14β-O-cinnamoylnaltrexone and related dihydrocodeinones are mu opioid receptor partial agonists with predominant antagonist activity

Article abstract of DOI:10.1021/jm8012272

14-O-Cinnamoyl esters of naltrexone (6) were synthesized and evaluated in isolated tissue assays in vitro and in vivo in mouse antinociceptive assays. Their predominant opioid receptor activity was mu receptor (MOR) antagonism, but the unsubstituted cinna

Full text of DOI:10.1021/jm8012272

J. Med. Chem. 2009, 52, 1553–1557
1553
14ꢀ-O-Cinnamoylnaltrexone and Related Dihydrocodeinones are Mu Opioid Receptor Partial
Agonists with Predominant Antagonist Activity
H. Moynihan,† A. R. Jales,† B. M. Greedy,‡ D. Rennison,‡ J. H. Broadbear,§ L. Purington,§ J. R. Traynor,§ J. H. Woods,§
J. W. Lewis,‡ and S. M. Husbands*,‡
Department of Pharmacy and Pharmacology, UniVersity of Bath, Bath BA2 7AY, U.K., School of Chemistry, UniVersity of Bristol,
Bristol BS8 1TS, U.K., and Department of Pharmacology, UniVersity of Michigan, Ann Arbor, Michigan 48109
ReceiVed September 29, 2008
14-O-Cinnamoyl esters of naltrexone (6) were synthesized and evaluated in isolated tissue assays in vitro
and in vivo in mouse antinociceptive assays. Their predominant opioid receptor activity was mu receptor
(MOR) antagonism, but the unsubstituted cinnamoyl derivative (6a) had partial MOR agonist activity in
vitro and in vivo. When compared to the equivalent 14-cinnamoylaminomorphinones (5), the cinnamoyloxy
morphinones (6) as MOR antagonists had a shorter duration of action and were less effective as
pseudoirreversible antagonists. The antinociceptive activity of the cinnamoyloxycodeinones (7) was not
significantly greater than that of the morphinones (6), but they exhibited no evidence of any pseudoirreversible
MOR antagonism. In both respects, these profiles differed from those of the equivalent 14-cinnamoylami-
nocodeinones (4).
Introduction
Naloxone (1b) and naltrexone (1a) are prototype opioid
antagonists having some limited selectivity for mu opioid
receptors (MORs). They have found clinical utility as a treatment
for opiate1 and alcohol dependence2 and in reversing narcotic
overdosage.3 14-O-Alkyl ethers (2) of naltrexone retain pre-
dominant MOR antagonist activity,4,5 but the 14-O-3-phenyl-
propyl ether (2a) has recently been shown to have high-efficacy
and high-potency MOR agonist activity in antinociceptive
assays.6 We have conducted extensive studies of derivatives (3)
of 14ꢀ-amino-7,8-dihydromorphinone with a major focus on
the cinnamoylamino derivatives (4 and 5), of which the MOR-
selective irreversible antagonists clocinnamox [C-CAM (5b)]
and methcinnamox [M-CAM (5c)] are the most studied
examples.7-10 We here report preparation and evaluation of 14-
O-cinnamoyl esters of naltrexone (6) and the equivalent
codeinones (7) for comparison with the 14-amino derivatives
lower affinity for delta opioid receptors (DORs) and kappa
opioid receptors (KORs) (Table 1). The affinity of the morphi-
nones (6) was generally higher than that of the codeinones (7),
(4 and 5) and with the 14-O-phenylpropyl ether of naltrexone
(2a).
with DOR affinity showing greater disparity than MOR and
KOR affinity. The unsubstituted cinnamoylmorphinone (6a) had
Synthesis
Acylation of naltrexone 3-O-methyl ether (8a) to give 7a-c
was achieved using the appropriate anhydrides (Scheme 1),
themselves prepared from their equivalent acid chlorides by the
method of Armesto et al.11 Ligands 6a-c were similarly
prepared from 3-O-(tert-butyldimethylsilyl)naltrexone (8b)12 by
acylation and then removal of the protecting group with
potassium fluoride to yield the morphinones (Scheme 1).
the highest affinity for all three receptors, comparable to that
of naltrexone, and for MOR, higher than C-CAM (5b).
The morphinones (6) were evaluated for opioid receptor
functional activity in the mouse vas deferens (MVD) and guinea
pig ileum (GPI) isolated tissue assays.13 In MVD, the morphi-
nones displayed little agonist activity but were very potent opioid
receptor antagonists of the standard selective opioid receptor
agonists DAMGO (MOR), DPDPE (DOR), and U69593 (KOR),
having subnanomolar Ke values for all three opioid receptors
(Table 2). Although MOR antagonist potency was higher than
DOR and KOR potency, there was no appreciable selectivity
for MOR over DOR and KOR. In GPI, morphinones 6 partially
inhibited the electrically stimulated contractions of the tissue.
This opioid receptor partial agonist effect was not reversed by
selective antagonists CTAP (MOR) or norBNI (KOR), indicat-
ing very slow receptor offset like that observed with the similarly
lipophilic opioid ligands buprenorphine (10)15 and C-CAM
(5b).16
Results
The new ligands (6 and 7) in opioid receptor binding
assays13,14 displayed high affinity for MOR and significantly
* To whom correspondence should be addressed: Department of
Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath
BA2 7AY, U.K. Telephone: 44-(0)1225 383103. Fax: 44-(0)1225 386114.
E-mail: s.m.husbands@bath.ac.uk.
†
University of Bristol.
University of Bath.
University of Michigan.
‡
§
10.1021/jm8012272 CCC: $40.75
2009 American Chemical Society
Published on Web 03/02/2009

1554 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Moynihan et al.
Table 1. Binding Affinities of New Ligands for Opioid Receptors
Ki (nM)d
R′
MOR
DOR
KOR
6aa
H
Cl
CH3
H
Cl
0.40 ( 0.05
1.3 ( 0.45
3.3 ( 0.1
2.5 ( 0.7
3.5 ( 1.0
4.2 ( 1.5
0.40 ( 0.05
0.20 ( 0.0
4.8 ( 0.6
3.0 ( 0.2
0.34 ( 0.06
3.4 ( 0.8
15 ( 6
3.6 ( 2
8.3 ( 0.2
8.1 ( 0.7
4.3 ( 0.7
52 ( 12
36 ( 8.0
0.6 ( 0.1
0.4 ( 0.1
16 ( 2.5
1.4 ( 0.5
0.41 ( 0.09
6ba
6ca
19 ( 0.6
180 ( 58
110 ( 20
270 ( 80
6.5 ( 1
7ab
7bb
7cb
CH3
naltrexonea (1)
naltrexoneb (1)
MC-CAMb (4b)
C-CAMb (5b)
11 ( 3
4.8 ( 0.7
2.7 ( 0.2
0.48 ( 0.05
PPN (2a)b c
,
Figure 1. Dose-response curves for morphine alone (9) and after
pretreatment with a 32 mg/kg dose of morphinones 6a, 6b, and 6c in
the mouse warm water tail withdrawal assay. Pretreatment times (ptt)
were 24 h (6a, 6b, and 6c) and 30 min (6b).
a Binding to guinea pig brain membranes (method in ref 13). b Binding
to cloned human opioid receptors transfected into CHO cells (method in
ref 14). c Figures from ref 6. d Values are the average from two experiments
each carried out in duplicate. Tritiated ligands were [3H]DAMGO (MOR),
[3H]Cl-DPDPE (DOR), and [3H]U69593 (KOR).
Scheme 1a
Table 2. Antagonist Activity of New Ligands in the Mouse Vas
Deferens
Kea (nM)
R′
MOR
DOR
KOR
6a
6b
6c
H
Cl
CH3
0.020 ( 0.007
0.060 ( 0.03
0.12 ( 0.02
0.44 ( 0.09
0.25 ( 0.06 0.19 ( 0.06
0.060 ( 0.01
0.66 ( 0.2
7.2 ( 0.3
1.3 ( 0.2
0.54 ( 0.07
8.0 ( 0.6
naltrexone (1)
a Ke vs the standard selective agonists DAMGO (MOR), DPDPE (DOR),
and U69593 (KOR). Values are the average of at least four experiments.
Table 3. Inhibition of Agonist-Stimulated [35S]GTPγS Binding in
Recombinant Human Opioid Receptors
MOR Ke
DOR Ke
KOR Ke
R′
(nM)a
(nM)b
(nM)c
a (i) (RCO)2O, toluene, reflux; (ii) KF, MeOH, CH2Cl2.
7a
7b
7c
H
Cl
CH3
agonistd
agonistd
57 ( 2.2
not tested
7.2 ( 0.57
5.4 ( 0.75
0.19 ( 0.02
agonistd
8.2 ( 0.34
6.4 ( 0.35
0.97 ( 0.15
0.59 ( 0.04
0.53 ( 0.12
96 ( 14
agonistd
was measured. 7c like 7b had antagonist activity at MOR
(Table 3) but was a KOR partial agonist (Table 4).
MC-CAM (4b)
naltrexone (1)
C-CAM (5b)
9.8 ( 0.88
1.9 ( 0.16
0.10 ( 0.006
The in vivo activity of the 14-O-acyl derivatives was
investigated in mouse antinociceptive tests using assays with
thermal [tail withdrawal from 50 °C warm water (TW)]a or
chemical [acetic acid-induced writhing (AW)] stimulation.8
None of the naltrexone derivatives (6 and 7) exhibited any
significant opioid receptor agonist activity in TW, but all were
effective antagonists of morphine in this assay. A high dose
(32 mg/kg given 30 min before morphine) of each of the mor-
phinones (6) flattened the morphine dose-response curve up
to 320-1000 mg/kg of the agonist (illustrated for 6b in Figure
1). Pretreatment (24 h) with antagonist 6b resulted in a 10-fold
parallel rightward shift of the morphine dose-response curve,
but the shift produced by 6a and 6c was negligible (Figure 1).
The codeinones (7b and 7c) were antagonists of morphine in
TW but at 32 mg/kg shifted the morphine dose-effect curve in
the standard assay only 3-4-fold to the right with no evidence
of flattening, and there was no antagonist effect with a 24 h
pretreatment (data not shown).
The para-substituted cinnamoyloxymorphinone 6c and the
equivalent codeinone 7c unimpressively inhibited the acetic acid-
induced writhing effect, whereas 6a was substantially more
potent and effective (Figure 2). The only opioid antagonists
without any in vivo agonist effects were the p-chlorocinnamoy-
loxy derivatives (6b and 7b). These data confirm that the
chemical nociceptor used in the AW assay presents a less intense
challenge than the thermal stimulus in TW.
a Ke vs DAMGO. b Ke vs DPDPE. c Ke vs U69593. d The agonist activity
of these compounds is reported in Table 4.
Table 4. Opioid Agonist Stimulation of [35S]GTPγS Binding in
Recombinant Human Opioid Receptors
EC50 (nM); % stimulationa
R′
MOR
DOR
KOR
7a
7c
H
CH3
34.4 ( 5.0; 35
ANT
17.8 ( 11; 8
430 ( 110; 64
not determined
not determined
26 ( 4.9; 76
157 ( 3.4; 37
ANT
MC-CAM
(4b)b
morphine
15.6 ( 0.5; 93
316 ( 4.9; 103
484 ( 213; 62
a Percent maximal stimulation with respect to the standard agonists
DAMGO (MOR), U69593 (KOR), and DPDPE (DOR). ANT indicates
antagonist activity (Ke values reported in Table 3). Values are the means
of five or six experiments. Data supplied by NIDA Addiction Treatment
Discovery Program. b Data from ref 19.
The opioid receptor functional activity of the codeinones
(7) was investigated by their effects on stimulating
[35S]GTPγS binding in the recombinant human opioid
receptor transfected into CHO cells (Tables 3 and 4).14 The
unsubstituted cinnamoyl ester (7a) exhibited partial agonist
activity of modest potency for all three opioid receptors
(Table 4), whereas the p-chloro analogue (7b) had insignifi-
cant agonist activity for any opioid receptor but was an
antagonist of the standard agonists DAMGO (MOR), DPDPE
(DOR), and U69593 (KOR) (Table 3) which were also used
as the standards against which the agonist stimulation of 7a
a Abbreviations: TW, tail withdrawal from warm water; AW, acetic acid-
induced writhing.

14ꢀ-O-Cinnamoylnaltrexone and Related Dihydrocodeinones
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1555
group functioning in a manner similar to that of the tert-butyl
group in buprenorphine (10).18 The present 14-O-acylmorphi-
nones (6) fell short of C-CAM and M-CAM as pseudoirrevers-
ible antagonists; though in TW they all flattened the morphine
dose-response curve 30 min after their administration, their
MOR antagonist effect was much reduced at 24 h, whereas the
amides C-CAM (5b) and M-CAM (5c) had very pronounced
MOR antagonist effects at 24 h and beyond.8 6b, with p-chloro
substitution in the cinnamoyl aromatic ring, was the most
effective pseudoirreversible antagonist among the esters; its
MOR antagonist profile was comparable to that of ꢀ-FNA.8
Since, together with the corresponding codeinone (7b), 6b was
the only ester to lack any demonstrable antinociceptive action,
the profile of 6b is not dissimilar to that of C-CAM (5b). The
unsubstituted morphinone ester 6a in vivo was also basically
similar to the equivalent amide 5a.9 This means it showed little
agonist activity in TW but substantial activity in AW. Again
the most significant difference between 6a and 5a is the duration
of morphine antagonist activity in TW. 5a with a 24 h
pretreatment produced a 0.5-1 log unit shift of the morphine
dose-response curve,9 whereas the shift with 6a was barely
significant.
Figure 2. Inhibition of acetic acid-induced writhing by 6a, 6c, and 7c
after subcutaneous administration.
The biggest difference between the 14-cinnamoyloxy mor-
phinones and equivalent 14-cinnamoylamino morphinones was
found in the p-methyl-substituted derivatives (6c and 5c).
Whereas in the cinnamoylamino series M-CAM (5c) had no
agonist activity in TW or AW and was a substantially more
effective pseudoirreversible MOR agonist than the p-chloro
analogue C-CAM (5b),8 the p-methylcinnamoyloxy derivative
6c was a less effective MOR antagonist than the p-chloro
congener 6b and had measurable agonist activity in AW.
However, the SAR established for the 14-cinnamoylamino series
(5) that the 4′-substituted derivatives (5b and 5c) in vivo had
lower MOR efficacy than the unsubstituted parent (5a)9 also
applied to the present 14-cinnamoyloxy series (6).
The cinnamoyloxy codeinones (7b and 7c) in the antinoci-
ceptive assays had no agonist activity in TW and exhibited
parallel rightward shifts of the morphine dose-response curve
in this assay, indicating a competitive MOR antagonist effect.
In AW, 7c but not 7b had a weak opioid receptor agonist effect.
These profiles are not dissimilar to those of the equivalent
morphinones (6b and 6c) in the antinociceptive assays, the main
difference being the lack of any flattening of the morphine
dose-response curve by the codeinones in the MOR antagonist
assay in TW. The similarity of the in vivo agonist effects of
the cinnamoyloxycodeinones and morphinones contrasts with
the 14-cinnamoylamino series in which the codeinones (4) all
had substantially higher MOR efficacy in vivo than the
equivalent morphinones (5).9 In the in vitro functional assays
(Tables 2 and 3), the cinnamoyloxymorphinones (6b and 6c)
were very much more potent as MOR antagonists than the
equivalent codeinones (7b and 7c). This contrasts with the very
small difference in potency between the cinnamoylamino
morphinone (C-CAM) and equivalent codeinone (MC-CAM)
(Table 3).10
Figure 3. Agonist selectivity of 6a (10 mg/kg, subcutaneous) in the
writhing assay: NorBNI (KOR), 32 mg/kg (24 h pretreatment); ꢀ-FNA
(MOR), 32 mg/kg (24 h pretreatment); and naltrindole (DOR), 10 mg/
kg (24 h pretreatment). t test p values.
Agonist selectivity for the individual opioid receptor in AW
was determined for 6a by the use of selective antagonists for
MOR, DOR, and KOR. These were antagonists ꢀ-FNA (MOR),
naltrindole (DOR), and norBNI (KOR). ꢀ-FNA and norBNI
were administered 24 h before 6a to ensure a competitive (and
selective) antagonist effect. The agonist effect of 6a in AW was
partially antagonized by ꢀ-FNA and by naltrindole but not by
norBNI (Figure 3), so that it appears that in AW the agonist
effects of 6a are primarily mediated by DOR and MOR. 6b
was evaluated as an antagonist versus the agonists morphine
(MOR), BW373U86 (DOR), and bremazocine (KOR), proving
to be effective against only morphine with a 24 h pretreatment
(data not shown).
Discussion
Our prime interest in the activity of the naltrexone esters (6)
was in comparison to the activity of the equivalent amides
C-CAM (5b) and M-CAM (5c). The latter are highly effective
and selective MOR antagonists with insignificant agonist effects
in vivo.7,8 They are more effective than ꢀ-FNA in flattening
the dose-response curve of MOR agonists,8 but since they do
not form covalent bonds in vitro by Michael addition of protein
nucleophilic groups, they have been termed pseudoirreversible
antagonists.16,17 The very powerful binding to MOR in vivo
seems very likely to involve the lipophilic cinnamoylamino
It is of interest to compare the activity of 14-cinnamoylnal-
trexone (6a) with that of the phenylpropyl ether (2a) which is
structurally similar in having a three-carbon chain linking the
side chain aromatic ring to the C14 oxygen atom. The ether (2a)
in vivo gave a full response in a battery of thermal antinoci-
ceptive assays with potency up to 400 times greater than that
of morphine.7 In comparison, the cinnamoyl ester has much
more modest in vitro and in vivo MOR agonist activity. It must
be assumed that the relative conformational restraint of the R,ꢀ-

1556 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Moynihan et al.
3-O-(tert-Butyldimethylsilyl)-14ꢀ-(4-chlorocinnamoyloxy)-N-cy-
clopropylmethyl-7,8-dihydronormorphinone (9b). 8b (429 mg, 0.94
mmol) and 4-chlorocinnamoyl anhydride (616 mg, 1.77 mmol) were
treated like 9a to yield 9b as a clear oil (228 mg, 21%): EIMS m/z
619 (M+); HRMS (EI) m/z 619.2537 (M+), C35H42NO5Si requires
unsaturated cinnamoyl ester prevents an optimum interaction
with MOR in the preferred agonist conformation.
Conclusions
1
619.2521; H NMR δ 0.04 (2H, m), 0.19 (3H, s), 0.27 (3H, s),
The 14-O-cinnamoyl esters of naltrexone have predominant
opioid receptor antagonist activity both in vitro and in vivo. In
this regard, they are similar to the equivalent 14-N-cinnamoy-
lamino derivatives, but the latter are more potent antagonists
with longer duration. Additionally, the naltrexone esters (6) have
in vivo and in vitro MOR efficacy similar to that of the
corresponding codeinones (7), whereas the codeinone amides
(4) have substantially higher MOR efficacy than the morphi-
nones (5). These differences are less significant than the
difference between 14-cinnamoylnaltrexone (6a) and 14-O-
phenylpropylnaltrexone (2a). The greater side chain conforma-
tional freedom of the latter allows it to display very high potency
in vivo MOR agonist activity.
0.44 (2H, m), 0.72 (1H, m), 1.02 (9H, s), 4.67 (1H, s), 6.55 (1H,
d), 6.56 (1H, d), 6.66 (1H, d), 7.28 (2H, d), 7.52 (2H, d), 7.65
(1H, d); 13C NMR δ -4.70, -4.54, 3.68, 3.94, 9.46, 18.25, 23.21,
25.68, 26.92, 30.45, 35.68, 43.94, 51.02, 55.43, 59.27, 82.96, 89.53,
119.34, 119.85, 122.55, 126.32, 128.61, 129.18, 129.31, 132.86,
136.23, 137.98, 143.12, 146.72, 165.53, 207.06.
14ꢀ-(4-Chlorocinnamoyloxy)-N-cyclopropylmethyl-7,8-dihy-
dronormorphinone (6b). 9b was treated with KF as described for
1
6a to yield 6b as a white foam (77%): EIMS m/z 505 (M+); H
NMR δ 0.04 (2H, m), 0.45 (2H, m), 0.74 (1H, m), 4.80 (1H, s),
6.57 (1H, d), 6.62 (1H, d), 6.76 (1H, d), 7.36 (2H, d), 7.50 (2H,
d), 7.64 (1H, d); 13C NMR δ 3.68, 3.97, 9.43, 23.11, 27.08, 30.19,
35.75, 43.97, 51.40, 55.46, 59.27, 82.93, 90.19, 118.26, 119.82,
120.01, 125.15, 128.16, 129.18, 129.31, 132.86, 136.23, 138.83,
143.21, 143.50, 165.56, 209.09. Anal. (C29H28NO5 · (CO2H)2 ·
2.5H2O) C, H, N.
Experimental Section
3-O-(tert-Butyldimethylsilyl)-14ꢀ-(4-methylcinnamoyloxy)-N-cy-
clopropylmethyl-7,8-dihydronormorphinone (9c). 8b (584 mg, 1.28
mmol) and 4-methylcinnamoyl anhydride (690 mg, 2.25 mmol)
were treated like 9a to yield 9c as a clear oil (424 mg, 55%): EIMS
m/z 599 (M+); HRMS (EI) m/z 599.3088, C36H45NO5Si requires
Column chromatography was performed under gravity, over silica
gel 60 (35-70 mm) purchased from Merck. Analytical TLC was
performed using aluminum-backed plates coated with Kieselgel 60
F
254, from Merck. The chromatograms were visualized using either
UV light (UVGL-58, short wavelength), ninhydrin (acidic), or
potassium permanganate (basic). Melting points were carried out
using a Reichert-Jung Thermo Galen Kopfler block or a Gallenkamp
MFB-595 melting point apparatus and are uncorrected. High- and
low-resolution electron impact (EI) mass spectra were recorded
using EI ionization at 70 eV, on a VG AutoSpec instrument,
equipped with a Fisons autosampler. 1H NMR and 13C NMR spectra
1
599.3067; H NMR δ 0.05 (2H, m), 0.21 (3H, s), 0.29 (3H, s),
0.44 (2H, m), 0.75 (1H, m), 0.99 (9H, s), 2.38 (3H, s), 4.67 (1H,
s), 6.53 (1H, d), 6.56 (1H, d), 6.65 (1H, d), 7.19 (2H, d), 7.48 (2H,
d), 7.68 (1H, d); 13C NMR δ -4.70, -4.51, 3.71, 4.48, 9.46, 18.25,
21.46, 23.24, 25.21, 30.70, 32.73, 35.68, 43.94, 51.05, 55.53, 59.30,
82.57, 89.56, 118.16, 119.31, 122.51, 126.36, 127.69, 128.61,
129.78, 137.98, 140.36, 143.34, 144.56, 146.77, 165.98, 207.09.
14ꢀ-(4-Methylcinnamoyloxy)-N-cyclopropylmethyl-7,8-dihy-
dronormorphinone (6c). 9c was treated with KF as described for
1
were recorded using a JEOL 270 (operating at 270 MHz for H
and 67.8 MHz for 13C) spectrometer. Chemical shifts (δ) are
measured in parts per million. Spectra were referenced internally
using TMS as the standard. Only diagnostic peaks have been quoted
for proton NMR. Microanalysis was performed with a Perkin-Elmer
240C analyzer. Chemicals and solvents were purchased from
Aldrich Chemical Co. Compounds were submitted for testing as
their oxalate salts, formed by adding 1 equiv of oxalic acid to an
ethanolic solution of the ligand.
1
9a to yield 6c as an oil (99%): EIMS m/z 485 (M+); H NMR δ
0.04 (2H, m), 0.44 (2H, m), 0.72 (1H, m), 4.77 (1H, s), 6.53 (1H,
d), 6.60 (1H, d), 6.75 (1H, d), 7.15 (2H, d), 7.48 (2H, d), 7.70
(1H, d); 13C NMR δ 3.62, 3.90, 9.49, 21.46, 24.70, 26.32, 30.99,
32.79, 43.97, 51.46, 55.59, 59.34, 82.61, 90.29, 118.23, 120.01,
125.24, 127.94, 128.23, 129.66, 131.66, 132.04, 138.90, 140.80,
143.53, 144.71, 166.61, 209.06. Anal. (C30H31NO5 ·(CO2H)2 ·2H2O)
C, H, N.
3-O-(tert-Butyldimethylsilyl)-14ꢀ-cinnamoyloxy-N-cyclopropy-
lmethyl-7,8-dihydronormorphinone (9a). A solution of 8b (593 mg,
1.3 mmol) and cinnamoyl anhydride (830 mg, 3.0 mmol) in dry
toluene (12 mL) was heated to reflux for 3 h. After cooling, the
reaction mixture was washed with a sodium bicarbonate solution
(2 × 5 mL) and water (5 mL) and dried over magnesium sulfate,
and the solvent was removed in vacuo. The residue was purified
by silica gel chromatography (CH2Cl2:MeOH, 49:1) to give 9a (269
mg, 44%): EIMS m/z 585 (M+); HRMS (EI) m/z 585.2925 (M+),
N-Cyclopropylmethyl-14ꢀ-cinnamoyloxy-7,8-dihydrocodei-
none (7a). A solution of 8a (500 mg, 1.41 mmol) in anhydrous
toluene (80 mL) was treated with cinnamoyl anhydride (512 mg,
1.84 mmol) and the resulting mixture heated to reflux and stirred
overnight. Upon cooling, the solution was washed with a Na2CO3
solution (2 × 20 mL) and water (20 mL), dried over MgSO4, and
evaporated to dryness. Silica gel chromatography (CH2Cl2:MeOH:
NH3, 198:1:1) gave 7a as a white solid (303 mg, 44%): ESMS m/z
486 (MH+); HRMS (ES) m/z 486.2259 (MH+), C30H32NO5 requires
486.2275; 1H NMR δ -0.01 to 0.08 (2H, m), 0.39-0.48 (2H, m),
0.69-0.77 (1H, m), 1.57-1.61 (1H, m), 1.69 (1H, dt), 2.13-2.20
(1H, m), 2.25-2.38 (3H, m), 2.53 (1H, dd), 2.60-2.75 (3H, m),
2.92-2.97 (1H, m), 3.11 (1H, d), 3.89 (3H, s), 4.58 (1H, d), 4.75
(1H, s), 6.57 (1H, d), 6.64 (1H, d), 6.71 (1H, d), 7.37-7.43 (3H,
m), 7.56-7.60 (2H, m), 7.70 (1H, d); 13C NMR δ 3.68, 3.90, 9.45,
23.06, 27.19, 30.26, 35.78, 43.93, 51.27, 55.43, 56.73, 59.29, 82.69,
90.13, 114.79, 119.22, 119.51, 125.88, 128.14, 128.64, 128.90,
130.35, 134.33, 142.92, 144.62, 144.88, 165.74, 207.54; mp
(oxalate) 124-126 °C. Anal. (C30H31NO5 ·(CO2H)2 ·0.5H2O) C, H,
N.
1
C35H43NO5Si requires 585.2910; H NMR δ 0.07 (2H, m), 0.19
(3H, s), 0.28 (3H, s), 0.44 (2H, m), 0.74 (1H, m), 1.00 (9H, s),
4.69 (1H, s), 6.57 (1H, d), 6.59 (1H, d), 6.66 (1H, d), 7.70 (1H, d);
13C NMR δ -4.64, -4.48, 3.75, 4.00, 9.49, 18.29, 23.24, 25.75,
26.99, 30.45, 35.75, 43.97, 51.08, 55.46, 59.31, 82.77, 89.95,
119.31, 119.37, 122.55, 126.39, 128.20, 128.71, 130.39, 134.39,
138.01, 144.01, 146.80, 165.85, 207.22.
14ꢀ-Cinnamoyloxy-N-cyclopropylmethyl-7,8-dihydronormor-
phinone (6a). A solution of 9a (140 mg, 0.24 mmol) and potassium
fluoride (35 mg, 0.60 mmol) in MeOH (11 mL) and CH2Cl2 (1
mL) was stirred for 1 h at ambient temperature. Solvent evaporation
gave a residue that was purified by silica gel column chromatog-
raphy (CH2Cl2:MeOH, 49:1) to give 6a as a white foam (57%):
EIMS m/z 505 (M+); 1H NMR δ 0.05 (2H, m), 0.43 (2H, m), 0.76
(1H, m), 4.83 (1H, s), 6.58 (1H, d), 6.62 (1H, d), 6.80 (1H, d),
7.38 (3H, m), 7.56 (2H, m), 7.72 (1H, d); 13C NMR δ 3.71, 4.00,
9.46, 23.18, 27.11, 30.19, 35.78, 44.00, 51.43, 55.56, 59.31, 82.77,
90.26, 118.29, 119.28, 120.07, 125.18, 128.39, 128.93, 129.31,
130.39, 134.39, 138.90, 143.53, 144.74, 165.88, 209.22. Anal.
(C29H29NO5 ·(CO2H)2 ·2H2O) C, H, N.
N-Cyclopropylmethyl-14ꢀ-4′-chlorocinnamoyloxy-7,8-dihydro-
codeinone (7b). 8a (310 mg, 0.87 mmol) in anhydrous toluene (50
mL) was added to 4-chlorocinnamoyl anhydride (400 mg, 1.16
mmol) as described for 7a to give 7b as a white solid (110 mg,
24%): EIMS m/z 519 (M+); HRMS (EI) m/z 519.1822 (M+),
1
C30H30NO5Cl requires 519.1813; H NMR δ 0.01-0.12 (2H, m),
0.37-0.52 (2H, m), 0.67-0.82 (1H, m), 2.54 (1H, dd), 3.13 (1H,

14ꢀ-O-Cinnamoylnaltrexone and Related Dihydrocodeinones
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1557
N-Substituted 14-phenylpropyloxymorphinan-6-ones with unantici-
pated agonist properties: Extending the scope of common structure-
activity relationships. J. Med. Chem. 2003, 46, 1758–1763.
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Medzihradsky, F.; Jacobson, A. E. Very long-acting narcotic antago-
nists: The 14ꢀ-p-substituted cinnamoylaminomorphinones and their
partial mu agonist codeinone relatives. Arzneim. Forsch. 1989, 39,
570–575.
d), 3.90 (3H, s), 4.58 (1H, d), 4.75 (1H, s), 6.56 (1H, d), 6.66 (1H,
d), 6.73 (1H, d), 7.38 (2H, m), 7.52 (2H, m), 7.66 (1H, d); 13C
NMR δ 3.62, 3.88, 9.40, 23.04, 27.11, 30.23, 35.67, 43.89, 51.17,
55.39, 56.72, 59.22, 82.83, 90.02, 114.88, 119.49, 119.76, 125.78,
128.55, 129.12, 129.25, 132.79, 136.17, 142.88, 143.10, 144.84,
165.42, 207.33; mp (oxalate) 122-124 °C. Anal. (C30H30-
NO5Cl·(CO2H)2 ·0.5H2O) C, H, N.
(8) Broadbear, J. H.; Sumpter, T. L.; Burke, T. F.; Husbands, S. M.; Lewis,
J. W.; Woods, J. H.; Traynor, J. R. Methcinnamox is a potent, long-
lasting and selective antagonist of morphine-mediated antinociception
in the mouse: Comparison with clocinnamox, ꢀ-FNA and ꢀ-chlorn-
altrexamine. J. Pharmacol. Exp. Ther. 2000, 294, 933–940.
(9) Nieland, N. P. R.; Moynihan, H.; Carrington, S.; Broadbear, J.; Woods,
J. H.; Traynor, J. R.; Husbands, S. M.; Lewis, J. W. Structural
determinants of opioid activity in derivatives of 14-aminomorphinones:
Effect of substitution in the aromatic ring of cinnamoylaminomor-
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aminomorphinones: Effects of changes to the C14-amino to aryl ring
linker chain. J. Med. Chem. 2006, 49, 6104–6110.
N-Cyclopropylmethyl-14ꢀ-4′-methylcinnamoyloxy-7,8-dihydro-
codeinone (7c). Using the same procedure described for 7b but with
4-methylcinnamoyl anhydride gave 7c (30%): EIMS m/z 499 (M+);
HRMS (EI) m/z 499.2361 (M+), C31H33NO5 requires 499.2359; 1H
NMR δ 0.06-0.13 (2H, m), 0.39-0.53 (2H, m), 0.69-0.82 (2H,
m), 2.40 (3H, s), 2.55 (1H, dd), 3.13 (1H, d), 3.92 (3H, s), 4.60
(1H, d), 4.77 (1H, s), 6.55 (1H, d), 6.66 (1H, d), 6.74 (1H, d), 7.23
(2H, m), 7.49 (2H, m), 7.70 (1H, d); 13C NMR δ 3.65, 3.85, 9.42,
21.43, 23.05, 27.16, 30.23, 35.73, 43.90, 51.22, 55.46, 56.73, 59.26,
82.50, 90.09, 114.86, 118.07, 119.47, 125.89, 128.09, 128.66,
129.58, 131.57, 140.74, 142.87, 144.57, 144.87, 165.89, 207.49;
mp (oxalate) 126-128 °C. Anal. (C31H33NO5 ·(CO2H)2 ·0.5H2O)
C, H, N.
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synthesis of 4-o-cinnamoyl quinic and shikimic acid derivatives. J.
Org. Chem. 2003, 68, 5784–5787.
Acknowledgment. This work was funded through NIDA
Grants DA00254 and DA07315 and the in vitro characterization
of compounds carried out through the NIDA Abuse Treatment
Discovery Program (ATDP).
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6
∆
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Lewis, J. W.; Toll, L. Characterization of opiates, neuroleptics, and
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2001, 428, 29–36.
Supporting Information Available: Full experimental details
and spectroscopic data (IR, 1H NMR, 13C NMR, mass spectra, and
microanalysis data), including biological assay methods. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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