Recent Advances in Melatonin Receptor Ligands

Abstract

Melatonin is a hormone exerting its multiple actions mainly through two G-protein-coupled receptors MT(1) and MT(2). Exploring the physiological role of each of these subtypes requires subtype selective MT(1) and MT(2) ligands. While several MT(2)-selective ligands were developed in the 1990s, no selective agonists and antagonists for the MT(1) subtype were described. The present article reviews mela toninergic ligands developed in the current millennium focusing on subtype selective agents and on drug candidates. Notable compounds are the MT(1)-selective agonists 35 and 134, MT(1)-selective antagonists 117 and 131, MT(2)-selective agonists 58, 70, 79, 97 and 125, MT(2)-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.

Agomelatine: The evidence for its place in the treatment of depression

“…Therefore, several melatonin agonists have been developed in recent years and examined in clinical trials for the treatment of insomnia (for a current review of melatonin receptor agonist development, see Turek and colleagues3). To date, agomelatine (S-20098; Valdoxan ® , Servier), a synthetic melatonergic MT 1 and MT 2 receptor agonist,4 is the best characterized melatonin receptor agonist in terms of preclinical studies. In contrast to melatonin, agomelatine also possesses serotonin (5-HT 2C ) receptor antagonistic properties5 within the central nervous system (CNS).…”

Bivalent ligand approach on N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide: Synthesis, binding affinity and intrinsic activity for MT1 and MT2 melatonin receptors

“…10 Elucidation of the distinct functions of MT 1 and MT 2 receptors in many target tissues is still under investigation and requires a continual development of specific and selective affinity ligands. Whereas some selective MT 2 receptor ligands have been recently described, 11,12 the limited availability of MT 1 subtype-selective ligands has hampered an exhaustive elucidation of the MT 1 receptor patho/physiological role. Although, a few monomeric ligands displaying moderate MT 1 -selectivity were reported, 13 the most applied approach for the design of MT 1 selective receptor ligands relies in the preparation of symmetric dimers, by coupling two moieties deriving from known MLT receptor ligands.…”

Synthesis, Enantiomeric Resolution, and Structure–Activity Relationship Study of a Series of 10,11‐Dihydro‐5H‐Dibenzo[a,d]cycloheptene MT2 Receptor Antagonists

“…[9] Parallel to the investigation of the pathophysiological role of MT 1 and MT 2 , various MLT receptor ligands have been developed. [10] The nonselective agonist ramelteon has been recently marketed as a new hypnotic drug, while other ligands are in clinical trials for the treatment of sleep disturbances or depression. [11] In the field of MLT receptor antagonists, different series of MT 2 -selective compounds have been described, [12] whereas examples of MT 1 -selective agents are still limited.…”