Melatonin and Melatoninergic Drugs as Therapeutic Agents: Ramelteon and Agomelatine, the Two Most Promising Melatonin Receptor Agonists

Emilio J. Sanchez-Barcelo; Carlos M. Martinez-Campa; Maria D. Mediavilla; Alicia Gonzalez; Carolina Alonso-Gonzalez; Samuel Cos

Abstract

Melatonin is a pineal hormone which basically acts through membrane receptors, but also as a free radical scavenger (requiring no receptors), and by binding to intracellular sites (calmodulin and nuclear receptors). Membrane receptors (MT1, MT2) are associated to G-proteins linked to inhibition of adenylyl cyclase and decrease of cAMP, and are expressed by almost all structures of the CNS (especially hypothalamic suprachiasmatic nucleus and pars tuberalis of the pituitary), as well as in peripheral tissues (gastrointestinal tract, thymus, smooth muscle of blood vessels, adipocytes, lymphocytes, etc). Among the actions attributed to melatonin are those of antioxidant, controller of circadian rhythms (especially sleep-wake and core body temperature), immunomodulation, antidepressant, etc. This wide spectrum of actions suggests many possible therapeutic applications for melatonin. However, its use as a drug presents some limitations (to optimise pharmacological responses of each subtype or receptors, its rapid metabolic inactivation, etc.) that have caused many laboratories to develop analogues without the above mentioned problems. Two are the patented melatoninergic drugs with more interesting properties: one is ramelteon (US6034239; Rozerem™), approved by the FDA for the long-term treatment of sleep disturbances characterized by difficulty with sleep onset; the second, agomelatine (US5318994; Valdoxan™), which is completing the phase III trial, was designed for the treatment of symptoms of major depressive disorders, particularly anxiety, sleep troubles and circadian disturbances.

Keywords: Melatonin, agomelatine, valdoxan, ramelteon, rozerem, sleep troubles, depression, MT1 melatonin receptors, MT2 melatonin receptors