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 α_2C 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 α_2C 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 α_2C AR antagonism and BDNF-dependent neuroplastic mechanisms.