Abstract
A series of N-methyl rac-cis-4a-aralkyl- and alkyl-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols have been prepared (2a-l) using a simple previously designed synthetic route, in order to find a ligand that would interact with both μ- and δ-opioid receptors. A C4a-phenethyl derivative 2a, was found to have modest receptor affinity both at μ- (K(i)=60 nM) and δ-opioid receptors (K(i)=64 nM). The N-methyl substituent of 2a and that of other ligands in the series was then modified to obtain compounds with different N-substituents that might provide higher affinity at both receptors. A number of compounds differently substituted at C4a and N were synthesized and evaluated. Binding studies and functional assays revealed a moderately selective δ-antagonist (2l), selective μ-δ antagonists (3d, 3g), and a μ-κ antagonist (3f).
Published by Elsevier Ltd.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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CHO Cells
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Cell Membrane / drug effects*
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Cell Membrane / metabolism
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Cricetulus
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Humans
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Ligands
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Molecular Structure
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Narcotic Antagonists / chemical synthesis*
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Narcotic Antagonists / chemistry
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Narcotic Antagonists / pharmacology*
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Receptors, Opioid, delta / antagonists & inhibitors*
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Receptors, Opioid, delta / metabolism
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Receptors, Opioid, kappa / antagonists & inhibitors*
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Receptors, Opioid, kappa / metabolism
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Receptors, Opioid, mu / antagonists & inhibitors*
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Receptors, Opioid, mu / metabolism
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Structure-Activity Relationship
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Sulfur Radioisotopes
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Tritium
Substances
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Ligands
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Narcotic Antagonists
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Pyridines
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Receptors, Opioid, delta
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Receptors, Opioid, kappa
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Receptors, Opioid, mu
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Sulfur Radioisotopes
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Tritium
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Guanosine 5'-O-(3-Thiotriphosphate)