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Probes for narcotic receptor mediated phenomena. 47.1 Novel C4a- and N-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols

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 derivat...

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Published in:Bioorganic & medicinal chemistry 2013-06, Vol.21 (11), p.3298-3309
Main Authors: Iyer, Malliga R., Rothman, Richard B., Dersch, Christina M., Jacobson, Arthur E., Rice, Kenner C.
Format: Article
Language:English
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Summary: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- (Ki=60nM) and δ-opioid receptors (Ki=64nM). 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).
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.02.060