Selective corticotropin-releasing factor 1 receptor antagonist E2508 reduces restraint stress-induced defecation and visceral pain in rat models.
N-Cyclopropylmethyl-7-(2,6-dimethoxy-4-methoxymethylphenyl)-2-ethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-amine tosylate (E2508) is a newly discovered selective corticotropin-releasing factor 1 receptor antagonist. Here, we investigated the effects of E2508 on wrap restraint stress-induced defecation and visceral pain in rats. Oral pretreatment with E2508 dose-dependently decreased stool weights after 20min wrap restraint stress and significant effects were observed at doses of 30 and 100mg/kg. However, E2508 did not affect basal defecation at doses up to 100mg/kg. In contrast, alosetron, a 5-HT3receptor antagonist, decreased both wrap restraint stress-induced and basal stool output at a dose of 0.1mg/kg. In a rat visceral pain model, subcutaneous injections of both E2508 (0.01 and 0.1mg/kg) and alosetron (0.001 and 0.01mg/kg) significantly decreased the number of abdominal muscle contractions induced by colonic distention, suggesting these drugs reduced visceral pain. Together, these results demonstrate E2508 has the potential to be an effective therapy for the treatment of irritable bowel syndrome with a lower risk of adverse events such as constipation compared with the current clinically used 5-HT3receptor antagonist.
Biopharmacology, Neuroscience and General Medicine Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan; Concept Creation, KAN Product Creation Unit, Eisai Product Creation Systems, KAN Research Institute, Inc., 6-8-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo 650-0047, Japan. Electronic address: r-taguchi@hhc.eisai.co.jp.
Ryota
R
Taguchi
Biopharmacology, Neuroscience and General Medicine Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Kodo
K
Shikata
Biopharmacology, Neuroscience and General Medicine Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Yoshiaki
Y
Furuya
Biopharmacology, Neuroscience and General Medicine Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Tetsuya
T
Hirakawa
Biopharmacology, Neuroscience and General Medicine Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan; Biomarkers and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Mitsuhiro
M
Ino
Medicinal Chemistry, Neuroscience and General Medicine Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Kogyoku
K
Shin
Biopharmacology, Neuroscience and General Medicine Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan; Pharmacological Evaluation Unit, Tsukuba Division, Sunplanet Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Hisashi
H
Shibata
D000818:Animals; D002243:Carbolines / Q000008:administration & dosage / Q000494:pharmacology; D003672:Defecation / Q000187:drug effects*; D004195:Disease Models, Animal; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013315:Stress, Psychological / Q000150:complications*; D059265:Visceral Pain / Q000188:drug therapy* / Q000209:etiology; D000099052:CRF Receptor, Type 1
D002243:Carbolines; D011720:Pyrazoles; D011725:Pyridines; D018019:Receptors, Corticotropin-Releasing Hormone; D058831:Serotonin 5-HT3 Receptor Antagonists; C090840:alosetron; D000099052:CRF Receptor, Type 1; C575281:N-(cyclopropylmethyl)-7-(2,6-dimethoxy-4-(methoxymethyl)phenyl)-2-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo(1,5-a)pyridin-3-amine
Alosetron; CRF(1) receptor antagonist; Corticotropin-releasing factor; E2508; Irritable bowel syndrome; Stress