A melatonin receptor agonist and 5-HT2B and 5-HT2C antagonist
Agomelatine is an agonist of melatonin (MT) receptors and a derivative of melatonin .1 It binds to MT1 and MT2 receptors (Kis = 0.14 and 0.41 nM, respectively) and has an EC50 value of 0.1 nM in a [35S]GTPγS binding assay using CHO cells expressing MT2 receptors. Agomelatine is also an antagonist of the serotonin (5-HT) receptor subtypes 5-HT2B and 5-HT2C (Kis = 0.26 and 0.71 nM, respectively, for the human receptors).2 Agomelatine (40 mg/kg) inhibits the penile erection response induced by the 5-HT2 agonist Ro 60-0175 in rats. It also increases extracellular levels of noradrenaline and dopamine in the frontal cortex of freely moving rats when administered at doses ranging from 20 to 80 mg/kg. Agomelatine (10 mg/kg) reduces immobility time in the forced swim test and increases the amount of time spent in the open arms of the elevated plus maze in mice, indicating antidepressant-like and anxiolytic-like activity, in a transgenic neuroendocrine model of depression.3 It also increases the rate of readjustment to circadian activity cycles following an induced phase shift.
1.Poissonnier-Durieux, S., Ettaoussi, M., Pérès, B., et al.Synthesis of 3-phenylnaphthalenic derivatives as new selective MT2 melatoninergic ligandsBioorg. Med. Chem.16(18)8339-8348(2008) 2.Millan, M.J., Gobert, A., Lejeune, F., et al.The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathwaysJ. Pharmacol. Exp. Ther.306(3)954-964(2003) 3.Barden, N., Shink, E., Labbé, M., et al.Antidepressant action of agomelatine (S 20098) in a transgenic mouse modelProg. Neuropsychopharmacol. Biol. Psychiatry29(6)908-916(2005)
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