Abstract
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.
MeSH terms
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Acetamides / chemical synthesis*
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Acetamides / chemistry
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Acetamides / pharmacology
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Animals
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Benzofurans / chemical synthesis*
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Benzofurans / chemistry
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Benzofurans / pharmacology
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CHO Cells
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Circadian Rhythm
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Cricetinae
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Cricetulus
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Cyclic AMP / biosynthesis
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Darkness
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Humans
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Ligands
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Light
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Male
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Mice
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Mice, Inbred ICR
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Motor Activity / drug effects
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Radioligand Assay
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Receptor, Melatonin, MT1 / agonists
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Receptor, Melatonin, MT2 / agonists*
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Structure-Activity Relationship
Substances
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Acetamides
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Benzofurans
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Ligands
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N-(2-(7-(cyclohexylmethyl)-1,6-dihydro-2H-indeno(5,4-b)furan-8-yl)ethyl)acetamide
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Receptor, Melatonin, MT1
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Receptor, Melatonin, MT2
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Cyclic AMP