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

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 wit...

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Bibliographic Details
Published in:	The Journal of pharmacology and experimental therapeutics Vol. 341; no. 2; p. 350
Main Authors:	Thompson, A J, Verheij, M H P, de Esch, I J P, Lummis, S C R
Format:	Journal Article
Language:	English
Published:	United States 01-05-2012
Subjects:	Animals Cells, Cultured Female Granisetron - pharmacology HEK293 Cells Humans Isotope Labeling - methods Ligands Mutation - drug effects Mutation - genetics Oocytes - drug effects Oocytes - metabolism Piperidines - pharmacology Protein Binding - drug effects Quinoxalines - pharmacology Receptors, Serotonin, 5-HT3 - genetics Receptors, Serotonin, 5-HT3 - metabolism Serotonin 5-HT3 Receptor Agonists - pharmacology Serotonin 5-HT3 Receptor Antagonists - pharmacology Xenopus laevis - metabolism
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Summary:	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.
ISSN:	1521-0103
DOI:	10.1124/jpet.111.190769