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, 55 (22), 9868-74

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

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

Humphrey A Moynihan et al. J Med Chem.

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.

Figures

Chart 1
Chart 1
Scheme 1
Scheme 1
(i) BBr3, CH2Cl2 (50%); (ii) MeO2CCHCHCOCl, Na2CO3, THF, H2O (81%); (iii) H2, Pd/C, MeOH (62%).
Scheme 2
Scheme 2
(i) (MeO2CCHCHCO)2O), toluene, heat (69%); (ii) 6 M HCl, MeOH (37%).
Scheme 3
Scheme 3
(i) MeO2CCHCHCOCl, NEt3, CH2Cl2 (4a, 65%; 5a, 48%).
Figure 1
Figure 1
Agonist effect of 2a and morphine in the mouse warm water tail withdrawal assay at 50 and 55 °C.
Figure 2
Figure 2
Antagonist activity of 2a after 24 h of pretreatment (10 and 100 mg/kg) on morphine antiniciceptive activity in the mouse warm water tail withdrawal assay (55 °C).
Figure 3
Figure 3
Duration of antagonist effect of 2a (100 mg/kg) on morphine antinociceptive activity in the mouse warm water tail withdrawal assay.
Figure 4
Figure 4
Effect of selective opioid antagonists on the antinociceptive effect of 2a in the mouse antiwrithing assay.
Figure 5
Figure 5
Substitution of 2a for morphine in nonwithdrawn morphine dependent monkeys.

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