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.
authors.affiliation: School of Chemistry, University of Bristol, Bristol, BS8 1TS, U.K.
authors.forename: Humphrey A
authors.initials: HA
authors.lastname: Moynihan
authors.forename: Ian
authors.initials: I
authors.lastname: Derrick
authors.forename: Jillian H
authors.initials: JH
authors.lastname: Broadbear
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Greedy
authors.forename: Mario D
authors.initials: MD
authors.lastname: Aceto
authors.forename: Louis S
authors.initials: LS
authors.lastname: Harris
authors.forename: Lauren C S
authors.initials: LC
authors.lastname: Purington
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Husbands
authors.forename: John W
authors.initials: JW
authors.lastname: Lewis
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000882:Haplorhini; D051379:Mice; D015394:Molecular Structure; D009022:Morphine Derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu