A novel series of 1,6-dihydro-2H-indeno[5,4-b]furan derivatives were designed and synthesized as MT(2)-selective ligands. This scaffold was identified as a potent mimic of the 5-methoxy indole core of melatonin, and introduction of a cyclohexylmethyl group at the 7-position of this scaffold afforded an MT(2)-selective ligand 15 (K(i) = 0.012 nM) with high MT(1)/MT(2) selectivity (799). Compound 15 was identified as a potent full agonist for the MT(2) subtype and exhibited reentrainment effects to a new light/dark cycle in ICR mice at 3-30 mg/kg. This result demonstrated the involvement of the MT(2) receptors in chronobiotic activity.