Preparation and pharmacological evaluation of a novel series of 2-(phenylthio)benzo[b]thiophenes as selective MT2 receptor ligands

A series of N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)acylamides was synthesized and evaluated for binding affinity and intrinsic activity at melatonin receptors. The affinity of each compound for the melatonin receptors was determined by binding studies on cloned human MT1 and MT2 receptors expressed in CHO cells. Agonist and antagonist potency was measured on the [35S]GTPγS binding assay for the most interesting compounds. The new derivatives 8-14 showed modest to high selectivity (between 4 and 220) for MT2 receptors. The most selective compound, N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)but-3-enamide (14), an MT2 ligand with affinity for the MT2 receptor similar to that of melatonin and a 220-fold preference over MT1 receptors, acts as a partial agonist. In addition, N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)propionamide (9), a nanomolar MT2 ligand with a good selectivity ratio (MT1/MT2 = 51) shows antagonist activity on both melatonin receptors.

The unexpected result of the cyclization of 1-(4-fluoro-phenylsulfanyl)-propan-2-one (2f) in PPA led us to prepare and evaluate a small series of novel 2-(phenylthio)benzothiophenes 8–14 as selective MT2 ligands.Figure optionsDownload as PowerPoint slideHighlights
► Unexpected cyclization of 1-(4-fluoro-phenylsulfanyl)-propan-2-one in PPA.
► Preparation and evaluation of a small series of novel 2-(phenylthio)benzothiophenes as selective MT2 ligands.
► Melatonin receptors ligands with modest to high selectivity for MT2.