In vitro comparison of duration of action of melatonin agonists on melatonin MT1 receptor: possible link between duration of action and dissociation rate from receptor

European Journal of Pharmacology
Keiji Nishiyama, Keisuke Hirai

Abstract

Melatonin MT1 and MT2 receptors are Gi protein-coupled receptors and promising therapeutic targets for a number of diseases. A proportion of G protein-coupled receptor agonists and antagonists have been classified according to their duration of action, which influences their pharmacological efficacy. However, the duration of action of melatonin agonists remains unclear. In this study, we investigated the duration of action of melatonin agonists (melatonin, 2-iodomelatonin, ramelteon, and the ramelteon metabolite M-II) at the melatonin MT1 receptor, which is more resistant to agonist-induced desensitization than the melatonin MT2 receptor. In Chinese hamster ovary cells stably expressing the human melatonin MT1 receptor, significant differences in the duration of action were observed after 2-h pretreatment with agonists followed by washout. In contrast to melatonin and M-II, the agonist activities of ramelteon and 2-iodomelatonin were persistent (i.e. inhibition of forskolin-stimulated cAMP formation and increase in ERK 1/2 phosphorylation) even after repeated washouts. Similar activities were observed for INS-1 cells endogenously expressing the rat MT1 receptor. Further, we examined potential factors linked to the duration of a...Continue Reading

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Citations

Aug 1, 2015·Drug Discovery Today·J Daniel HothersallPhilip Rawlins
Mar 24, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jin-Young SungDae-Kwang Kim
Nov 6, 2021·Hypertension·Diego A DuarteClaudio M Costa-Neto

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