D-morphinan analogs with favorable pharmacokinetic profiles as dual-acting antidepressants

Dextromethorphan (DM) is a dual inhibitor of NMDAR and SERT (IC_{50 (NMDAR)}: IC_{50 (SERT)} = 31), but lacks therapeutic clinical value for the treatment of depression due to its low exposure in the human body. In this study, a series of d-morphinan derivatives were designed, synthesized and evaluated both in vitro and in vivo to identify dual inhibitors with improved metabolic stability. Structure-activity relationship studies revealed that a methyl group at the morphinan N-17 position is essential for maintaining SERT activity. Amino-morphinan compounds 24 and 27 exhibited moderate yet more balanced inhibitory activity against both NMDAR and SERT (1< IC_50(NMDAR): IC_50(SERT) < 5). Compared to DM, compound 24 demonstrated favorable metabolic stability and higher plasma exposure. In vivo, 24 showed significant antidepressant-like effects in the forced swim test in mice after acute administration.