Agomelatine (Valdoxan) is structurally closely related to melatonin. Agomelatine is a potent agonist at melatonin receptors and an antagonist at serotonin-2C (5-HT2C) receptors, tested in an animal model of depression.

5-HT2C (porcine):6.4(pKi), 5-HT2C (human):6.2(pKi)

Agomelatine enhances cell proliferation and neurogenesis in the ventral hippocampus (VH) of adult rats, a region associated with emotional disorders. It effectively reverses behavior alterations in transgenic mice observed in Porsolt forced swimming tests and elevated plus mazes. Agomelatine significantly accelerates the re-adjustment of circadian rhythms of temperature and activity after induced phase shifts. It increases the duration of positive social interactions in mice exposed to new environments. In the ventral dentate gyrus of rats, which is involved in emotional responses, Agomelatine promotes cell proliferation and neurogenesis, consistent with its anti-depressant and anti-anxiety properties. Across the entire dentate gyrus, Agomelatine boosts the survival of newly generated neurons. It enhances the ratio of mature to immature neurons and promotes dendritic sprouting in the granule cells of adult rats, indicating accelerated maturation. Furthermore, Agomelatine activates several cellular signaling pathways (extracellular signal-regulated kinases 1/2, protein kinase B, and glycogen synthase kinase 3 beta) known to be modulated by antidepressants and involved in proliferation/survival control.

In mice subjected to chronic electroshock stress, Agomelatine fully normalized the survival of stress-affected cells in the hippocampus and partially reversed the reduction in glucocorticoid receptor expression.