The chronobiotic
neurohormone melatonin, synthetized in the pineal gland during darkness periods governs the circadian and seasonal biological rhythms. Physiologically,
melatonin regulates the sleep/activity alternance, together with the circadian cycle of body temperature and
cortisol secretion, and influences various immune, endocrine and metabolic functions. Dysfunction of the endogenous
melatonin secretion is associated with mood and behavioral disorders including
body weight. Patients with severe depression exhibit desynchronized and reduced
melatonin secretion, in parallel with marked sleep disturbances whereas exogenous
melatonin administration and antidepressive drugs restore
melatonin secretion. A dysregulated
melatonin secretion is also observed in obese subjects. Implication of
melatonin in these disorders stimulated the search for
melatonin analogues with enhanced antidepressive and
body weight control effects. The melatoninergic agonist
S 20098, or agomelatin, disclosed a potent antidepressive and
anxiolytic activity in preclinical studies, which was confirmed in clinical trials in patients with major depression. The antagonist
S 20928 was shown to limit seasonal
weight gain in an hibernating rodent model. Thus, development of melatoninergic agonists and antagonists appear as an innovative approach in the treatment of depression and
obesity, two major public health problems.