Quinine, Chloroquine and Mefloquine antagonism at human 5-HT3 receptors

Andrew Thompson, Sarah Lummis. Deptartment of Biochemistry, Cambridge University, Cambridge, United Kingdom.

The antimalarial compounds quinine (Q), chloroquine (C) and mefloquine (M) have been known to inhibit nACh receptor currents for some time (Ballestero et al, 2005; Sieb et al, 1996). More recently we showed that they also inhibit mouse 5-HT3 receptors (5-HT3R; Thompson et al, 2007). Here we extend these studies by reporting the effects of Q, C and M on human 5-HT3R.

Human 5-HT3A (accession number: P46098) and 5-HT3B (AF080582) subunit cDNA was cloned into pGEMHE for oocyte expression (Liman et al., 1992). cRNA was in vitro transcribed from linearised plasmid cDNA template using the mMessage mMachine T7 Transcription kit (Ambion, Austin, Texas, USA). Xenopus oocytes were injected with 5 ng cRNA, and currents recorded 1 - 4 days post-injection. A ratio of 1:3 (A:B) was used for the expression of heteromeric 5-HT3R.

IC50 values for Q and M at human 5-HT33A were approximately 10-fold less than previously reported in mouse, while C had a similar potency (Table 1, Thompson et al, 2007). Increasing concentrations of Q and C caused parallel rightward shifts in 5-HT concentration-response curves with no decrease in the maximal current, a behaviour that is consistent with competitive antagonism. M caused non-parallel shifts that were insurmountable, indicating non-competitive antagonism. These actions are equivalent to those we previously reported at mouse 5-HT33AR (Thompson et al., 2007). At 5-HT3ABR, Q and M were less potent than at homomeric receptors, but C was similar. At these heteromeric receptors, C and M displayed properties that were consistent with competitive antagonism, but Q was non-competitive.

Table 1. 5-HT3R inhibition at EC50 concentrations of 5-HT. Values are shown as mean ± SEM.

At human 5-HT3 R, the IC50 values for C and M are close to blood concentrations required for malarial treatment (pEC99; 4.35 µM and 5.66 µM for C and M respectively, Ramharter et al, 2004). However, these compounds are usually very well tolerated when used at these recommended doses, and we suggest that their therapeutic use could be extended to include the treatment of 5-HT3R-related disorders.

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