Pharmacodynamics
Agomelatine acts as a highly potent and selective melatonin MT1 and MT2 receptor agonist (Ki = 0.1nM and 0.12nM, respectively) and also as a relatively weak serotonin 5-HT2B and 5-HT2C receptor antagonist (Ki = 660nM and 631nM, respectively; ~6,000-fold lower than for the melatonin receptors).[33][34] It is a silent antagonist rather than an inverse agonist of the serotonin 5-HT2C receptor.[35] The drug has negligible affinity for the serotonin 5-HT2A receptor or for a variety of other targets.[33]
By antagonizing the serotonin 5-HT2C receptor, agomelatine has been found to disinhibit and increase norepinephrine and dopamine release in the frontal cortex in animals, although notably not in the striatum or nucleus accumbens.[33][36][34] In contrast to agomelatine, other serotonin 5-HT2C receptor antagonists and inverse agonists, such as SB-242084 and SB-206553, have been found to increase dopamine and norepinephrine levels in the nucleus accumbens.[37] These differences may in part be related to constitutive activity of the serotonin 5-HT2C receptor and resulting differences between neutral antagonists and inverse agonists of the receptor.[38][39] In addition, there are multiple isoforms of the serotonin 5-HT2C receptor with different properties.
Although agomelatine is widely claimed to act as a serotonin 5-HT2C receptor antagonist, the clinical significance of this action has been disputed.[42] Unlike with other serotonin 5-HT2C receptor antagonists, therapeutic doses of agomelatine fail to acutely increase slow-wave sleep in humans.[43][44] Additionally, no receptor occupancy studies of agomelatine have been conducted in humans to demonstrate significant occupancy of serotonin 5-HT2C receptors at therapeutic doses.[43]
Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, behavioral despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. Agomelatine has been found to resynchronize circadian rhythms in animal models of delayed sleep phase syndrome (DSPS).[45] In humans, agomelatine has positive phase-shifting properties; it induces a phase advance of sleep, body temperature decline, and melatonin onset.[10]
In depressed patients, treatment with the drug increases slow-wave sleep without modification of REM (rapid eye movement) sleep amount or REM latency.[46] From the first week of treatment, onset of sleep and the quality of sleep significantly improved without daytime clumsiness as assessed by patients.[2][10]
