MT2 selective melatonin receptor antagonists: Design and structure-activity relationships

Abstract

The neurohormone melatonin is involved in the regulation of many physiological functions, in particular those related to circadian and seasonal rhythms. In mammals, melatonin activates two GPCRs, named MT1 and MT2, and ligands of these receptors have been proposed for the treatment of different pathologies. In this article we describe the results of our researches in the field of melatonin receptor ligands, pointing the attention to the investigation of structure-activity relationships and to the development of novel MT2 selective antagonists. Molecular modeling studies led us to formulate a hypothesis about the structural requirements for MT2 selective antagonism. This hypothesis was supported by 3D-QSAR analysis, that allowed the definition of the molecular determinants correlated with binding affinity, receptor subtype selectivity and intrinsic activity. Three-dimensional models of the MT1 and MT2 receptors were built by homology modeling and they provided an explanation, at the receptor level, for the MT2 receptor selectivity evidenced by the antagonists. The information obtained from our ligand-based and structure-based studies was exploited for the design of different series of potent and selective melatonin receptor antagonists with novel structures. ©ARKAT.