Antidepressant and anxiolytic profiles of newly synthesized arginine vasopressin V_1B receptor antagonists: TASP0233278 and TASP0390325

Abstract

BACKGROUND AND PURPOSEVasopressin 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. EXPERIMENTAL APPROACHWe 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. KEY RESULTSBoth 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). CONCLUSIONTASP0233278 and TASP0390325 are potent and orally active V1B receptor antagonists with antidepressant and anxiolytic activities in rodents.

TASP0434299: A Novel Pyridopyrimidin-4-One Derivative as a Radioligand for Vasopressin V1B Receptor

“…were synthesized at the Taisho Chemistry Laboratories (Iijima et al, 2014 ]-vasopressin were dissolved in distilled water containing 0.1% bovine serum albumin (BSA) and diluted with each assay buffer to various concentrations for the in vitro studies. TASP0390325 was dissolved and diluted in distilled water for i.v.…”

“…Chinese hamster ovary K1 cells stably expressing the human V 1B receptor (Iijima et al, 2014) were used for an AVP-induced intracellular calcium concentration ([Ca 21 ] i ) assay. The cells were cultured in Ham's F-12 (Invitrogen) containing 10% fetal bovine serum, 100 units/ml penicillin, 100 mg/ml streptomycin, and 0.5 mg/ml geneticin in a humidified 5% CO 2 incubator maintained at 37°C.…”

“…The anterior pituitary was separated from the pituitary in ice-cold saline. Tissue membranes of the anterior pituitary were prepared as previously reported (Iijima et al, 2014). (Iijima et al, 2014).…”

“…Tissue membranes of the anterior pituitary were prepared as previously reported (Iijima et al, 2014). (Iijima et al, 2014). Briefly, 5 mg of the membrane proteins were incubated for 60 minutes at room temperature in binding buffer containing 0.4 nM [ 3 H]AVP and 0.1% BSA with or without various concentrations of the test compounds in a volume of 0.2 ml.…”

“…[ ]AVP binding to the rat V 1B receptor was conducted under the same conditions, as described previously (Iijima et al, 2014).…”