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.
Highlights
Melatonin (N-acetyl-5-methoxytryptamine) is a serotonin-derived neurohormone primarily secreted by the pineal gland with a circadian rhythm and reaching its highest plasma concentrations during the dark phase
At least three different binding sites have been recognized for melatonin; the MT1 and MT2 membrane receptors belong to the GPCR family and are mainly coupled to inhibition of adenylyl cyclase; the lower affinity MT3 binding site has been recently identified as the enzyme NRH:quinone oxydoreductase 2.2,3
In this article we report and discuss our researches in the field of melatonin receptor ligands, which led us to the development of novel classes of MT2 selective antagonists
Summary
Melatonin (N-acetyl-5-methoxytryptamine) is a serotonin-derived neurohormone primarily secreted by the pineal gland with a circadian rhythm and reaching its highest plasma concentrations during the dark phase. We synthesized different series of melatonin analogues, obtaining very potent derivatives, such as 2-bromomelatonin.[8,9,10,11] Starting from a series of conformationally constrained compounds, we proposed a pharmacophore model for agonists and a bioactive conformation for the natural ligand.[12] A 3D-QSAR CoMFA analysis allowed the rationalization of the structure-activity relationships for more than one hundred agonists.[13] To investigate the effect of different mutual arrangements of the pharmacophoric elements on binding affinity and intrinsic activity, the structure of melatonin was modified by shifting the acylaminoalkyl side chain at position 2 of the indole ring and by inserting different substituents on the indole nitrogen.
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