Ramelteon - Mechanism of Action

Mechanism of Action

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT₁ and MT₂ receptors and selectivity over the MT₃ receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT₁ or MT₂ receptors, and high selectivity for human MT₁ and MT₂ receptors compared to the MT₃ receptor.

The activity of ramelteon at the MT₁ and MT₂ receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.

The significance of ramelteon's lack of affinity for the MT₃ receptor is not clear, despite the manufacturer's emphasis of this fact in commercial advertisements. The MT₃ receptor appears almost exclusively in the gut and might not have any relationship to sleep or wakefulness.

The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT₁ and MT₂ receptors, respectively, and is 17 – 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT₁ and MT₂ receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20 – 100 fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.

All other known metabolites of ramelteon are inactive.

No published studies have indicated whether ramelteon, in humans, is more or less safe or effective than the hormone melatonin which it mimics; melatonin is much less expensive and is widely available over-the-counter in the US and Canada. The biological action of melatonin is similar to that of ramelteon. Ramelteon has been directly compared to melatonin in cats, and Ramelteon had a significant (3x) longer effect and had a more profound effect on the EEG of the sleeping cats.