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Effects of novel TRPA1 receptor agonist ASP7663 in models of drug-induced constipation and visceral pain.
Eur J Pharmacol. 2014 Jan 15; 723:288-93.EJ

Abstract

Constipation is a major gastrointestinal motility disorder with clinical need for effective drugs. We previously reported that transient receptor potential ankyrin 1 (TRPA1) is highly expressed in enterochromaffin (EC) cells, which are 5-hydroxytryptamine (5-HT)-releasing cells, and might therefore be a novel target for constipation. Here, we examined the effects of ASP7663, a novel and selective TRPA1 agonist, in constipation models as well as an abdominal pain model. ASP7663 activated human, rat, and mouse TRPA1 and released 5-HT from QGP-1 cells, and oral but not intravenous administration of ASP7663 significantly improved the loperamide-induced delay in colonic transit in mice. While pretreatment with the TRPA1 antagonist HC-030031 and vagotomy both inhibited the ameliorating effect of oral ASP7663 on the colonic transit, both orally and intravenously administered ASP7663 significantly inhibited colorectal distension (CRD)-induced abdominal pain response in rats. Taken together, these results demonstrate that ASP7663 exerts both anti-constipation and anti-abdominal pain actions, the former is likely triggered from the mucosal side of the gut wall via activation of vagus nerves while the latter is assumed to be provoked through systemic blood flow. We conclude that ASP7663 can be an effective anti-constipation drug with abdominal analgesic effect.

Authors+Show Affiliations

Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ryosuke.kojima@astellas.com.Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.Chemistry Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24291101

Citation

Kojima, Ryosuke, et al. "Effects of Novel TRPA1 Receptor Agonist ASP7663 in Models of Drug-induced Constipation and Visceral Pain." European Journal of Pharmacology, vol. 723, 2014, pp. 288-93.
Kojima R, Nozawa K, Doihara H, et al. Effects of novel TRPA1 receptor agonist ASP7663 in models of drug-induced constipation and visceral pain. Eur J Pharmacol. 2014;723:288-93.
Kojima, R., Nozawa, K., Doihara, H., Keto, Y., Kaku, H., Yokoyama, T., & Itou, H. (2014). Effects of novel TRPA1 receptor agonist ASP7663 in models of drug-induced constipation and visceral pain. European Journal of Pharmacology, 723, 288-93. https://doi.org/10.1016/j.ejphar.2013.11.020
Kojima R, et al. Effects of Novel TRPA1 Receptor Agonist ASP7663 in Models of Drug-induced Constipation and Visceral Pain. Eur J Pharmacol. 2014 Jan 15;723:288-93. PubMed PMID: 24291101.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of novel TRPA1 receptor agonist ASP7663 in models of drug-induced constipation and visceral pain. AU - Kojima,Ryosuke, AU - Nozawa,Katsura, AU - Doihara,Hitoshi, AU - Keto,Yoshihiro, AU - Kaku,Hidetaka, AU - Yokoyama,Toshihide, AU - Itou,Hiroyuki, Y1 - 2013/11/28/ PY - 2013/05/14/received PY - 2013/10/17/revised PY - 2013/11/03/accepted PY - 2013/12/3/entrez PY - 2013/12/3/pubmed PY - 2014/10/8/medline KW - Abdominal pain KW - Constipation model KW - IBS KW - TRPA1 SP - 288 EP - 93 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 723 N2 - Constipation is a major gastrointestinal motility disorder with clinical need for effective drugs. We previously reported that transient receptor potential ankyrin 1 (TRPA1) is highly expressed in enterochromaffin (EC) cells, which are 5-hydroxytryptamine (5-HT)-releasing cells, and might therefore be a novel target for constipation. Here, we examined the effects of ASP7663, a novel and selective TRPA1 agonist, in constipation models as well as an abdominal pain model. ASP7663 activated human, rat, and mouse TRPA1 and released 5-HT from QGP-1 cells, and oral but not intravenous administration of ASP7663 significantly improved the loperamide-induced delay in colonic transit in mice. While pretreatment with the TRPA1 antagonist HC-030031 and vagotomy both inhibited the ameliorating effect of oral ASP7663 on the colonic transit, both orally and intravenously administered ASP7663 significantly inhibited colorectal distension (CRD)-induced abdominal pain response in rats. Taken together, these results demonstrate that ASP7663 exerts both anti-constipation and anti-abdominal pain actions, the former is likely triggered from the mucosal side of the gut wall via activation of vagus nerves while the latter is assumed to be provoked through systemic blood flow. We conclude that ASP7663 can be an effective anti-constipation drug with abdominal analgesic effect. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/24291101/Effects_of_novel_TRPA1_receptor_agonist_ASP7663_in_models_of_drug_induced_constipation_and_visceral_pain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(13)00892-3 DB - PRIME DP - Unbound Medicine ER -