Université Lille Nord de France, F-59000 Lille, France.
Eur J Med Chem. 2011 May;46(5):1835-40. doi: 10.1016/j.ejmech.2011.02.044. Epub 2011 Feb 23.
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.
合成了一系列 N-(2-(5-氟-2-(4-氟苯基硫代)苯并[b]噻吩-3-基)乙基)酰基酰胺，并评估了它们在褪黑素受体上的结合亲和力和内在活性。通过在 CHO 细胞中表达的克隆人 MT1 和 MT2 受体的结合研究，确定了每种化合物与褪黑素受体的亲和力。在 [35S]GTPγS 结合测定中，对最有趣的化合物测量了激动剂和拮抗剂的效力。新的衍生物 8-14 对 MT2 受体表现出中等至高的选择性（4 到 220 之间）。最具选择性的化合物 N-(2-(5-氟-2-(4-氟苯基硫代)苯并[b]噻吩-3-基)乙基)丁酰胺（14）是一种 MT2 配体，对 MT2 受体的亲和力与褪黑素相似，对 MT1 受体的选择性是 220 倍，它是一种部分激动剂。此外，N-(2-(5-氟-2-(4-氟苯基硫代)苯并[b]噻吩-3-基)乙基)丙酰胺（9）是一种纳摩尔 MT2 配体，具有良好的选择性比值（MT1/MT2=51），对两种褪黑素受体均表现出拮抗活性。
