title: Antidepressant and anxiolytic profiles of newly synthesized arginine vasopressin V1B receptor antagonists: TASP0233278 and TASP0390325.
abstract: OBJECTIVE
  Vasopressin V1B receptor antagonists may be effective for the treatment of depression and anxiety and the objective of this study was to characterize the pharmacological profiles of two newly synthesized arginine vasopressin receptor 1B (V1B receptor) antagonists, TASP0233278 and TASP0390325.
  
  
  METHODS
  We investigated the in vitro profiles of TASP0233278 and TASP0390325. In addition, the effect of TASP0390325 on the increase in plasma adrenocorticotropic hormone (ACTH) levels induced by corticotropin-releasing factor (CRF)/desmopressin (dDAVP) was investigated. We also investigated the antidepressant and anxiolytic profiles of TASP0233278 and TASP0390325 in animal models.
  
  
  RESULTS
  Both TASP0233278 and TASP0390325 showed a high affinity and potent antagonist activity for V1B receptors. Oral administration of TASP0390325 antagonized the increase in plasma ACTH levels induced by CRF/dDAVP in rats, indicating that TASP0390325 blocks the anterior pituitary V1B receptor in vivo. Oral administration of TASP0233278 or TASP0390325 also exerted antidepressant effects in two models of depression (a forced swimming test and an olfactory bulbectomy model). Moreover, TASP0233278 improved depressive-like behaviour induced by repeated treatment with corticosterone, a model that has been shown to be resistant to treatment with currently prescribed antidepressants. In addition to depression models, TASP0233278 or TASP0390325 exerted anxiolytic effects in several anxiety models (social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization and sodium lactate-induced panic-like responses in panic-prone rats).
  
  
  CONCLUSIONS
  TASP0233278 and TASP0390325 are potent and orally active V1B receptor antagonists with antidepressant and anxiolytic activities in rodents.
authors.affiliation: Discovery Pharmacology I, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Iijima
authors.forename: T
authors.initials: T
authors.lastname: Yoshimizu
authors.forename: T
authors.initials: T
authors.lastname: Shimazaki
authors.forename: K
authors.initials: K
authors.lastname: Tokugawa
authors.forename: K
authors.initials: K
authors.lastname: Fukumoto
authors.forename: S
authors.initials: S
authors.lastname: Kurosu
authors.forename: T
authors.initials: T
authors.lastname: Kuwada
authors.forename: Y
authors.initials: Y
authors.lastname: Sekiguchi
authors.forename: S
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D065092:Antidiuretic Hormone Receptor Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D003345:Corticosterone; D003412:Cricetulus; D003863:Depression / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000378:metabolism*
chemical_list: C000597003:1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-fluoro-N,N-dimethylprolinamide; C000597004:2-(2-(3-chloro-4-fluorophenyl)-6-(3-(morpholin-4-yl)propoxy)-4-oxopyrido(2,3-d)pyrimidin-3(4H)-yl)-N-isopropylacetamide; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D011725:Pyridines; D011744:Pyrimidinones; D017483:Receptors, Vasopressin; D011392:Proline; D003345:Corticosterone
keywords: HPA axis; V1B receptor antagonist; anxiety; arginine vasopressin; depression