Melatonin

Melatonin is the principal hormone secreted by the pineal gland, produced i n humans with a circadian rhythm characterized by elevated blood levels dur ing the night. It is involved in the regulation of several rhythmic functio ns in various vertebrates, and participates in the processing of photoperio dic information. Although its role in human physiologic and pathologic proc esses is not yet completely understood, MLT exerts a number of actions, in physiological or pharmacological concentrations, which could be of interest for future therapeutic uses. The mechanisms involved in MLT actions includ e interaction with membrane receptors, recently classified as mt(1)/MT2/MT3 , and with nuclear sites corresponding to orphan members of the nuclear rec eptor superfamily, RZR/ROR; MLT also acts as a radical scavenger, exerting a protective action against various oxidative injuries. The present review is mainly addressed to the medicinal chemistry of ligands at the MLT membra ne receptors, focusing on the models of binding interaction published in th e literature. Several different pharmacophore and 3D-QSAR models have been reported so far, and a reconsideration of known active compounds, in the li ght of the recently developed biological tests on cloned receptors, could h elp to resolve the incongruities among these models; to this end, additiona l information is becoming available from new, conformationally constrained ligands, and from antagonist compounds with a selective affinity for recept or subtypes.