Selective corticotropin-releasing factor 1 receptor antagonist E2508 has potent antidepressant-like and anxiolytic-like properties in rodent models

Abstract

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.