A compelling case for the potential utility of vasopressin (AVP) antagonists as a novel therapeutic class for the treatment of stress-related affective illness has emerged based on observations in depressed individuals, findings in animal models of anxiety and depression, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. This proposal seeks support for the continued development of SRX246.HCl, a novel vasopressin 1a (V1a) receptor antagonist that has shown efficacy in preclinical animal models of anxiety and depression, good plasma bioavailability and CNS penetration following oral administration, a strong safety profile, and high affinity and selectivity for the target receptor. The scientific bases for V1a antagonists as a pharmacotherapy for anxiety and depression include: 1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of anxiety and depression, 2) recognition that AVP, not CRF, drives HPA function associated with chronic psychological stress, 3) the CNS localization of V1a receptors in limbic system regions involved in HPA regulation and control of social behaviors, and 4) preclinical data with SRX246 showing efficacy in animal models employed as screens for anxiolytic/antidepressant activity.
