MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential

J Med Chem. 2014 Apr 24;57(8):3161-85. doi: 10.1021/jm401343c. Epub 2013 Nov 14.


Numerous physiological functions of the pineal gland hormone melatonin are mediated via activation of two G-protein-coupled receptors, MT1 and MT2. The melatonergic drugs on the market, ramelteon and agomelatine, as well as the most advanced drug candidates under clinical evaluation, tasimelteon and TIK-301, are high-affinity nonselective MT1/MT2 agonists. A great number of MT2-selective ligands and, more recently, several MT1-selective agents have been reported to date. Herein, we review recent advances in the field focusing on high-affinity agonists and antagonists and those displaying selectivity toward MT1 and MT2 receptors. Moreover, the existing models of MT1 and MT2 receptors as well as the current status in the emerging field of melatonin receptor oligomerization are critically discussed. In addition to the already existing indications, such as insomnia, circadian sleep disorders, and depression, new potential therapeutic applications of melatonergic ligands including cardiovascular regulation, appetite control, tumor growth inhibition, and neurodegenerative diseases are presented.

MeSH terms

  • Animals
  • Binding Sites
  • Depressive Disorder / drug therapy
  • Humans
  • Ligands
  • Melatonin / physiology
  • Models, Molecular
  • Protein Multimerization*
  • Receptor, Melatonin, MT1 / chemistry
  • Receptor, Melatonin, MT1 / drug effects
  • Receptor, Melatonin, MT1 / physiology*
  • Receptor, Melatonin, MT2 / chemistry
  • Receptor, Melatonin, MT2 / drug effects
  • Receptor, Melatonin, MT2 / physiology*
  • Sleep Initiation and Maintenance Disorders / drug therapy
  • Structure-Activity Relationship


  • Ligands
  • Receptor, Melatonin, MT1
  • Receptor, Melatonin, MT2
  • Melatonin