Pharmacological profile of DA-6886, a novel 5-HT4 receptor agonist to accelerate colonic motor activity in mice.

Abstract

DA-6886, the gastrointestinal prokinetic benzamide derivative is a novel 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). The purpose of this study was to characterize in vitro and in vivo pharmacological profile of DA-6886. We used various receptor binding assay, cAMP accumulation assay, organ bath experiment and colonic transit assay in normal and chemically constipated mice. DA-6886 exhibited high affinity and selectivity to human 5-HT4 receptor splice variants, with mean pKi of 7.1, 7.5, 7.9 for the human 5-HT4a, 5-HT4b and 5-HT4d, respectively. By contrast, DA-6886 did not show significant affinity for several receptors including dopamine D2 receptor, other 5-HT receptors except for 5-HT2B receptor (pKi value of 6.2). The affinity for 5-HT4 receptor was translated into functional agonist activity in Cos-7 cells expressing 5-HT4 receptor splice variants. Furthermore, DA-6886 induced relaxation of the rat oesophagus preparation (pEC50 value of 7.4) in a 5-HT4 receptor antagonist-sensitive manner. The evaluation of DA-6886 in CHO cells expressing hERG channels revealed that it inhibited hERG channel current with an pIC50 value of 4.3, indicating that the compound was 1000-fold more selective for the 5-HT4 receptor over hERG channels. In the normal ICR mice, oral administration of DA-6886 (0.4 and 2mg/kg) resulted in marked stimulation of colonic transit. Furthermore, in the loperamide-induced constipation mouse model, 2mg/kg of DA-6886 significantly improved the delay of colonic transit, similar to 10mg/kg of tegaserod. Taken together, DA-6886 is a highly potent and selective 5-HT4 receptor agonist to accelerate colonic transit in mice, which might be therapeutic agent having a favorable safety profile in the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation.

• Authors: Min Jung Lee, Kang Hun Cho, Hyun Min Park, Hyun Jung Sung, Sunghak Choi, Weonbin Im
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 735 Pg. 115-22 (Jul 15 2014) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 24769304 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Benzamides
• N-((1-(3-(1,2,3-triazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide
• Serotonin 5-HT4 Receptor Agonists
• Triazoles
• Receptors, Serotonin, 5-HT4
• Loperamide
• Carbachol

Topics

• Animals
• Benzamides (pharmacology)
• Carbachol
• Colon (drug effects, physiology)
• Esophagus (drug effects, physiology)
• Gastrointestinal Motility (drug effects)
• Loperamide
• Male
• Mice, Inbred ICR
• Muscle Contraction (drug effects)
• Rats
• Receptors, Serotonin, 5-HT4 (physiology)
• Serotonin 5-HT4 Receptor Agonists (pharmacology)
• Triazoles (pharmacology)