Selective corticotropin-releasing factor 1 receptor antagonist E2508 has potent antidepressant-like and anxiolytic-like properties in rodent models.
Corticotropin-releasing factor (CRF) is a hormone secreted by the hypothalamus in response to stress, and CRF antagonists may be effective for the treatment of stress-related disorders including major depressive and anxiety disorders. Here, we investigated the in vivo pharmacological profile of 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), a recently synthesized, orally active CRF1 receptor antagonist. Oral administration of a single dose of E2508 (3 or 10mg/kg), but not fluoxetine (30mg/kg), a selective serotonin reuptake inhibitor (SSRI), significantly shortened immobility time in rats in the forced swim test. E2508 (10, 30, or 100mg/kg) also showed an antidepressant-like effect in the forced swim test in mice, with no sedative or muscle relaxant effects for doses up to 100mg/kg. Moreover, E2508 (5 or 20mg/kg) significantly reduced anxiety-like behavior in the rat defensive burying test. Diazepam, a benzodiazepine anxiolytic agent, also showed an anxiolytic effect in the defensive burying test at the same dose that induced a muscle relaxant effect in mice. Administration of E2508 (30mg/kg) for 14 consecutive days did not affect sexual behavior. By contrast, fluoxetine (30mg/kg) administration for ≥7 consecutive days decreased sexual behavior. These results indicate that E2508 has both potent antidepressant-like and anxiolytic-like effects in rodent models, and is well tolerated compared with a commonly prescribed therapeutic SSRI or benzodiazepine.
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; 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
D000109:Acetylcholine / Q000097:blood; D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001008:Anxiety Disorders / Q000378:metabolism / Q000517:prevention & control*; D000242:Cyclic AMP / Q000378:metabolism; D003865:Major Depressive Disorder / Q000378:metabolism / Q000517:prevention & control*; D003975:Diazepam / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053580:Muscle Strength / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D012726:Sexual Behavior, Animal / Q000187:drug effects
D000109:Acetylcholine; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D000242:Cyclic AMP; D003975:Diazepam; D005473:Fluoxetine; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D017367:Selective Serotonin Reuptake Inhibitors; C412383:R 121919; 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
Antidepressant; Anxiolytic; CRF(1) receptor antagonist; Corticotropin-releasing factor; E2508; Sexual dysfunction