Agomelatine

Agomelatine is an agonist of melatonin (MT) receptors and a derivative of melatonin (Item No. 14427).¹ It binds to MT₁ and MT₂ receptors (K_is = 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-HT_2B and 5-HT_2C (K_is = 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 (Item No. 29500) 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.

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1. Poissonnier-Durieux, S., Ettaoussi, M., Pérès, B., et al. Synthesis of 3-phenylnaphthalenic derivatives as new selective MT2 melatoninergic ligands. Bioorg. 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 pathways. J. 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 model. Prog. Neuropsychopharmacol. Biol. Psychiatry 29(6), 908-916 (2005).

Leis, H.J., and Windischhofer, W. Phospholipase D₁ activity is crucial for cytosolic phospholipase A₂ -dependent prostaglandin E₂ formation in murine osteoblastic MC3T3-E₁ cells. Prostaglandins Leukot. Essent. Fatty Acids 198-199, 102592 (2023).