α2C Adrenoceptor antagonist KMCA-0011 alleviated depressive-like behaviors in a maternal separation mouse model.

Despite the widespread use of monoaminergic antidepressants, their clinical efficacy is often limited by delayed onset and adverse effects. Targeting the α2C adrenoceptor (AR) has emerged as a promising strategy to overcome these limitations. Here, a series of benzoxazole and oxalamide derivatives were designed, synthesized, and biologically evaluated as potential antidepressants targeting α2C AR. Among them, 11e (KMCA-0011), 21b (KMCA-0002), and 21e (KMCA-0028) exhibited the highest binding affinity. Molecular docking studies provided a rationale for the differences in their binding affinities. These compounds demonstrated antagonistic activity by inhibiting ERK phosphorylation without agonistic effects. In a maternal separation (MS) mouse model, all three compounds significantly alleviated depressive-like behaviors, with 11e (KMCA-0011) and 21e (KMCA-0028) showing the most consistent efficacy. Mechanistically, 11e (KMCA-0011) increased hippocampal brain-derived neurotrophic factor (BDNF) levels and restored corticosterone-induced impairments in long-term potentiation (LTP), indicating modulation of synaptic plasticity. Additionally, 11e (KMCA-0011) and 21e (KMCA-0028) displayed favorable ADME profiles, including high plasma stability and minimal CYP inhibition. Given the predicted limited blood-brain barrier (BBB) permeability of 21e (KMCA-0028), these results collectively identify 11e (KMCA-0011) as a promising lead compound that demonstrates robust antidepressant-like activity, likely mediated through α2C AR antagonism and BDNF-dependent neuroplastic mechanisms.