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: Tadayoshi Mikami, Tohru Komada, Hiromi Sugimoto, Keiko Suzuki, Takashi Ohmi, Naoji Kimura, Rie Naganeo, Eriko Nakata, Keigo Nakatani, Tetsuo Toga, Hiroyuki Eda, Minoru Sakakibara
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 609 Issue 1-3 Pg. 5-12 (May 01 2009) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19285067 (Publication Type: Journal Article)

Chemical References

• (1-piperidinyl)ethyl 1H-indole-3-carboxylate
• 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
• Benzimidazoles
• Cholinergic Agonists
• Indoles
• Piperidines
• Serotonin 5-HT4 Receptor Agonists
• Serotonin 5-HT4 Receptor Antagonists
• Serotonin Receptor Agonists
• Carbachol
• Cyclic AMP

Topics

• Administration, Oral
• Animals
• Benzimidazoles (administration & dosage, agonists, chemistry, pharmacology)
• CHO Cells
• Carbachol (pharmacology)
• Cell Line
• Cholinergic Agonists (pharmacology)
• Cricetinae
• Cricetulus
• Cyclic AMP (analysis)
• Dogs
• Dose-Response Relationship, Drug
• Esophagus (cytology)
• Gastrointestinal Motility (drug effects)
• Humans
• Indoles (pharmacology)
• Kidney (cytology)
• Male
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects)
• Piperidines (pharmacology)
• Rats
• Rats, Inbred Strains
• Sensitivity and Specificity
• Serotonin 5-HT4 Receptor Agonists
• Serotonin 5-HT4 Receptor Antagonists
• Serotonin Receptor Agonists (administration & dosage, chemistry, pharmacology)
• Time Factors