Agomelatine, which is developed by the French Servier company, is the world's first melatonin receptors MT1 and MT2 agonist class of antidepressants. It applies to the treatment of adult patients with severe depressive. We know that melatonin is an endogenous neural hormones. It is only produced by the pineal gland anterior pituitary at night, and acts on the melatonin receptor that focuses on the presence of hypothalamic suprachiasmatic nucleus (SCN). It is involved in mediating the circadian rhythms in mammals. It is the well-known time guardian in the body, which can regulate the biological clock that is modulated by external circadian cycle. However, since that melatonin has high catabolism rate in vivo which mikes its half-life shorter and the selectivity of its receptor located in the SCN poorer, the treatment of circadian rhythms disorders is limited. Therefore, in order to overcome these drawbacks of melatonin, the researchers designed a series of melatonin analogues. Molecular modeling studies have shown that indole ring of melatonin is the structure sites of catabolic inactivation. Indole ring is an ideal site of isosteric modifications. Agomelatine developed by Servier company is melatonin’s naphthalene biological (electronic) isostere analogs. Indole ring is substituted by naphthalene nucleus, which leads it have more metabolic stability than melatonin.
The listing of agomelatine is a new breakthrough in the field of the treatment of depression. It is melatonin MT1/MT2 receptor agonist and serotonin 2c (5-HT2C) receptor antagonist. It can make depressed patients’ biological rhythm disorders return to normal through the synergy between the two and then result in antidepressant efficacy. Its unique mechanism of action has opened up an innovative way to treat depression. Agomelatine’s mechanism of drug action is completely different with antidepressants that are commonly used today, such as selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI). SSRI and SNRI antidepressants achieve antidepressant efficacy by increasing concentration of serotonin. But it also brings a lot of side effects, such as weight changes, sexual dysfunction, withdrawal syndrome and the like. The molecular structure of agomelatine directly combines with serotonin 2c (5HT2c) receptor of post-synaptic membrane so as to exert its antidepressant efficacy without increasing serotonin concentration in the synaptic cleft. This unique mechanism of action makes agomelatine quickly and effectively exert its antidepressant efficacy at the same time, and avoid the occurrence of adverse drug reactions to an extreme.
Another unique targets of agomelatine is in melatonin receptors. MT1 and MT2 receptors densely distribute in the human suprachiasmatic nucleus. The nucleus mainly control human sleep rhythm. Agomelatine can well improve the quality of patients’ sleep by agonism on MT1 MT2 receptors, and improve patients’ wakefulness during the day. The quality of sleep has both cause and effect relationship with depression outcomes state. It is reported that 80% of patients with depression have the problems of sleep disorders at different levels. The improvement of sleep quality can directly contribute to the improvement of the overall clinical condition of patients with depression.
The above information is edited by the Chemicalbook of Ge Qian.
October 30, 2012, the British Medicines and Healthcare Products Agency (MHRA) released agomelatine (agomelatine, Valdoxan/Thymanax) security information. MHRA found that several cases appears serious reports of liver toxicity with agomelatine, including six cases of liver failure patients within worldwide report. Agomelatine's drug information already includes in the recommendations that all patients need liver function tests at the start of treatment and during treatment. Now liver function tests should also be recommended when the drug dose is increased. MHRA recommends that if the patients have potential liver damage symptoms or signs, or that the increases of serum transaminase beyond the upper limit of normal (ULN) three times is found in the function tests, it should be immediately suspended.
The earliest agomelatine compound patent is French Patent FR902393, which is applied in February 27, 1990. This patent has the same patent family in Europe, USA, Canada, Japan and Australia. But there is no Chinese patent. The above patents were all authorized after January 1, 1993. Therefore China is also ineligible for administrative protection. Agomelatine has both technology patent and polymorph patent in China. But it also can be avoided.
Agomelatine is an agonist of melatonin (MT) receptors and a derivative of melatonin . 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). 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. It also increases the rate of readjustment to circadian activity cycles following an induced phase shift.
Agomelatine is a melatoninergic agonist and selective antagonist of 5-HT2C receptors, and has been shown to be active in several animal models of depression. Agomelatine (S20098) displayed pKi values
of 6.4 and 6.2 at native (porcine) and cloned, human (h)5-hydroxytryptamine (5-HT)2C receptors, respectively.
Agomelatine has been used:
- to study its effects on adult neurogenesis and hippocampus apoptosis using the stress-induced depression model of rats
- to explore its effects on tau protein phosphorylation and to study its neuroprotective mechanism
- to study its effects on intracellular calcium ([Ca2+]i) signaling in peripheral neurons of rat dorsal root ganglion (DRG) neurons
Agomelatine is an antidepressant drug. It is classified as a norepinephrine-dopamine disinhibitor (NDDI) due to its antagonism of the 5-HT2C receptor. Activation of 5-HT2C receptors by serotonin inhibits dopamine and norepinephrine release. Antagonism of
ChEBI: Agomelatine is a member of acetamides.
Agomelatine is an extremely potent agonist at both melatonin receptors (MT1 and MT2), with additional antagonism at 5HT2C. It is a novel antidepressant with many desired in vivo properties, including neuroprotection and neurogenesis in depression-sensitive brain areas. Agomelatine′s efficacy appears to be due to both melatonergic and serotonergic properties. In neurogenesis assays, both in vitro and in vivo, the compound effects were differentially affected by antagonists for MT1/MT2 and 5HT2C, demonstrating actions through all three receptors.
TNF-α | IL Receptor | P450 (e.g. CYP17) | 5-HT Receptor
Potentially hazardous interactions with other drugs
Antibacterials: avoid with ciprofloxacin.
Antidepressants: metabolism inhibited by
fluvoxamine.
Antimalarials: avoid with artemether with
lumefantrine and artenimol with piperaquine.
Agomelatine is rapidly metabolised, mainly by the hepatic
cytochrome P450 isoenzyme CYP1A2; the isoenzymes
CYP2C9 and CYP2C19 also make a minor contribution.
The major metabolites, hydroxylated and demethylated
agomelatine, are not active and are rapidly conjugated and
eliminated in the urine.
[1] zupancic m, guilleminault c. agomelatine. cns drugs, 2006, 20(12): 981-992.
