title: Effects of novel TRPA1 receptor agonist ASP7663 in models of drug-induced constipation and visceral pain.
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.affiliation: Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ryosuke.kojima@astellas.com.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kojima
authors.affiliation: Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Katsura
authors.initials: K
authors.lastname: Nozawa
authors.affiliation: Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Doihara
authors.affiliation: Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Keto
authors.affiliation: Chemistry Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kaku
authors.affiliation: Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Itou
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy* / Q000503:physiopathology; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D003000:Clonidine; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D005772:Gastrointestinal Transit / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008139:Loperamide; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000819:agonists*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists*; D050051:Transient Receptor Potential Channels / Q000819:agonists*; D059265:Visceral Pain / Q000188:drug therapy / Q000503:physiopathology
chemical_list: C000592144:(7-fluoro-1-(2-methylpropyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetic acid; D000700:Analgesics; D015220:Calcium Channels; D007210:Indoleacetic Acids; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C480976:Trpa1 protein, rat; D012701:Serotonin; D008139:Loperamide; D003000:Clonidine; D002118:Calcium
keywords: Abdominal pain; Constipation model; IBS; TRPA1