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Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible μ Opioid Receptor Antagonist Effects

[Image: see text] We have previously shown that cinnamoyl derivatives of 14β-amino-17-cyclopropylmethyl-7,8-dihydronormorphinone and 7α-aminomethyl-6,14-endoethanonororipavine have pronounced pseudoirreversible μ opioid receptor (MOR) antagonism. The present communication describes the synthesis and...

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Autores principales: Moynihan, Humphrey A., Derrick, Ian., Broadbear, Jillian H., Greedy, Benjamin M., Aceto, Mario D., Harris, Louis S., Purington, Lauren C. S., Thomas, Mark P., Woods, James H., Traynor, John R., Husbands, Stephen M., Lewis, John W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2012
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506128/
https://www.ncbi.nlm.nih.gov/pubmed/23043264
http://dx.doi.org/10.1021/jm301096s
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author Moynihan, Humphrey A.
Derrick, Ian.
Broadbear, Jillian H.
Greedy, Benjamin M.
Aceto, Mario D.
Harris, Louis S.
Purington, Lauren C. S.
Thomas, Mark P.
Woods, James H.
Traynor, John R.
Husbands, Stephen M.
Lewis, John W.
author_facet Moynihan, Humphrey A.
Derrick, Ian.
Broadbear, Jillian H.
Greedy, Benjamin M.
Aceto, Mario D.
Harris, Louis S.
Purington, Lauren C. S.
Thomas, Mark P.
Woods, James H.
Traynor, John R.
Husbands, Stephen M.
Lewis, John W.
author_sort Moynihan, Humphrey A.
collection PubMed
description [Image: see text] We have previously shown that cinnamoyl derivatives of 14β-amino-17-cyclopropylmethyl-7,8-dihydronormorphinone and 7α-aminomethyl-6,14-endoethanonororipavine have pronounced pseudoirreversible μ opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism. The fumaroylamino analogues (2a, 5a) of the pseudoirreversible antagonist cinnamoylamino morphinones and oripavines (2b, 5b) were themselves irreversible antagonists in vivo. However the fumaroylamino derivatives had significantly higher MOR efficacy than the cinnamoylamino derivatives in mouse antinociceptive tests. Comparison of 2a and 5a with the prototypic fumaroylamino opioid β-FNA (1a) shows that they have similar MOR irreversible antagonist actions but differ in the nature of their opioid receptor agonist effects; 2a is a predominant MOR agonist and 5a shows no opioid receptor selectivity, whereas the agonist effect of β-FNA is clearly κ opioid receptor (KOR) mediated.
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spelling pubmed-35061282012-11-27 Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible μ Opioid Receptor Antagonist Effects Moynihan, Humphrey A. Derrick, Ian. Broadbear, Jillian H. Greedy, Benjamin M. Aceto, Mario D. Harris, Louis S. Purington, Lauren C. S. Thomas, Mark P. Woods, James H. Traynor, John R. Husbands, Stephen M. Lewis, John W. J Med Chem [Image: see text] We have previously shown that cinnamoyl derivatives of 14β-amino-17-cyclopropylmethyl-7,8-dihydronormorphinone and 7α-aminomethyl-6,14-endoethanonororipavine have pronounced pseudoirreversible μ opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism. The fumaroylamino analogues (2a, 5a) of the pseudoirreversible antagonist cinnamoylamino morphinones and oripavines (2b, 5b) were themselves irreversible antagonists in vivo. However the fumaroylamino derivatives had significantly higher MOR efficacy than the cinnamoylamino derivatives in mouse antinociceptive tests. Comparison of 2a and 5a with the prototypic fumaroylamino opioid β-FNA (1a) shows that they have similar MOR irreversible antagonist actions but differ in the nature of their opioid receptor agonist effects; 2a is a predominant MOR agonist and 5a shows no opioid receptor selectivity, whereas the agonist effect of β-FNA is clearly κ opioid receptor (KOR) mediated. American Chemical Society 2012-10-08 2012-11-26 /pmc/articles/PMC3506128/ /pubmed/23043264 http://dx.doi.org/10.1021/jm301096s Text en Copyright © 2012 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.
spellingShingle Moynihan, Humphrey A.
Derrick, Ian.
Broadbear, Jillian H.
Greedy, Benjamin M.
Aceto, Mario D.
Harris, Louis S.
Purington, Lauren C. S.
Thomas, Mark P.
Woods, James H.
Traynor, John R.
Husbands, Stephen M.
Lewis, John W.
Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible μ Opioid Receptor Antagonist Effects
title Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible μ Opioid Receptor Antagonist Effects
title_full Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible μ Opioid Receptor Antagonist Effects
title_fullStr Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible μ Opioid Receptor Antagonist Effects
title_full_unstemmed Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible μ Opioid Receptor Antagonist Effects
title_short Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible μ Opioid Receptor Antagonist Effects
title_sort fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506128/
https://www.ncbi.nlm.nih.gov/pubmed/23043264
http://dx.doi.org/10.1021/jm301096s
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