The Development of Small Molecule Angiotensin IV-Based Analogs to Treat Depression

Major depression is a common form of mental disorder affecting approximately 15% of the population at least once during lifetime. The etiology of depression is complex with potential contributions from central and peripheral systemic factors, and several CNS impacting diseases. Presently employed antidepressant medications are poorly responded to by upwards of 50% of patients and typically require weeks of treatment to be effective. Recent post-mortem brain scans indicate significant volume reductions in two limbic brain structures, the hippocampus and prefrontal cortex of depressed patients. These findings focus attention on hippocampal plasticity in the neuropathology of depression and the possible dysfunction of several important processes including neurogenesis, synaptogenesis, and contributions by neurotrophic growth factors. The hepatocyte growth factor (HGF)/c-Met receptor system is a powerful mediator of synaptogenesis and neurogenesis, and if adequately activated may serve to counter the neuropathology of depression. The brain renin-angiotensin system (RAS) interacts with the HGF/c-Met system and plays a major role in responding to stress and the pathophysiology of depression. We have developed an angiotensin IV-based small molecule designed to activate the HGF/c-Met receptor system in order to provide neuroprotection, synaptogenesis, and neurogenesis in the hippocampus and prefrontal cortex. This analog may be efficacious in treating the neuropathology of depression.