Send to:

Choose Destination
See comment in PubMed Commons below
J Pharmacol Exp Ther. 2012 May;341(2):350-9. doi: 10.1124/jpet.111.190769. Epub 2012 Feb 3.

VUF10166, a novel compound with differing activities at 5-HT₃A and 5-HT₃AB receptors.

Author information

  • 1Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.


The actions of a novel, potent 5-HT₃ receptor ligand, [2-chloro-(4-methylpiperazine-1-yl)quinoxaline (VUF10166)], were examined at heterologously expressed human 5-HT₃A and 5-HT₃AB receptors. VUF10166 displaced [³H]granisetron binding to 5-HT₃A receptors expressed in human embryonic kidney cells with high affinity (K(i) = 0.04 nM) but was less potent at 5-HT₃AB receptors (K(i) = 22 nM). Dissociation of [³H]granisetron in the presence of VUF10166 was best fit with a single time constant (t(1/2) = 53 min) at 5-HT₃A receptors, but with two time constants (t(1/2) = 55 and 2.4 min) at 5-HT₃AB receptors. Electrophysiological studies in oocytes revealed that VUF10166 inhibited 5-HT-induced responses at 5-HT₃A receptors at nanomolar concentrations, but inhibition and recovery were too slow to determine an IC₅₀. At 5-HT₃AB receptors, inhibition and recovery were faster, yielding an IC₅₀ of 40 nM. Cysteine substitutions in the complementary (-), but not the principal (+), face of the 5-HT₃B subunit produced heteromeric receptors in which the actions of VUF10166 resembled those at homomeric receptors. At 5-HT₃A receptors, VUF10166 at higher concentrations also behaved as a partial agonist (EC₅₀ = 5.2 μM; R(max) = 0.24) but did not elicit significant responses at 5-HT₃AB receptors at ≤100 μM. Thus, we propose that VUF10166 binds to the common A+A- site of both receptor types and to a second A+B- modulatory site in the heteromeric receptor. The ability of VUF10166 to distinguish between 5-HT₃A and 5-HT₃AB receptors could help evaluate differences between these receptor types and has potential therapeutic value.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk