Probes for narcotic receptor mediated phenomena. Part 42: Synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans

A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged p...

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Published in:Bioorganic & medicinal chemistry 2011-06, Vol.19 (11), p.3434-3443
Main Authors: Kim, Jin-Hee, Deschamps, Jeffrey R., Rothman, Richard B., Dersch, Christina M., Folk, John E., Cheng, Kejun, Jacobson, Arthur E., Rice, Kenner C.
Format: Article
Language:English
Subjects:
antagonists
Biological and medical sciences
chemistry
Crystallography, X-Ray
Functional assays
Medical sciences
Molecular Conformation
Molecular shape
Morphinans - chemical synthesis
Morphinans - chemistry
Morphinans - pharmacology
N-Phenethyl substituent
naloxone
Narcotic Antagonists
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Opioid antagonist activity
Opioid receptor affinity
Ortho-c and para-c oxide bridged phenylmorphans
Oxides - chemistry
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Protein Binding
Racemates
Receptors, Opioid - metabolism
Stereoisomerism
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Summary:A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged phenylmorphan( rac-(3 R,6a S,11a S)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1 H-3,6a-methanobenzofuro[2,3- c]azocin-10-ol ( 12)) was found to have the highest μ-opioid receptor affinity ( K i = 1.1 nM) of all of the a- through f-oxide-bridged phenylmorphans. Functional data ([ 35S]GTP-γ-S) showed that the racemate 12 was more than three times more potent than naloxone as an μ-opioid antagonist.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.04.028