Melatonin receptor ligands: A pharmaco‐chemical perspective

Abstract

Melatonin MT1 and MT2 receptor ligands have been vigorously explored for the last 4 decades. Inspection of approximately 80 publications in the field revealed that most melatonergic ligands were structural analogues of melatonin combining three essential features of the parent compound: an aromatic ring bearing a methoxy group and an amide side chain in a relative arrangement similar to that present in melatonin. While several series of MT2‐selective agents—agonists, antagonists, or partial agonists—were reported, the field was lacking MT1‐selective agents. Herein, we describe various approaches toward the development of melatonergic ligands, keeping in mind that most of the molecules/pharmacophores obtained were essentially melatonin copies, even though diverse tri‐ or tetra‐cyclic compounds were explored. In addition to lack of structural diversity, only few studies examined the activity of the reported melatonergic ligands in vivo. Moreover, an extensive pharmacological characterization including biopharmaceutical stability, pharmacokinetic properties, specificity toward other major receptors to name a few remained scarce. For example, many of the antagonists described were not stable in vivo, were not selective for the melatonin receptor subtype of interest, and were not fully characterized from a pharmacological standpoint. Indeed, virtual screening of large compound libraries has led to the recent discovery of potent and selective melatonin receptor agonists and partial agonists of new chemotypes. Having said this, the melatonergic field is still lacking subtype‐selective melatonin receptor antagonists “active” in vivo, which are critical to our understanding of melatonin and melatonin receptors’ role in basic physiology and disease.

Melatonin Receptor 2 Promotes Lipid Metabolism of Cumulus-oocyte Complexes via the cAMP/PKA Pathway

“…It is well known that G protein-coupled receptors (GPCRs) are the most functional cell surface proteins and mediate a series of physiological processes [26]. The melatonin receptors, MT1 and MT2, are GPCRs that receive external melatonin signals and are also involved in a vast array of physiological processes [27][28][29]. Nevertheless, the bene cial effects of melatonin on the reproductive system have been explained simply as being due to indirect, antioxidant effects, and so little information is available on the underlying mechanism by which melatonin concretely acts on porcine COC development.…”

Melatonin controversies, an update

“…The use of µM or even mM concentrations does not make sense in this context. At the same low MLT concentrations, other events like receptor internalization are triggered 128,129 and the duration of stimulation with MLT (the whole night under physiological conditions) must be also taken into account. Whether these events lead to receptor desensitization or sensitization of signaling pathways, that is the cAMP pathway 129 and to what extent differences between MT 1 and MT 2 exist 130 remains largely unknown.…”

“…These considerations are also valid for luzindole and 4PP‐DOT. These “gold standard” antagonists used throughout the literature to block MLT's action may be agonists or inverse agonists depending on the signaling pathway and cell context considered 97,121 (see 128 for more details). The compound with the most reliable antagonistic activity observed in a large range of signaling assays is S20928 (see IUPHAR web site for more information 131 ).…”

Chiral Recognition of Flexible Melatonin Receptor Ligands Induced by Conformational Equilibria

“…The melatonin bioisosteres ramelteon, agomelatine, and tasimelteon have been approved for the treatment of sleep disturbances, depression, and non-24-h sleep–wake disorder, respectively [ 4 ]. Several classes of melatoninergic ligands have been synthesized in the last decades in which modification of the relevant structural features of melatonin (i.e., the aromatic core, the methoxy group and the amide side chain) were carried out, leading to receptor ligands characterized by diverse pharmacological profiles in terms of binding affinity, receptor-subtype selectivity, and intrinsic activity [ 6 ]. Further attempts to improve ligand efficacy and metabolic stability were made by introducing substituents on the alkylamide side chain.…”