Abstract
Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT(1)/MT(2)) ligands based on the previously reported 1,6-dihydro-2H-indeno[5,4-b]furan 1a. By screening the central tricyclic cores, we identified 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine as a potent scaffold with a high ligand-lipophilicity efficiency (LLE) value. Subsequent optimization of the side chains led to identification of the potent MT(1)/MT(2) agonist 4d (MT(1), K(i) = 0.062 nM; MT(2), K(i) = 0.420 nM) with good oral absorption and blood-brain barrier (BBB) penetration in rats. The oral administration of compound 4d exhibited a sleep-promoting action in freely moving cats at 0.1 mg/kg.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Blood-Brain Barrier / metabolism
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CHO Cells
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Cats
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Cricetinae
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Cricetulus
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Cyclic AMP / biosynthesis
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Female
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Furans / chemical synthesis*
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Furans / pharmacokinetics
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Furans / pharmacology
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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In Vitro Techniques
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Ligands
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Male
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Microsomes, Liver / metabolism
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Rats
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Receptor, Melatonin, MT1 / metabolism*
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Receptor, Melatonin, MT2 / metabolism*
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Sleep / drug effects
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Structure-Activity Relationship
Substances
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Furans
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Heterocyclic Compounds, 3-Ring
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Ligands
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N-(2-(2-ethyl-8,9-dihydrofuro(3,2-c)pyrazolo(1,5-a)pyridin-1-yl)ethyl)acetamide
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Pyrazoles
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Pyridines
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Receptor, Melatonin, MT1
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Receptor, Melatonin, MT2
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Cyclic AMP