Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects

Humphrey A. Moynihan; Ian Derrick; Jillian H. Broadbear; Benjamin M. Greedy; Mario D. Aceto; Louis S. Harris; Lauren C.S. Purington; Mark P. Thomas; James H. Woods; John R. Traynor; Stephen M. Husbands; John W. Lewis

doi:10.1021/jm301096s

Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects

Humphrey A. Moynihan
, Ian Derrick
, Jillian H. Broadbear
, Benjamin M. Greedy
, Mario D. Aceto
, Louis S. Harris
, Lauren C.S. Purington
, Mark P. Thomas
, James H. Woods
, John R. Traynor
, Stephen M. Husbands
, John W. Lewis

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	9868-9874
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	22
DOIs	https://doi.org/10.1021/jm301096s
Publication status	Published - 26 Nov 2012
Externally published	Yes

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10.1021/jm301096s

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Moynihan, H. A., Derrick, I., Broadbear, J. H., Greedy, B. M., Aceto, M. D., Harris, L. S., Purington, L. C. S., Thomas, M. P., Woods, J. H., Traynor, J. R., Husbands, S. M., & Lewis, J. W. (2012). Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects. Journal of Medicinal Chemistry, 55(22), 9868-9874. https://doi.org/10.1021/jm301096s

@article{42f026b06c2741628ee289f504bd7698,

title = "Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects",

abstract = "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.",

author = "Moynihan, \{Humphrey A.\} and Ian Derrick and Broadbear, \{Jillian H.\} and Greedy, \{Benjamin M.\} and Aceto, \{Mario D.\} and Harris, \{Louis S.\} and Purington, \{Lauren C.S.\} and Thomas, \{Mark P.\} and Woods, \{James H.\} and Traynor, \{John R.\} and Husbands, \{Stephen M.\} and Lewis, \{John W.\}",

year = "2012",

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doi = "10.1021/jm301096s",

language = "English",

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issn = "0022-2623",

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T1 - Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects

AU - Moynihan, Humphrey A.

AU - Derrick, Ian

AU - Broadbear, Jillian H.

AU - Greedy, Benjamin M.

AU - Aceto, Mario D.

AU - Harris, Louis S.

AU - Purington, Lauren C.S.

AU - Thomas, Mark P.

AU - Woods, James H.

AU - Traynor, John R.

AU - Husbands, Stephen M.

AU - Lewis, John W.

PY - 2012/11/26

Y1 - 2012/11/26

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84870033137

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Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects

Abstract

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