Exploring the Therapeutic Potential of Arginine Vasopressin V1B Receptor Antagonists: TASP0233278 and TASP0390325 for Depression and Anxiety

The study aimed to examine the potential of two novel vasopressin V1B receptor antagonists, TASP0233278 and TASP0390325, in treating depression and anxiety disorders. The research involved in vitro analysis of the antagonists' profiles and an investigation into TASP0390325's impact on plasma adrenocorticotropic hormone (ACTH) levels, which are elevated by corticotropin-releasing factor (CRF) and desmopressin (dDAVP). Additionally, the study explored the antidepressant and anxiolytic effects of TASP0233278 and TASP0390325 in various animal models.

Key findings revealed that both TASP0233278 and TASP0390325 demonstrated high affinity and strong antagonistic activity towards V1B receptors. TASP0390325, when administered orally, was found to counteract the CRF/dDAVP-induced rise in plasma ACTH levels in rats, suggesting its ability to block the anterior pituitary V1B receptor in vivo. Furthermore, both compounds displayed antidepressant properties in two depression models: the forced swimming test and the olfactory bulbectomy model. TASP0233278 notably improved depressive-like behavior in a corticosterone-induced model, which is typically resistant to currently available antidepressants. The study also highlighted the anxiolytic effects of TASP0233278 and TASP0390325 across multiple anxiety models, including social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization, and sodium lactate-induced panic-like responses in panic-prone rats.

In conclusion, TASP0233278 and TASP0390325 emerged as effective, orally bioavailable V1B receptor antagonists with demonstrated antidepressant and anxiolytic properties in rodent studies.