Melatonin is a
neurohormone that is believed to be involved in a wide range of physiological functions. In humans, appropriate clinical trials confirm the efficacy of
melatonin or melatoninergic agonists for the MT1 and
MT2 receptor subtypes in
circadian rhythm sleep disorders only. Nevertheless, preclinical animal model studies relevant to human pathologies involving validated reference compounds lead to other therapeutic possibilities. Among these is a recently developed treatment concept for depression, which has been validated by the clinical efficacy of
agomelatine, an agent having both MT1 and MT2 agonist and
5-HT2C antagonist activity. A third
melatonin binding site has been purified and characterized as the
enzyme quinone reductase 2 (QR2). The physiological role of this
enzyme is not yet known. Recent results obtained by different groups suggest: (1) that inhibition of QR2 may lead to "protective" effects and (2) that over-expression of this
enzyme may have deleterious effects. The inhibitory effect of
melatonin on QR2 observed in vitro may explain the protective effects reported for
melatonin in different animal models, such as cardiac or renal
ischemia-effects that have been attributed to the controversial
antioxidant properties of the
hormone. The development of specific
ligands for each of these
melatonin binding sites is necessary to link physiological and/or
therapeutic effects.