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

Abstract 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 MT 1 and MT 2 receptors expressed in CHO cells. Agonist and antagonist potency was measured on the [ 35 S]GTPγS binding assay for the most interesting compounds. The new derivatives 8 - 14 showed modest to high selectivity (between 4 and 220) for MT 2 receptors. The most selective compound, N -(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)but-3-enamide ( 14 ), an MT 2 ligand with affinity for the MT 2 receptor similar to that of melatonin and a 220-fold preference over MT 1 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 MT 2 ligand with a good selectivity ratio (MT 1 /MT 2  = 51) shows antagonist activity on both melatonin receptors.