Approaches
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Original article (peer-reviewed)

Journal Journal of Pharmacology and Experimental Therapeutics
Volume (Issue) 351(3)
Page(s) 674 - 684
Title of proceedings Journal of Pharmacology and Experimental Therapeutics
DOI 10.1124/jpet.114.218461


Proguanil is an antimalarial prodrug that is metabolised to 4-chlorophenyl-1-biguanide (CPB) and the active metabolite cycloguanil (CG). These compounds are structurally related to 3-chlorophenyl-1-bigunaide (mCPBG), a 5-HT3 receptor agonist. Here we examine the effects of proguanil and its metabolites on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells respectively. 5-HT3 receptor-responses were reversibly inhibited by proguanil with an IC50 of 1.81 μM. Competitive antagonism was shown by a lack of voltage-dependence, Schild plot (Kb = 1.70 µM) and radioligand competition (Ki = 2.61 µM) with the 5-HT3 receptor antagonist [3H]granisetron. Kinetic measurements (Kon = 4.0 x 104 M-1 s-1; Koff = 0.23 s-1) were consistent with a simple bimolecular reaction scheme with a Kb of 4.35 µM. The metabolites CG and CPB similarly inhibited 5-HT3 receptors as assessed by IC50 (1.48 µM and 4.36 µM respectively), Schild plot (Kb = 2.97 µM and 11.4 µM) and radioligand competition (Ki 4.89 µM and 0.41 µM). At higher concentrations CPB was a partial agonist (EC50 = 14.1 µM; I/Imax, 0.013). These results demonstrate that proguanil competitively inhibits 5-HT3 receptors with an IC50 that exceeds whole-blood concentrations following its oral administration. They may therefore be responsible for the occasional gastrointestinal side-effects, nausea and vomiting reported following its use. Clinical development of related compounds should therefore consider effects at 5-HT3 receptors as an early indication of possible unwanted gastro-intestinal side-effects.