Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist.

Abstract Ramelteon (TAK-375) is a novel melatonin receptor agonist currently under investigation for the treatment of insomnia. This study describes the neurochemical and receptor binding characteristics of ramelteon in vitro. Ramelteon showed very high affinity for human MT 1 (Mel 1a ) and MT 2 (Mel 1b ) receptors (expressed in Chinese hamster ovary [CHO] cells), and chick forebrain melatonin receptors (consisting of Mel 1a and Mel 1c receptors) with K i values of 14.0, 112, and 23.1 pM, respectively, making the affinities of ramelteon for these receptors 3–16 times higher than those of melatonin. The affinity of ramelteon for hamster brain MT 3 binding sites was extremely weak ( K i : 2.65 μM) compared to melatonin's affinity for the MT 3 binding site ( K i : 24.1 nM). In addition, ramelteon showed no measurable affinity for a large number of ligand binding sites (including benzodiazepine receptors, dopamine receptors, opiate receptors, ion channels, and transporters) and no effect on the activity of various enzymes. Ramelteon inhibited forskolin-stimulated cAMP production in the CHO cells that express the human MT 1 or MT 2 receptors. Taken together, these results indicate that ramelteon is a potent and highly selective agonist of MT 1 /MT 2 melatonin receptors.