Recent advances in melatonin receptor ligands

Melatonin is a hormone exerting its multiple actions mainly through two G-protein-coupled receptors MT1 and MT2. Exploring the physiological role of each of these subtypes requires subtype selective MT1 and MT2 ligands. While several MT2-selective ligands were developed in the 1990s, no selective agonists and antagonists for the MT1 subtype were described. The present article reviews melatoninergic ligands developed in the current millennium focusing on subtype selective agents and on drug candidates. Notable compounds are the MT1-selective agonists 35 and 134, MT1-selective antagonists 117 and 131, MT2-selective agonists 58, 70, 79, 97 and 125, MT2-selective antagonists 27, 73 and 119, and the highly potent non-selective agonist 120. The non-selective agonists agomelatine 2, and ramelteon 87 are drug candidates as antidepressive agent and for the treatment of insomnia and circadian rhythm disfunction, respectively.