Abstract
The inhibition of radioligand binding and [35S]GTPgammaS functional assay data for N-methyl- and N-phenethyl-9beta-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c) show that these compounds are pure antagonists at the micro, delta, and kappa opioid receptors. Since 5b and 5c have the 5-(3-hydroxyphenyl) group locked in a conformation comparable to an equatorial group of a piperidine chair conformation, this information provides very strong evidence that opioid antagonists can interact with opioid receptors in this conformation. In addition, it suggests that the trans-3, 4-dimethyl-4-(3-hydroxyphenyl)piperidine class of antagonist operates via a phenyl equatorial piperidine chair conformation. Importantly, the close relationship between the 4-(3-hydroxyphenyl)piperidines and 5-(3-hydroxyphenyl)morphan antagonists shows that the latter class of compound provides a rigid platform on which to build a novel series of opioid antagonists.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Crystallography, X-Ray
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Guinea Pigs
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In Vitro Techniques
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Molecular Conformation
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Morphinans / chemical synthesis*
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Morphinans / chemistry
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Morphinans / metabolism
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Morphinans / pharmacology
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Narcotic Antagonists*
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Putamen / drug effects
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Putamen / metabolism
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Radioligand Assay
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Rats
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Receptors, Opioid / metabolism
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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
Substances
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Morphinans
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N-methyl-9-methyl-5-(3-hydroxyphenyl)morphan
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N-phenethyl-9-methyl-5-(3-hydroxyphenyl)morphan
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Narcotic Antagonists
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Receptors, Opioid
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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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Guanosine 5'-O-(3-Thiotriphosphate)