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

Agomelatine (S20098) displayed pK_i 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-HT_2B receptors (6.6), whereas it showed low affinity at native (rat)/cloned, human 5-HT_2A (<5.0/5.3) and 5-HT_1A (<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-HT_2C receptor-mediated activation of Gq/11 and Gi₃ (pA₂ values of 6.0 and 6.1). As measured by [³H]phosphatidylinositol depletion, agomelatine abolished activation of phospholipase C by h5-HT_2C (pK_B value of 6.1) and h5-HT_2B (pK_B value of 6.6) receptors. In vivo, it dose dependently blocked induction of penile erections by the 5-HT_2C agonists (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine (Ro60,0175) and 1-methyl-2-(5,8,8-trimethyl-8H-3-aza-cyclopenta[a]inden-3-yl) ethylamine (Ro60,0332). 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. Although the electrical activity of ventrotegmental dopaminergic neurons was unaffected agomelatine, it abolished their inhibition by Ro60,0175. 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. These increases in noradrenaline and dopamine levels were unaffected by the selective melatonin antagonist N-[2-(5-ethyl-benzo[b]thien-3-yl)ethyl] acetamide (S22153) and likely flect blockade of 5-HT_2C receptors inhibitory to frontocortical dopaminergic and adrenergic pathways. Correspondingly, distinction to agomelatine, melatonin showed negligible activity 5-HT_2C receptors and failed to modify the activity of adrenergic and dopaminergic pathways. In conclusion, in contrast to melatonin, agomelatine behaves as an antagonist at 5-HT_2B and 5-HT_2C receptors: blockade of the latter reinforces frontocortical adrenergic and dopaminergic transmission.