title: Pharmacological characterization and determination of pharmacokinetic and pharmacodynamic relationship of PF-00885706, a novel partial agonist selective for the 5-HT(4) receptor.
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.
authors.affiliation: Discovery Biology Research, Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Komada
authors.forename: Tomomi
authors.initials: T
authors.lastname: Matsuura
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Mikami
authors.forename: Keiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Naoji
authors.initials: N
authors.lastname: Kimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohmi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Toga
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Eda
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakakibara
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002460:Cell Line; D003503:Cyclobutanes / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004285:Dogs; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005764:Gastroesophageal Reflux / Q000188:drug therapy; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists
chemical_list: C545705:1-((4-((((3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl)amino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid; D001562:Benzimidazoles; D003503:Cyclobutanes; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4