Thompson, Andrew James; Lochner, Martin; Lummis, S. C. R. (2007). The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT 3 receptors. British journal of pharmacology, 151(5), pp. 666-677. Wiley-Blackwell 10.1038/sj.bjp.0707238
![[img]](https://boris.unibe.ch/style/images/fileicons/text.png) |
Text
BJP2007.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (266kB) |
Background and Purpose:
The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys-loop receptors and have structural similarities to 5-HT3 receptor antagonists. They may therefore act at 5-HT3 receptors.
Experimental Approach:
The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5-HT3A receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site.
Key Results:
5-HT3 responses were blocked with IC50 values of 13.4 μM, 11.8 μM and 9.36 μM for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with pA2 values of 4.92 (KB=12.0 μM) and 4.97 (KB=16.4 μM). Mefloquine displayed weakly voltage-dependent, non-competitive inhibition consistent with channel block. On and off rates for quinine and chloroquine indicated a simple bimolecular reaction scheme. Quinine, chloroquine and mefloquine displaced [3H]granisetron with Ki values of 15.0, 24.2 and 35.7 μM. Docking of quinine into a homology model of the 5-HT3 receptor binding site located the tertiary ammonium between W183 and Y234, and the quinoline ring towards the membrane, stabilised by a hydrogen bond with E129. For chloroquine, the quinoline ring was positioned between W183 and Y234 and the tertiary ammonium stabilised by interactions with F226.
Conclusions and Implications:
This study shows that quinine and chloroquine competitively inhibit 5-HT3 receptors, while mefloquine inhibits predominantly non-competitively. Both quinine and chloroquine can be docked into a receptor binding site model, consistent with their structural homology to 5-HT3 receptor antagonists.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) |
UniBE Contributor: |
Thompson, Andrew James, Lochner, Martin |
Subjects: |
500 Science > 570 Life sciences; biology 500 Science > 540 Chemistry 500 Science |
ISSN: |
0007-1188 |
Publisher: |
Wiley-Blackwell |
Language: |
English |
Submitter: |
Martin Lochner |
Date Deposited: |
19 Dec 2014 10:40 |
Last Modified: |
05 Dec 2022 14:38 |
Publisher DOI: |
10.1038/sj.bjp.0707238 |
Uncontrolled Keywords: |
5-HT3 receptor, Cys-loop receptor, binding site, ligand docking, malaria, quinine, chloroquine, mefloquine, antagonist |
BORIS DOI: |
10.7892/boris.60957 |
URI: |
https://boris.unibe.ch/id/eprint/60957 |
Actions (login required)
 |
Edit item |