Investigations into the binding affinities of different human 5-HT 4 receptor splice variants

Helen Ruth Irving, Nathalie Tochon-Danguy, Kenneth Anye Chinkwo, Jian Guo Li, Carmen Grabbe, Marina Shapiro, Colin William Pouton, Ian Michael Coupar

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This study examined whether the drug-receptor-binding sites of 5 selected human 5-HT(4) receptor splice variants [h5-HT4(a), h5-HT4(b), h5-HT4(c), h5-HT4(d) and h5-HT4(g)] display preferential affinities towards agonists. The agonists selected on the basis of chemical diversity and clinical relevance were: 5-HT4 benzamides, renzapride, zacopride and prucalopride; the benzimidazolones, DAU 6236 and BIMU 1; the aromatic ketone, RS67333, and the indole carbazimidamide tegaserod. The rank order of affinities ranging across the splice variants was: tegaserod (pKi: 7.38-7.91) > or = Y-36912 (pKi: 7.03-7.85) = BIMU 1 (pKi: 6.92-7.78) > or = DAU 6236 (pKi: 6.79-7.99) > or = 5-HT (pKi: 5.82-7.29) > or = 5-MeOT (pKi: 5.64-6.83) > or = renzapride (pKi: 4.85-5.56). We obtained affinity values for the 5-HT4(b), (d) and (g) variants for RS67333 (pKi: 7:48-8.29), prucalopride (pKi: 6.86-7.37) and zacopride (pKi: 5.88-7.0). These results indicate that the ligands interact with the same conserved site in each splice variant. Some splice variants have a higher affinity for certain agonists and the direction of selectivity followed a common trend of lowest affinity at the (d) variant. However, this trend was not evident in functional experiments. Our findings suggest that it may be possible to design splice variant selective ligands, which may be of relevance for experimental drugs but may be difficult to develop clinically.
Original languageEnglish
Pages (from-to)224-233
Number of pages10
Issue number4
Publication statusPublished - 2010


  • Aniline Compounds/metabolism Animals Benzamides/metabolism Benzimidazoles/metabolism Benzofurans/metabolism Bicyclo Compounds, Heterocyclic/metabolism Binding Sites Binding, Competitive COS Cells Cercopithecus aethiops Cyclic AMP/metabolism Dose-Response Relationship, Drug Humans Indoles Kinetics Ligands Piperidines/metabolism Protein Isoforms/metabolism Receptors, Serotonin, 5-HT4/*genetics/metabolism Serotonin 5-HT4 Receptor Agonists Serotonin Antagonists/metabolism

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