European journal of medicinal chemistry

Melatonin, a neurohormone secreted by the pineal gland and regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is synthesized and directly released into the cerebrospinal fluid (CSF) of the third ventricle (3rdv), where it undergoes rapid absorption by surrounding tissues to exert its physiological function. The hippocampus, a vital structure in the limbic system adjacent to the ventricles, plays a pivotal role in emotional response and memory formation. Melatonin MT 1 and MT 2 receptors are G protein-coupled receptors (GPCRs) that primarily mediate melatonin's receptor-dependent effects. In comparison to the MT 1 receptor, the widely expressed MT 2 receptor is crucial for mediating melatonin's biological functions within the hippocampus. Specifically, MT 2 receptor is implicated in hippocampal synaptic plasticity and memory processes, as well as neurogenesis and axogenesis. Numerous studies have demonstrated the involvement of MT 2 receptors in the pathophysiology and pharmacology of Alzheimer's disease, depression, and epilepsy. This review focuses on the anatomical localization of MT 2 receptor in the hippocampus, their physiological function in this region, and their signal transduction and pharmacological roles in neurological disorders. Additionally, we conducted a comprehensive review of MT 2 receptor ligands used in psychopharmacology and other MT 2 -selective ligands over recent years. Ultimately, we provide an outlook on future research for selective MT 2 receptor drug candidates.

In crystal structures of melatonin MT 1 and MT 2 receptors, a lipophilic subpocket has been characterized which accommodates the phenyl ring of the potent agonist 2-phenylmelatonin. This subpocket appears a key structural element to achieve high binding affinity and selectivity for the MT 2 receptor. A series of 2-arylindole ligands was synthesized to probe the requirements for the optimal occupation and interaction with the 2-phenyl binding pocket. Thermodynamic integration simulations applied to MT 1 and MT 2 receptors in complex with the α-naphthyl derivative provided a rationale for the MT 2 -selectivity and investigation on the binding mode of a couple of atropisomers allowed to define the available space and arrangement of substituents inside the subpocket. Interestingly, more hydrophilic 2-aza-substituted compounds displayed high binding affinity and molecular dynamics simulations highlighted polar interaction with residues from the subpocket that could be responsible for their potency.