In vitro and in vivo pharmacological characterization of PF-01354082, a novel partial agonist selective for the 5-HT4 receptor

Abstract The pharmacological profile of PF-01354082, a selective 5-HT 4 receptor partial agonist, was investigated. PF-01354082 displayed high affinity for human 5-HT 4d and dog 5-HT 4h receptors in binding studies, having Ki values of 2.0 nM and 4.2 nM, respectively. By contrast, PF-01354082 did not show significant affinity for several other 5-HT receptors (5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 3A , and 5-HT 7 ) or the dopamine D 2long receptor. Functional assays using either cells expressing human recombinant 5-HT 4d receptors or rat tunica muscularis mucosae demonstrated that PF-01354082 exhibited partial agonist activity at the 5-HT 4 receptor. The effects of PF-01354082 on in vitro receptor binding, ion channel activity, and sites of uptake were further investigated. PF-01354082 did not show biologically relevant binding activity at concentrations up to 10 µM except for binding to the 5-HT 4e receptor. Furthermore, PF-01354082 decreased I HERG current by only 11% at a concentration of 300 µM, indicating that the compound had greater than 150,000-fold selectivity for the human 5-HT 4d receptor over hERG channels. An in vivo study using a gastric motility model in conscious dogs demonstrated that oral administration of PF-01354082 resulted in marked and sustained stimulation of gastric motility in a dose-dependent manner. These results indicate that PF-01354082 is an orally active, highly selective, partial agonist of the human 5-HT 4 receptor that is expected to exert a favorable effect on gastrointestinal motor disorders with reduced adverse effects mediated by other related receptors.