Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors.

S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPA-PAM). S 47445 enhanced glutamate's action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants) (EC50 between 2.5-5.4 µM), except a higher EC50 value for GluA4 flop (0.7 µM) and a greater amount of potentiation on GluA1 flop. A low concentration of S 47445 (0.1 µM) decreased receptor response decay time of GluA1flop/GluA2flip AMPA receptors and increased the sensitivity to glutamate. Furthermore, S 47445 (0.1 and 0.3 µM) in presence of repetitive glutamate pulses induced a progressive potentiation of the glutamate-evoked currents from the second pulse of glutamate confirming a rapid-enhancing effect of S 47445 at low concentrations. The potentiating effect of S 47445 (1 µM) was concentration-dependently reversed by the selective AMPA receptor antagonist GYKI52466 demonstrating the selective modulatory effect of S 47445 on AMPA receptors. Using an AMPA-kainate chimera approach, it was confirmed that S 47445 binds to the common binding pocket of AMPA-PAMs. S 47445 did not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro, in contrast significantly protected rat cortical neurons at 10 µM. S 47445 was shown to improve both episodic and spatial working memory in adult rodents at 0.3 mg/kg, as measured in the natural forgetting condition of object recognition and T-maze tasks. Finally, no deleterious effect on spontaneous locomotion and general behavior was observed up to 1000 mg/kg of S 47445 given acutely in rodents, neither occurrence of convulsion or tremors. Collectively, these results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties. This drug is currently evaluated in clinical phase 2 studies in Alzheimer's disease and in Major Depressive Disorder.

Agomelatine affects rat suprachiasmatic nucleus neurons via melatonin and serotonin receptors.

AIMS: The hypothalamic suprachiasmatic nucleus (SCN), which functions as a circadian pacemaker in mammals, is influenced by melatonin and serotonin. Agomelatine, which acts as an antidepressant and can synchronize disturbed circadian rhythms, displays a unique mechanism of action involving both melatonergic agonist and 5-HT2C antagonist properties. This study investigated the dose-dependent effects of agomelatine, melatonin and a selective 5-HT2C receptor antagonist, S32006, on SCN neurons in an in vitro slice preparation. MAIN METHODS: Brain slices containing the SCN were prepared from male Wistar rats and maintained in a recording chamber. Changes in firing rates of SCN neurons were recorded after perfusion of drugs. KEY FINDINGS: SCN firing rates were dose-dependently suppressed by 19.2-80.9% following perfusion of 0.04-0.32mM agomelatine (p<0.001, IC50=0.14mM). Perfusion with melatonin (0.4-3.2mM) resulted in 16.6-62.5% dose-dependent reductions in firing rates (at least p<0.01, IC50=1.59mM) and of the duration of suppression. A selective melatonin receptor antagonist (S22153 at 0.32mM) and a 5-HT2c receptor agonist (Ro60-0175) reduced the suppressive effects of 0.16mM agomelatine by 35% and 50.2%, respectively. A 5-HT2C receptor antagonist (S32006; 0.03-0.12mM) significantly decreased SCN firing rates (19.6-91.8%; at least p<0.05, IC50=0.05mM). Co-perfusion of S32006 (0.06mM) with a 5-HT2C agonist (Ro60-0175; 0.003mM) reduced suppressions evoked by S32006 alone by ~72.1%. SIGNIFICANCE: These results are consistent with the hypothesis that agomelatine acts directly on the SCN via both agonist effects at melatonergic receptors and antagonist effects at 5-HT2C receptors, which parallel its mechanisms of action as an antidepressant.

Evaluation of the effects of therapeutic and supratherapeutic doses of agomelatine on the QT/QTc interval: a phase I, randomized, double-blind, placebo-controlled and positive-controlled, crossover thorough QT/QTc study conducted in healthy volunteers.

: The effects of the antidepressant agomelatine up to a supratherapeutic dose (400 mg, single dose) on the QT corrected (QTc) interval were assessed in a randomized, double-blind, placebo- and positive-controlled, crossover thorough QT/QTc study in young healthy volunteers (29 males and 31 females). The primary criterion was the study of male or female population-derived QT-corrected interval (QTcP). The main analysis on the QTcP demonstrated that among the 10 postdose measurement times planned, the largest 1-sided 95% confidence interval upper bound of the difference between agomelatine 50 mg and placebo-adjusted means, and 1 of the differences between agomelatine 400 mg and placebo-adjusted means were both strictly inferior to the 10 millisecond upper-bound threshold of regulatory concern. The assay sensitivity was established with the positive control moxifloxacin (400 mg) and detected an effect on the mean QTcP interval that is around the threshold of regulatory concern (5 milliseconds). No relationship between QTcP and plasma concentrations of agomelatine was observed. In conclusion, agomelatine up to 400 mg has no effect on the QTc interval as demonstrated in the present regulatory thorough QT/QTc study.

Like melatonin, agomelatine (S20098) increases the amplitude of oscillations of two clock outputs: melatonin and temperature rhythms.

Depression and biological rhythms disturbances are strongly associated. Agomelatine is an antidepressant with melatoninergic MT1-MT2 agonist and serotoninergic 5-HT2c antagonist properties. Both melatonin and 5-HT are known to modulate circadian rhythmicity controlled by the endogenous clock located in the suprachiasmatic nuclei (SCN). The aim of the present study was to compare the effect of an acute injection of agomelatine (Ago), melatonin (MLT) or an antagonist 5-HT2c (S32006), on the rhythms of two robust clock outputs: the pineal MLT secretion and the body temperature rhythm (Tc). Daily endogenous MLT profiles were measured using transpineal microdialysis over 4 consecutive days in rats maintained on a 12 h light/12 h dark cycle. Simultaneously, Tc was recorded. The drugs were injected subcutaneously at three doses (1, 2.5 or 5 mg/kg) at the onset of darkness. Both Ago and MLT, at the dose of 2.5 mg/kg, increased the amplitude of the peak of MLT secretion and this effect was observed 2 d after injection. Moreover, both drugs induced a dose-dependent advance of the rhythm onset which resulted in lengthening of the MLT peak. S32006 had no effect on the rhythm of MLT. Ago, MLT and S32006 increased the amplitude of the rhythm of Tc. These data suggest a central action of Ago, directly on the SCN, via melatoninergic receptors responsible for both the increased amplitude of MLT rhythm and the phase advance. The increase in the amplitude of the body temperature could involve both MLT agonist and/or 5-HT2c antagonist properties of Ago.

Memory facilitating effects of agomelatine in the novel object recognition memory paradigm in the rat.

The aim of the present study was to evaluate the effects of agomelatine, an antidepressant with melatonergic agonist and 5-HT(2C) antagonist properties, in the rat novel object recognition (NOR) task, a model of short-term episodic memory. To assess the potential involvement of its chronobiotic activity, single intraperitoneal administration of agomelatine and NOR testing were performed either in the evening or in the morning. In both conditions, using a 24h retention interval, vehicle-treated rats did not discriminate between the novel and the familiar object (recognition index was not different from chance performance) while object memory performance of rats treated with agomelatine either in the evening (10 and 40mg/kg) or in the morning (2.5, 10, and 40mg/kg) was significantly improved. Moreover, the selective 5-HT(2C) antagonist SB 242,084 (0.63, 2.5, and 10mg/kg) and melatonin (2.5, 10, and 40mg/kg) displayed also memory facilitating effects in both administration conditions. Finally, thioperamide used as positive reference compound to validate the experimental conditions, demonstrated a memory facilitating effect. In conclusion, agomelatine was shown to possess memory facilitating effects in the rat NOR task and both melatonergic agonist and 5-HT(2C) antagonist properties could be involved in these effects.

Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress.

The antidepressant agomelatine is a MT(1)/MT(2) receptor agonist and 5-HT(2C) antagonist. Its antidepressant activity is proposed to result from the synergy between these sets of receptors. Agomelatine-induced changes in the brain have been reported under basal conditions. Yet, little is known about its effects in the brain exposed to chronic stress as a risk factor for major depressive disorder. Recently, we described agomelatine-induced changes on neuronal activity and adult neurogenesis in the hippocampus of rats subjected to chronic footshock stress. In order to better characterize the actions of agomelatine in the stress-compromised brain, here we investigated its effects on hippocampal neurogenesis in the chronic mild stress (CMS) model. Adult male rats were subjected to various mild stressors for 5 weeks, and treated with agomelatine during the last 3 weeks of the stress period. The sucrose preference test was performed weekly to measure anhedonia, and the marble burying test was carried out at the end of the experiment to assess anxiety-like behavior. In our model, the CMS paradigm did not change sucrose preference; however, it increased marble burying behavior, indicating enhanced anxiety. Interestingly, this stress model differentially affected distinct stages of the neurogenesis process. Whereas CMS did not influence the rate of hippocampal cell proliferation, it significantly decreased the newborn cell survival and doublecortin expression in the dentate gyrus. Importantly, treatment with agomelatine completely normalized stress-affected cell survival and partly reversed reduced doublecortin expression. Taken together, these data show that agomelatine has beneficial effects on hippocampal neurogenesis in the CMS paradigm.