Abstract:
:The pharmacological profile of PF-00885706, a selective 5-HT(4) receptor partial agonist, was investigated. PF-00885706 displayed a high binding affinity for the human 5-HT(4d) receptor with a K(i) of 3.7 nM that translates to functional agonist activity in vitro with EC(50) values of 4.0 nM and 6.6 nM in cell-based assays of human recombinant 5-HT(4d) receptors and rat tunica muscularis mucosae tissues, respectively. In both assays, partial agonism was confirmed with E(max) values of 84% and 78%, respectively. Notably, PF-00885706 was highly selective, displaying >1000-fold higher affinity for 5-HT(4d) receptors compared to 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), 5-HT(2B), 5-HT(2C), 5-HT(3), 5-HT(7), and D(2long) 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 microM except for binding to the sigma(2) receptor. PF-00885706 exhibited weak binding affinity for the sigma(2) receptor yielding a K(i) value of 3 microM, which is more than 800-fold weaker than that for the 5-HT(4d) 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-HT(4) receptors that is expected to be effective for the treatment with gastrointestinal dysmotility disorders with reduced adverse effects mediated by other related receptors.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Komada T,Matsuura T,Mikami T,Suzuki K,Sugimoto H,Kimura N,Ohmi T,Toga T,Nakai Y,Eda H,Sakakibara Mdoi
10.1016/j.phrs.2009.03.013subject
Has Abstractpub_date
2009-10-01 00:00:00pages
237-46issue
4eissn
1043-6618issn
1096-1186pii
S1043-6618(09)00100-5journal_volume
60pub_type
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