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

@article{Millan2003TheNM,
  title={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},
  author={Mark J Millan and Alain P. Gobert and Françoise Lejeune and Anne Dekeyne and Adrian Newman-Tancredi and Valérie Pasteau and Jean Michel Rivet and Didier Cussac},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2003},
  volume={306},
  pages={954 - 964}
}
  • M. Millan, A. Gobert, D. Cussac
  • Published 1 September 2003
  • Biology, Chemistry
  • Journal of Pharmacology and Experimental Therapeutics
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. It also interacted with h5-HT2B receptors (6.6), whereas it showed low affinity at native (rat)/cloned, human 5-HT2A (<5.0/5.3) and 5-HT1A (<5.0/5.2) receptors, and negligible (<5.0) affinity for other 5-HT receptors. In antibody capture/scintillation proximity assays, agomelatine concentration dependently and competitively abolished h5-HT2C… 

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References

SHOWING 1-10 OF 76 REFERENCES
5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential.
TLDR
The results suggest that 5-HT2C receptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression.
5-HT2C receptors mediate penile erections in rats: actions of novel and selective agonists and antagonists.
5-HT 2C Receptor Agonists: Pharmacological Characteristics and Therapeutic Potential
TLDR
The results suggest that 5-HT2C receptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression.
Serotonin 5-HT2c agonists mimic the effect of light pulses on circadian rhythms
Melatonin agonists modulate 5-HT2A receptor-mediated neurotransmission: behavioral and biochemical studies in the rat.
TLDR
The present data support an interaction between melatonin and 5-HT2A receptors in the central nervous system and in vitro incubation of cortical slices with melatonin agonists robustly inhibited 5- HT2A receptor-mediated PI hydrolysis in a noncompetitive manner.
Differential activation of Gq/11 and Gi(3) proteins at 5-hydroxytryptamine(2C) receptors revealed by antibody capture assays: influence of receptor reserve and relationship to agonist-directed trafficking.
TLDR
H5-HT(2C) receptors couple to both Gq/11 and Gi(3) in CHO cells, and efficacy for G protein subtype activation is both ligand- and receptor reserve-dependent, as determined by a guanosine 5'-O-(3-[(35)S]GTPgammaS]thio)triphosphate binding assay.
Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study
TLDR
It is demonstrated that agomelatine is efficient in the treatment of major depressive disorder and that 25 mg is the target dose.
Characterization of phospholipase C activity at h5-HT2C compared with h5-HT2B receptors: influence of novel ligands upon membrane-bound levels of [3H]phosphatidylinositols
TLDR
This rapid and innovative method for determination of PLC activity permitted characterization of an extensive range of novel ligands at h5-HT2C receptors, including Ro600332, Ro600175 and BW723C86, which showed "full" efficacy at h3HPI sites and antagonist potency and binding affinity were highly correlated.
...
1
2
3
4
5
...