Pharmacological characterization and determination of pharmacokinetic and pharmacodynamic relationship of PF-00885706, a novel partial agonist selective for the 5-HT4 receptor

The pharmacological profile of PF-00885706, a selective 5-HT4 receptor partial agonist, was investigated. PF-00885706 displayed a high binding affinity for the human 5-HT4d receptor with a Ki of 3.7 nM that translates to functional agonist activity in vitro with EC50 values of 4.0 nM and 6.6 nM in cell-based assays of human recombinant 5-HT4d receptors and rat tunica muscularis mucosae tissues, respectively. In both assays, partial agonism was confirmed with Emax values of 84% and 78%, respectively. Notably, PF-00885706 was highly selective, displaying >1000-fold higher affinity for 5-HT4d receptors compared to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT7, and D2long receptors. Furthermore, in vitro binding assays demonstrated that PF-00885706 had no biologically significant interaction with physiologically important enzymes, ion channels including hERG channel, or receptors at concentrations up to 10 μM except for binding to the σ2 receptor. PF-00885706 exhibited weak binding affinity for the σ2 receptor yielding a Ki value of 3 μM, which is more than 800-fold weaker than that for the 5-HT4d receptor. Oral administration of PF-00885706 to dogs resulted in marked and long-lasting stimulation of gastric motility with a minimum effective dose of 0.001 mg/kg. Pharmacokinetic analysis revealed that PF-00885706 has a low to moderate volume of distribution and the complete absorption in dogs. Pharmacokinetic and pharmacodynamic analysis of PF-00885706 in the dog gastric motility model showed a correlation between plasma concentrations and enhancement of gastric motility. Thus, PF-00885706 is an orally active, highly selective partial agonist for 5-HT4 receptors that is expected to be effective for the treatment with gastrointestinal dysmotility disorders with reduced adverse effects mediated by other related receptors.