title: In vitro and in vivo pharmacological characterization of PF-01354082, a novel partial agonist selective for the 5-HT(4) 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 microM except for binding to the 5-HT(4e) receptor. Furthermore, PF-01354082 decreased I(HERG) current by only 11% at a concentration of 300 microM, 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.
authors.affiliation: Discovery Biology Research, Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Mikami
authors.forename: Tohru
authors.initials: T
authors.lastname: Komada
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohmi
authors.forename: Naoji
authors.initials: N
authors.lastname: Kimura
authors.forename: Rie
authors.initials: R
authors.lastname: Naganeo
authors.forename: Eriko
authors.initials: E
authors.lastname: Nakata
authors.forename: Keigo
authors.initials: K
authors.lastname: Nakatani
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Toga
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Eda
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakakibara
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000032:analysis; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004947:Esophagus / Q000166:cytology; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012680:Sensitivity and Specificity; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C088817:(1-piperidinyl)ethyl 1H-indole-3-carboxylate; C541903:4-((4-((((3-Isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl)amino)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid; D001562:Benzimidazoles; D018679:Cholinergic Agonists; D007211:Indoles; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D002217:Carbachol; D000242:Cyclic AMP