Melatonin is commonly used as a sleep-promoting supplement or an agent to relieve jet lag for its regulatory role in circadian rhythm of the central nervous system. In addition, melatonin also functions as an important hormone in synchronizing activities of peripheral tissues mainly through MT₁ and MT₂ melatonin receptors. Thus, developing subtype-selective melatonin receptor compounds to overcome the undesirable pharmaceutical properties of melatonin, such as non-selectivity and rapid elimination, would provide new treatment avenues for diseases associated with altered melatonergic system. With increasing evidence suggesting the involvement of MT₂ melatonin receptor in pathogenesis of diseases like depression, insomnia and type 2 diabetes, the development of MT₂-specific selective liga...[ Read more ]

Melatonin is commonly used as a sleep-promoting supplement or an agent to relieve jet lag for its regulatory role in circadian rhythm of the central nervous system. In addition, melatonin also functions as an important hormone in synchronizing activities of peripheral tissues mainly through MT₁ and MT₂ melatonin receptors. Thus, developing subtype-selective melatonin receptor compounds to overcome the undesirable pharmaceutical properties of melatonin, such as non-selectivity and rapid elimination, would provide new treatment avenues for diseases associated with altered melatonergic system. With increasing evidence suggesting the involvement of MT₂ melatonin receptor in pathogenesis of diseases like depression, insomnia and type 2 diabetes, the development of MT₂-specific selective ligands would facilitate the investigation of the pathogenic processes at the molecular level. Besides, current one-size-fits-all medications for these diseases need to be further improved, due to their several side effects and weak competency in controlling disease progression. Precise medicine, taking into account differences in an individual’s genetic composition, is thus proposed as an effective alternative to lower the risk of unfavorable outcome in treatment process. Therefore, this study investigated the effect of a highly selective MT₂-specific compound 7b on five MT₂ receptor variants (A52T, A74T, R138C, L166I, R222H) that are related to type 2 diabetes to support the notion of developing selective melatonergic ligands based on precise medicine strategy. The results of agonist-induced Ca²⁺ mobilization, ERK phosphorylation and cAMP accumulation displayed a decreased response from variants, compared to that from wild type. Interestingly, the response from 7b-stimulated MT₂ receptor variants was higher than that from melatonin-induced. Further investigations pertaining to the effect of melatonin on glucose-induced insulin secretion from pancreatic β cells tended to support the possibility of applying melatonergic ligands in type 2 diabetes treatments. Furthermore, a clear map between MT₂ receptor variants with different diseases, such as depression, insomnia, and type 2 diabetes, is required to construct a sound precision medicine system targeting the MT₂ melatonin receptor.