Disease relevance of Agomelatine

• Uveal melanoma cells and melanocytes were cultured for 24 hr, then melatonin or one of its membrane receptor agonists, 6-chloromelatonin (Mel1a-1b) or S-20098 (Mel1b) or its putative nuclear agonist, CGP-52608 (Mel2), was added to the medium [1].
• Due to its pharmacological profile, agomelatine does not induce the side-effects typical of other therapies, such as selective serotonin reuptake inhibitors (i.e. gastrointestinal disorders, weight gain, serotonergic syndrome and insomnia) [2].
• Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome (DSPS) [3].
• These findings indicate that exogenous melatonin and S-20098 exert a selective regulatory action on sleep fragmentation during experimental trypanosomiasis [4].
• The RNA expression levels of human catalytic subunit (TERT) and the RNA subunit (TR) of telomerase were analysed after treatment with the agonists of the membrane receptor (S 20098) and the nuclear receptor (CGP 52608) for melatonin in the MCF-7 human breast tumor cell line [5].

Psychiatry related information on Agomelatine

• Agomelatine in the treatment of seasonal affective disorder [6].
• Furthermore, the selective melatonin antagonist, S22153, did not modify anxiolytic properties of agomelatine in either the social interaction or the Vogel Conflict tests [7].
• Chronobiology has provided efficacious non-pharmaceutical treatments for mood disorders (such as sleep deprivation or light therapy) as well as novel approaches to new drugs (e.g. agomelatine) [8].
• Major depressive disorders: clinical efficacy and tolerability of agomelatine, a new melatonergic agonist [9].
• In both species, the phase advance portion of the PRC to S-20098 is limited to a 3 h window preceding the onset of locomotor activity, but the magnitude of phase shifts is larger in mice [10].

High impact information on Agomelatine

• Here, we determined the effects of agomelatine (S-20098), a new antidepressant, on various phases of neurogenesis in the dentate gyrus of adult rat [11].
• RESULTS: Chronic (3 weeks) but not acute (4 hours) or subchronic (1 week) administration of agomelatine increased cell proliferation and neurogenesis in the ventral dentate gyrus, a region notably implicated in response to emotion, which is consistent with the antidepressant-anxiolytic properties of the drug [11].
• In contrast, the agonist of the Mel(1b) receptor, S-20098 (Servier, Paris, France), produced singlet oxygen with a quantum efficiency of psidelta = 0.34 [12].
• In contrast to the reference compounds, melatonin, agomelatine (S 20098), and N-[2-(2, 7-dimethoxynaphth-1-yl)ethyl]acetamide, which were very potent at lightening the skin of X. laevis tadpoles, compounds 4a-c were inactive or weakly active (EC50 > 1 microM) [13].
• Previous studies showed that agomelatine is able to restore disrupted circadian rhythms, which were implicated in the pathophysiology of seasonal affective disorder (SAD) [6].

Biological context of Agomelatine

• Finally, neither S 21517 nor S 21540 seemed to participate to the observed inhibition of penile erections by agomelatine [14].
• Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men [15].
• Plasma protein binding of S 20098 ranged from 75 to 95% [16].
• Melatonin and S-20098 increase REM sleep and wake-up propensity without modifying NREM sleep homeostasis [17].

Anatomical context of Agomelatine

• Extending agomelatine treatment over several weeks, however, increases survival of newly formed neurons in the entire dentate gyrus [11].
• Neither acute nor chronic treatment with agomelatine (10 mg/kg i.p. for 14 days or 50 mg/kg i.p. for 21 days) changed the density of 5-HT(1A) receptors and their coupling with G proteins in the DRN and the hippocampus in rats [18].
• Because functional desensitization of 5-HT(1A) autoreceptors in the dorsal raphe nucleus (DRN) occurs after chronic administration of several classes of antidepressants, we investigated whether this adaptive change could also be induced by agomelatine [18].
• Extracellular levels of noradrenaline in frontal cortex were also dose dependently enhanced by agomelatine in parallel with an acceleration in the firing rate of adrenergic cell bodies in the locus coeruleus [19].
• Furthermore, agomelatine dose dependently enhanced dialysis levels of dopamine in frontal cortex of freely moving rats, whereas they were unaffected in nucleus accumbens and striatum [19].

Associations of Agomelatine with other chemical compounds

• Differential effects of the novel antidepressant agomelatine (S 20098) versus fluoxetine on 5-HT1A receptors in the rat brain [18].
• Whereas clorazepate reduced dialysate levels of 5-HT and noradrenaline in hippocampus and frontal cortex of freely moving rats, agomelatine did not affect extracellular levels of 5-HT and elevated those of noradrenaline [7].
• However, six agonists showed 10 to 60 fold higher affinity for the Mel1b melatonin receptor as indicated by the affinity selectivity ratios (Mel1a/Mel1b) [8-methoxy-2-acetamidotetraline (11); S20098 (14); 8-methoxy-2-propionamidotetraline (20); 6, 7 di-chloro-2-methylmelatonin (21); 6-chloromelatonin (57); 6-methoxymelatonin (59)] [20].
• A double-blind, placebo-controlled trial investigating the effect of abrupt cessation of treatment demonstrated the absence of discontinuation symptoms with agomelatine, which was in contrast with the results observed with paroxetine [2].

Gene context of Agomelatine

• On the contrary, we observed a significant decreased in the RNA levels of TERT after treatment with CGP 52608 while S 20098 produced a significant increase in the RNA levels of TERT [5].
• The effects of agomelatine were assessed in transgenic mice with low glucocorticoid receptor (GR) function, after acute stress or induced phase shift, and compared to desipramine and melatonin [21].
• In conclusion, in contrast to melatonin, agomelatine behaves as an antagonist at 5-HT2B and 5-HT2C receptors: blockade of the latter reinforces frontocortical adrenergic and dopaminergic transmission [19].
• OBJECTIVES: This study was conducted to investigate the effects of two MT(1/2)-R agonists, melatonin and agomelatine, and a NK1-R antagonist, GR205171, on tolerance to delay of food reward in rats [22].
• Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade [7].

Analytical, diagnostic and therapeutic context of Agomelatine

• SUBJECTS AND DESIGN: Eight healthy elderly men participated in a double-blind, two-period, cross-over study of 15 days of daily administration of either agomelatine (50 mg) or placebo at 1830 h [15].
• Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety [23].
• The present study determined first the dose-response (0.5 to 10 mg.kg-1) to daily oral administration of S-20098, a melatonin agonist, in entraining circadian rhythms of rats free-running in constant darkness; second, the relation between entrainment and the plasma concentration of S-20098 [24].

References