查看文章

Three-dimensional homology models of human MT₁ and MT₂ melatonin receptors were built with the aim to investigate the structure−activity relationships (SARs) of MT₂ selective antagonists. A common interaction pattern was proposed for a series of structurally different MT₂ selective antagonists, which were positioned within the binding site by docking and simulated annealing. The proposed antagonist binding mode to the MT₂ receptor is characterized by the accommodation of the out-of-plane substituents in a hydrophobic pocket, which resulted as being fundamental for the explanation of the antagonist behavior and the MT₂ receptor selectivity. Moreover, to assess the ability of the MT₂ receptor model to reproduce the SARs of MT₂ antagonists, three new derivatives of the MT₂ selective antagonist N-[1-(4-chloro-benzyl)-4-methoxy-1H-indol-2-ylmethyl]-propionamide (7) were synthesized and tested for their …