Adrenomedullin Receptor Antagonists as a Potential Therapeutic Target for Major Depressive Disorder

Major Depressive Disorder (MDD) is one of the most common mental health disorders in the world and yet, current treatments for MDD are very ineffective. There is an urgent need to find novel treatments with increased efficacy and reduced side effects. Increased levels of adrenomedullin (ADM), a short vasodilator peptide, are found in the blood of MDD patients. There are currently no known small molecular inhibitors of the two ADM receptors, ADM1 and ADM2. We procured seven small molecular compounds capable of antagonising the ADM2 receptor, from the European Lead Factory. These compounds were selected by high throughput screening. The ability of the compounds to block different pathways involved in ADM signalling was assessed. The most canonical pathway for ADM signalling is the activation of adenylate cyclase to increase intracellular cAMP. Measurements of intracellular ATP concentration revealed promising results for two of the compounds, TC14 and TC02. SKNSH cells pre-treated with 100 μM of these antagonist compounds and then treated with 1 μM of ADM peptide agonist had reduced cAMP, compared with cells treated with 1 μM of ADM agonist only. Pre-treatment with TC14 and TC02 resulted in intracellular cAMP concentrations of 0.7 nM and 5.3 nM, respectively, compared to a cAMP concentration of 31.3 nM in cells treated only with ADM agonist. We suggest that these compounds can be used in further research into the role of ADM in MDD. The hypothesis that some of the effects mediated by ADM, in health and disease, are dependent on the phosphorylation and inhibition of the transcription factor FoxO3a, via PI3K/Akt signalling, was also investigated.