DRUG REPOSITIONING: Revisiting the basic psychopharmacological mechanism of action for agomelatine and where it should be classified?

Abstract

Concerning Agomelatine, as of this present moment and deeply analyzing things from the psychopharmacological point of view, the utmost important question yet to be answered is “why should the drug Agomelatine be regarded as an antidepressant agent when it did not actually possess the necessary pharmacoactivities and mechanism of actions that adequately qualified it to be classified under the family of antidepressants as done in previously published reference literatures?” The mystery, approach, and rationale behind this act of classification phenomenon were actually and inevitably putting a square peg inside a round hole, which is scientifically deemed unfit and inappropriate. This act of classification phenomenon makes Agomelatine to be referred to as a paradoxical agent that contradicts itself. Agomelatine is a melatonergic MT1 and MT2 receptors agonist and a selective serotonergic 5-HT2B and 5-HT2C receptors antagonist (MASSA). The 5-HT2B receptors are poorly represented in the central nervous system (CNS) in contrast to the 5-HT2C receptors. Its prochronobiological activity resynchronizes circadian rhythms in experimental animal models of delayed sleep phase syndrome via its melatonergic MT1 and MT2 receptors agonistic effect. By antagonizing 5-HT2C receptors, Agomelatine disinhibits/increases norepinephrine and dopamine release specifically in the neocortical areas such as the prefrontal cortex but neither in the subcortical areas such as the striatum nor nucleus accumbens; therefore, it is sometimes referred to as a norepinephrine–dopamine disinhibitor (NDD). Furthermore, by antagonizing 5-HT2C receptors in the subcortical areas such as basal ganglia, mesolimbic cortex and hippocampus; Agomelatine produces anxiolytic effect clinically. Because Agomelatine lacks inhibitory pharmacoactivity at the monoaminergic reuptake transporter pumps (SERT, NET, and DAT), does not inhibit the enzyme monoamine oxidase, has neither weak antagonist nor partial agonist activity at the dopaminergic D2 receptor, and also lacks antagonistic activity at both the noradrenergic α2-receptor and N- methyl-D-aspartic acid (NMDA)-glutamatergic ionoceptor, it should not be regarded and accepted as an antidepressant but rather it should be classified as an anxiolytic sedative agent on account of its melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2C receptor antagonistic (MASSA) properties.

Keywords

• Agomelatine
• antidepressant
• anxiolytic-sedative
• classification
• drug repositioning
• mechanism of action
• paradoxical agent