Melatonin receptor ligands: A pharmaco-chemical perspective

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Neuroscience

Background:

• Melatonin MT1 and MT2 receptor ligands have been extensively studied for four decades.
• Most developed ligands are structural analogues of melatonin, lacking significant structural diversity.
• A notable gap exists in the availability of MT1-selective agents compared to MT2-selective ones.

Purpose of the Study:

• To review and discuss various approaches in the development of melatonergic ligands.
• To highlight the limitations in structural diversity and in vivo characterization of existing ligands.
• To identify the unmet need for subtype-selective melatonin receptor antagonists with in vivo activity.

Main Methods:

• Review of approximately 80 publications in the field of melatonergic ligands.
• Analysis of structural features and pharmacological profiles of reported ligands.
• Discussion of virtual screening approaches leading to new chemotypes.

Main Results:

• Most melatonergic ligands are melatonin analogues, with limited structural variation.
• Few studies provide comprehensive in vivo data, biopharmaceutical stability, or pharmacokinetic properties.
• While potent agonists and partial agonists of new chemotypes have been discovered, subtype-selective antagonists with in vivo efficacy are still lacking.

Conclusions:

• The field requires greater structural diversity in melatonergic ligand development.
• Thorough in vivo characterization and pharmacological profiling are crucial for future drug candidates.
• The development of in vivo-active, subtype-selective melatonin receptor antagonists is critical for advancing research into melatonin's physiological and pathological roles.