A Molecular and Chemical Perspective in Defining Melatonin Receptor Subtype Selectivity

Abstract

Melatonin is primarily synthesized and secreted by the pineal gland during darkness in a normal diurnal cycle. In addition to its intrinsic antioxidant property, the neurohormone has renowned regulatory roles in the control of circadian rhythm and exerts its physiological actions primarily by interacting with the G protein-coupled MT1 and MT2 transmembrane receptors. The two melatonin receptor subtypes display identical ligand binding characteristics and mediate a myriad of signaling pathways, including adenylyl cyclase inhibition, phospholipase C stimulation and the regulation of other effector molecules. Both MT1 and MT2 receptors are widely expressed in the central nervous system as well as many peripheral tissues, but each receptor subtype can be linked to specific functional responses at the target tissue. Given the broad therapeutic implications of melatonin receptors in chronobiology, immunomodulation, endocrine regulation, reproductive functions and cancer development, drug discovery and development programs have been directed at identifying chemical molecules that bind to the two melatonin receptor subtypes. However, all of the melatoninergics in the market act on both subtypes of melatonin receptors without significant selectivity. To facilitate the design and development of novel therapeutic agents, it is necessary to understand the intrinsic differences between MT1 and MT2 that determine ligand binding, functional efficacy, and signaling specificity. This review summarizes our current knowledge in differentiating MT1 and MT2 receptors and their signaling capacities. The use of homology modeling in the mapping of the ligand-binding pocket will be described. Identification of conserved and distinct residues will be tremendously useful in the design of highly selective ligands.

Phylogenetic reclassification of vertebrate melatonin receptors to include Mel1d

“…Indeed, most of the residues identified as key for melatonin binding are readily identifiable in the Mel1d transmembrane domains (Fig. 6), in particular TM3, 6 and 7 (Gubitz & Reppert 2000, Kokkola et al 2003, Mazna et al 2005, 2008, Chan & Wong 2013). The only notable difference in the TMDs was that several Mel1d orthologues had threonine replacements at position 254, specific to this MTR.…”

Dampening of neurotransmitter action: molecular similarity within the melatonin structure

“…Molecular similarity is evident in GPCR and ion channel ligands relative to the structures of purine nucleotides that control signal transduction events (Williams 2018). The 3-acylaminoethyl chain and 5-methoxy group are crucial components in the binding of melatonin to MT 1 and MT 2 receptors, as is the relative distance between the amide group and methoxy group (Chan and Wong 2013). The nucleotide template fits of the melatonin conformer via acyl and methoxy groups, given in Figures 1[2] and 2[2], may relate to MT 1 and MT 2 receptor pharmacophores.…”

“…Identical MT ligand-binding characteristics and the limited modelling of melatonin receptors hinder the development of specific therapeutic agents (Chan and Wong 2013). Melatonin MT 1 and MT 2 receptors couple to the Gi/o family of G-proteins, initiating signal transduction by inhibiting adenyl cyclase, K + channel opening via βλ subunits and Ca 2+ channel closure (Tosini et al 2014).…”

Melatonin in Sperm Biology: Breaking Paradigms

“…The possible identification of selective small molecule ligands is one of the major goals of orphan nuclear receptor research, which would make new therapeutic interventions available for a variety of human diseases. Nevertheless, this melatonin action has not been validated yet (Chan and Wong ). The presence of these receptors in ovine, and particularly in spermatozoa, is currently being studied by our group.…”