138112-76-2

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Description

Agomelatine is an agonist of melatonin (MT) receptors and a derivative of melatonin . 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). 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.

Chemical Properties

White Solid

Definition

ChEBI: Agomelatine is a member of acetamides.

Synthesis Reference(s)

[1]A Comprehensive Review on New Emerging Antidepressant Agomelatine from Synthesis to Analysis
[2]Yu, Z., Cheng, Z., Xie, C., Zeng, S., Deng, H., Liu, P., Hu, H., Li, G., Ding, L., Gauthier, M., & Li, S. (2019). Synthesis of Agomelatine by One-pot Catalytic Hydrogenation and Acetylation with NiO. Journal of Wuhan University of Technology-Mater. Sci. Ed., 34(2), 453–458. https://doi.org/10.1007/s11595-019-2073-3
[3]Vujjini, S. K., Vyala, S., Badarla, K. R., Kandala, S. C., Bandichhor, R., Kagga, M., & Cherukupalli, P. (2015). Simple and Efficient Process for the Large-Scale Preparation of Agomelatine: An Antidepressant Drug. Synthetic Communications, 45(16), 1864–1870. https://doi.org/10.1080/00397911.2015.1050524

Biochem/physiol Actions

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.

Mechanism of action

Agomelatine is both a potent agonist of the melatonin MT₁ and MT₂ receptors and a neutral antagonist of the 5-HT₂C receptor. The core of its mechanism of action as an antidepressant lies in the dual synergistic interaction between melatonin receptor (MT₁/MT₂) agonism and 5-HT₂C receptor neutral antagonism. It also integrates circadian reset, promotion of neuroplasticity, regulation of glutamate homeostasis, and anti-inflammatory effects. In terms of regulating circadian rhythms, agomelatine, as a melatonin receptor agonist, acts directly on the suprachiasmatic nucleus (SCN)—the body’s master clock—to produce a phase-advancing effect, thereby restoring disrupted circadian rhythms (such as the sleep-wake cycle and core body temperature rhythms). This is a key feature that distinguishes it from other antidepressants[2].

Clinical Use

Antidepressant

Synthesis

Agomelatine can be prepared starting from (7-methoxynaphth-1-yl)acetic acid, or synthesized from 8-amino-2-naphthol via diazotization-iodination, formylation, nitro-aldol C-C bond formation, and Pd/C hydrogenation[2]. Agomelatine is prepared in a linear manner from 2-naphthol via Friedel-Crafts acylation of 2-naphthyl acetate with chloroacetyl chloride, reduction of the keto intermediate, and nucleophilic displacement of the chloro intermediate with sodium diformylamide[3]. Agomelatine synthesis begins with 7-methoxy-1-tetralone via oxidation to 7-methoxy-1-naphthaldehyde, condensation with acetonitrile, hydrogenation, and final acylation with acetic anhydride[1].

target

TNF-α | IL Receptor | P450 (e.g. CYP17) | 5-HT Receptor

Drug interactions

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.

Metabolism

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.

References

[1] zupancic m, guilleminault c. agomelatine. cns drugs, 2006, 20(12): 981-992.

Questions And Answer

• Antidepressants

  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.;

• Pharmacological effects

  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.;

• Health risk

  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.;

• Patent cases

  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.;

• Uses

  Melatonin drugs.;

Spectrum Detail

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