Pharmacological profile of DA-6886, a novel 5-HT4 receptor agonist to accelerate colonic motor activity in mice.
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.
Dong-A ST Research Institute, 21 Geumhwa-ro, 105beon-gil, Giheung-gu, Yongin-si 446-905, Gyeonggi-do, Republic of Korea; Department of Anatomy and Cell Biology, School of Medicine, Sungkyunkwan University, Suwon-si 440-746, Gyeonggi-do, Republic of Korea. Electronic address: liferadar@gmail.com.
Min Jung
MJ
Lee
Dong-A ST Research Institute, 21 Geumhwa-ro, 105beon-gil, Giheung-gu, Yongin-si 446-905, Gyeonggi-do, Republic of Korea.
Kang Hun
KH
Cho
Dong-A ST Research Institute, 21 Geumhwa-ro, 105beon-gil, Giheung-gu, Yongin-si 446-905, Gyeonggi-do, Republic of Korea.
Hyun Min
HM
Park
Dong-A ST Research Institute, 21 Geumhwa-ro, 105beon-gil, Giheung-gu, Yongin-si 446-905, Gyeonggi-do, Republic of Korea.
Hyun Jung
HJ
Sung
Dong-A ST Research Institute, 21 Geumhwa-ro, 105beon-gil, Giheung-gu, Yongin-si 446-905, Gyeonggi-do, Republic of Korea.
Sunghak
S
Choi
Dong-A ST Research Institute, 21 Geumhwa-ro, 105beon-gil, Giheung-gu, Yongin-si 446-905, Gyeonggi-do, Republic of Korea.
Weonbin
W
Im
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002217:Carbachol; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D004947:Esophagus / Q000187:drug effects / Q000502:physiology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D008139:Loperamide; D008297:Male; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
D001549:Benzamides; C000594645:N-((1-(3-(1,2,3-triazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide; D058828:Serotonin 5-HT4 Receptor Agonists; D014230:Triazoles; D044422:Receptors, Serotonin, 5-HT4; D008139:Loperamide; D002217:Carbachol
5-HT(4) receptor agonist; Colonic transit; Constipation; Irritable bowel syndrome