The pharmacological evaluation of novel and high‐affinity melatonin receptor ligands

Abstract

Melatonin exerts its multiple pharmacological actions via activation of two G protein‐coupled receptors, MT1 and MT2. The exploration of the physiological role of the distinct receptor subtypes requires the use of highly selective ligands (both agonists and antagonists). The compounds being presented serve as MT2 selective ligands. The introduction of the bulky lipophilic substituent at the position corresponding with the C‐2 position of melatonin provides MT2 selectivity potentially through an interaction with the NH group of the His‐208. Competitive binding assays were performed with 2‐[125I]‐iodomelatonin in Chinese hamster ovary cells stably transfected with the human MT1 and MT2 melatonin receptors. Competition analysis showed that large electron rich aromatic ring structures enhance binding and MT2 receptor selectivity. With the creation of highly selective, high affinity ligands, the binding pockets of each receptor subtype can be better understood and further the development of novel melatonergic drugs.