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J Pharmacol Sci. 2008 Jul;107(3):251-9. Epub 2008 Jun 28.

Contribution of active and inactive states of the human 5-HT4d receptor to the functional activities of 5-HT4-receptor agonists.

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Discovery Biology Research, Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., Taketoyo, Aichi, Japan.


In the present study, binding affinities of 5-hydroxytryptamine-4 (5-HT(4)) ligands for the human 5-HT(4d) receptor were determined using the agonist [(3)H]5-HT and the selective 5-HT(4) antagonist [(3)H]GR113,808. We also compared the affinity differences between [(3)H]5-HT binding (K(H)) and [(3)H]GR113,808 binding (K(L)) with their activities as 5-HT(4) ligands. Binding studies using [(3)H]5-HT revealed that the human 5-HT(4d) receptor has two binding sites, whereas [(3)H]GR113,808 yielded a single binding site. Additionally, the number of [(3)H]5-HT binding sites decreased in the presence of guanosine-5'-O-(3-thiotriphosphate) (GTPgammaS), but the number of [(3)H]GR113,808 sites did not change. In competitive binding assays, full agonists such as 5-methoxytryptamine and tegaserod showed 2- to 8-fold higher affinities for [(3)H]5-HT binding (K(H)) than for [(3)H]GR113,808 binding (K(L)) (K(H)<K(L)). Conversely, antagonists showed lower affinities for [(3)H]5-HT binding than for [(3)H]GR113,808 binding (K(H)>K(L)). Finally, partial agonists displayed similar binding affinities for both radioligands (K(H) = K(L)). These findings suggest that the equilibrium between active and inactive states of the human 5-HT(4d) receptor relies on the functional activities of 5-HT(4) ligands, and these states affect the affinities of 5-HT(4) ligands in the competitive binding assay.

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