Melatonin, Light, and the Circadian System

This review summarizes evidence on the modulation of functional responses mediated by activation of the MT1 and/or MT2 melatonin receptors by endogenous or exogenous melatonin. Selective MT1 inverse agonists, discovered by docking ultra large compound libraries to the MT1 crystal structure, decelerated the rate of re-entrainment of activity rhythms to a new dark onset. Surprisingly, these inverse agonists advanced circadian phase when given at subjective dusk mimicking melatonin through actions at MT1 receptors. The efficacy of environmental carbamates with structural similarity to melatonin interact with melatonin receptors and in turn advance circadian clock phase, as with melatonin. In summary, melatonin receptors are targets for drugs modulating circadian rhythms to yield therapeutic effects (i.e., synchronization), as well as for environmental chemicals that may induce harmful effects on human health due to actions on melatonin and on/off target receptors (e.g., serotonin) involved in signaling circadian time at inappropriate times of day.