Efficacy of SAL0114, an Oral NMDA Receptor Antagonist with Multimodal Activity, in Major Depressive Disorder

Abstract The first FDA-approved rapid-acting antidepressant was esketamine, but its use was limited because of the risk of addiction, and although the subsequent combination of dextromethorphan (DM) + bupropion (BUP) has alleviated some of the problems, there is still a clinical need for safer and more effective compounds. In this paper, we use a strategy of deuterated substitution of DM to improve stability and reduce metabolites to improve safety and efficacy. We analyzed the effects of deuterium substitution on the in vitro activities of DM and deDX (deDM metabolite) by radioligand competition binding assay, evaluated the antidepressant and synergistic effects of deDM and BUP by a mouse behavioral despair model, and further assessed the synergistic mechanism of deDM and BUP by a reserpine-induced hypothermia rats model and an ammonia-induced cough mice model, which showed that deuterium substitution does not change the DM and deDX (deDM metabolite) in vitro activity, but can improve the in vivo effectiveness of DM, suggesting that deDM has the potential to be more stable in vivo with fewer metabolites, i.e., fewer side effects, and therefore, deDM and BUP is a safer and more potent combination for depressed patients than the combination of DM and BUP.