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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2012
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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. |
format | Online Article Text |
id | pubmed-3506128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
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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