Acta Pharmacologica Sinica 2008 December; 29 (12): 1515-1521; doi: 10.1111/j.1745-7254.2008.00903.x

Aim:Melatonin (MT) is a neurohormone produced and secreted primarily by the pineal gland in a circadian manner, and mainly acts through 2 receptor subtypes: MT₁ and MT₂ in humans. The diversity in their tissue distribution is in favor of different functions for each receptor subtype. Selective modulators are therefore required to determine the physiological roles of these melatonin receptor subtypes and their implications in pathological processes.

Methods: A homogenous MT₁/MT₂ receptor binding assay was established for high-throughput screening of new ligands at the hMT₁ and/or hMT₂ receptors. The functional properties (agonists or antagonists) were assessed by a conventional guanosine-5'[γ-³⁵S]triphosphate (GTP-γS) assay.

Results: Three hMT₁ receptor-selective small molecule antagonists and 1 hMT₂ receptor-selective small molecule antagonist with novel structural features were identified following a high-throughput screening campaign of 48 240 synthetic and natural compounds.

Conclusion: The findings may assist in the expansion of chemical probes to these 2 receptor subtypes.

Keywords: melatonin; receptor; selectivity; agonist; antagonist