14β-Arylpropiolylamino-17-cyclopropylmethyl-7,8-dihydronormorphinones and related opioids. Further examples of pseudoirreversible μ opioid receptor antagonists

Article abstract of DOI:10.1021/jm901074a

14β-4′-Chlorocinnamoylaminodihydronormorphinone (2a), and analogues, are selective pseudoirreversible antagonists of the μ opioid receptor (MOR). The preparation of analogues with ethynic bonds, replacing the ethenic bond of 2a, is described. The new liga

Full text of DOI:10.1021/jm901074a

6926 J. Med. Chem. 2009, 52, 6926–6930
DOI: 10.1021/jm901074a
14β-Arylpropiolylamino-17-cyclopropylmethyl-7,8-dihydronormorphinones and Related Opioids.
Further Examples of Pseudoirreversible μ Opioid Receptor Antagonists
Nick P.R. Nieland,† David Rennison,† Jillian H. Broadbear,§ Lauren Purington,§ James H. Woods,§ John R. Traynor,§
John W. Lewis,‡ and Stephen M. Husbands*,‡
†School of Chemistry, University of Bristol, Bristol, U.K., ‡Department of Pharmacy and Pharmacology, University of Bath, Claverton Down,
Bath, BA2 7AY, U.K., and §Department of Pharmacology, University of Michigan, Ann Arbor, Michigan
Received July 21, 2009
14β-40-Chlorocinnamoylaminodihydronormorphinone (2a), and analogues, are selective pseudoirre-
versible antagonists of the μ opioid receptor (MOR). The preparation of analogues with ethynic bonds,
replacing the ethenic bond of 2a, is described. The new ligands, in mouse antinociceptive assays, had
pseudoirreversible MOR antagonist activity, which, in the case of 8b was of longer duration than that of
2a. The related codeinone (9b) had only antagonist activity in vivo, in contrast to 2a’s codeinone
equivalent 3a, which had potent antinociceptive activity.
Introduction
appropriate cinnamic acid (Scheme 1).4,5 Target compounds
(9) were then accessed by acylation of N-cyclopropylmethyl-
14β-aminodihydronorcodeinone (18b) (Scheme 2).6,7 The
equivalent morphinones (8) were accessed from codeinones
(9) by 3-O-demethylation with boron tribromide. Direct
alkylation of N-cyclopropylmethyl-14β-aminodihydronorco-
deinone and N-cyclopropylmethyl-14β-aminodihydronorco-
deinone using the arylpropargyl bromide (17) gave target
compounds 10, 11 (Scheme 2).
The 14β-hydroxy-7,8-dihydronormorphinone derivatives
naloxone (1a) and naltrexone (1b) were the prototypic
μ opioid receptor (MORa) antagonists, and both have been
introduced into clinical practice. We have been interested in
derivatives of the structurally equivalent 14β-amino-17-cyclo-
propylmethyl-7,8-dihydronormorphinone (1c) for some time,
with particular attention to the 14β-cinnamoylamino deriva-
tives (2, 3)1 and related side-chain analogues (6-7).2 The most
studied derivatives have been clocinnamox (C-CAM, 2a)11
and methcinnamox (M-CAM, 2b)10 and their codeinone
precursors (3a, 3b).3 They are impressive MOR-selective
pseudoirreversible antagonists, with only the codeinones
(3a, 3b) having any in vivo antinociceptive activity.1 The
present study was undertaken to determine the OR profile
of the analogues of 14β-cinnamoylamino and 14β-cinnamyl-
amino derivatives (2-5) in which the trans-ethenic bond in the
cinnamoyl or cinnamyl group is replaced by an ethynic bond
in the arylpropiolylamino derivatives (8, 9) and arylpropar-
gylamino derivatives (10, 11). The ethynic bond in the new
ligands places the key aromatic group further from C14 than
in the cinnamoylamino and cinnamylamino ligands pre-
viously studied. The data collected in the present study show
that the arylpropiolylamino morphinones (8) are pseudoirre-
versible MOR antagonists at least the equal of their cinna-
moylamino analogues (Chart 1).
Results
Affinity for the individual types of opioid receptors (OR)
was determined by displacement binding assays using mem-
branes prepared from Chinese hamster ovary (CHO) cells
expressing recombinant human opioid receptors. The selec-
tive radioligands used were [3H]-DAMGO (MOR), [3H]U-
69593 (κopioid receptor, KOR), and [3H]Cl-DPDPE (δopioid
receptor, DOR).8 All the new morphinones (8a, 8b, 10) had
high affinity for all OR with no selectivity for any one
(Table 1). The equivalent codeinones (9a, 9b, 11) had generally
lower OR affinity, particularly at DOR and KOR. Overall, the
affinities of the new series (8-11) were similar to the affinities
displayed by the equivalent cinnamoylamino derivatives (2, 3)
and cinnamylamino derivatives (4, 5).
In vitro OR functional activity of the new ligands was
determined in assays in which stimulation of [35S]GTPγS
binding is measured for individual recombinant human OR
transfected into CHO cells.8,9 The morphinones (8a, 8b, 10)
were potent antagonists for all three OR, except that 8a
showed low efficacy agonism at KOR (Table 1). The equiva-
lent codeinones (9a, 9b, 11) had MOR antagonist activity of
lower potency than their morphinone equivalents (8a, 8b, 10).
The only codeinone with both KOR and DOR antagonist
activitywas the arylpropargyl derivative(11), but potency was
low in each case so that 11 profiled as a MOR antagonist of
some selectivity. The arylpropiolylamino codeinones (9a, 9b)
were KOR partial agonists; 9a also had DOR partial agonist
activity, whereas 9b was a DOR antagonist (Table 1).
Synthesis
While phenylpropiolic acid is commercially available,
p-chlorophenylpropiolic acid (15) and p-chlorophenylpropar-
gyl bromide (17) were obtained by preparation from the
*To whom correspondence should be addressed. Phone: (0)1225
383103.Fax: (0)1225 386114. E-mail: s.m.husbands@bath.ac.uk.
a Abbreviations: OR, opioid receptors; C-CAM, 14β-40-chlorocinna-
moylaminodihydronormorphinone; M-CAM, 14β-40-methylcinnamoyl-
aminodihydronormorphinone; norBNI, nor-binaltorphimine; TW, tail
withdrawal; AS, abdominal stretch.
r
pubs.acs.org/jmc
Published on Web 10/20/2009
2009 American Chemical Society

Brief Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21 6927
Scheme 1a
a (i) EtOH, c H2SO4, reflux, 4 h, 80%; (ii) Br2, DCM, rt, overnight, 70%; (iii) KOH, EtOH, reflux, 6 h, 40%; (iv) DIBAL, Et2O, -78 °C to rt,
overnight, 64%; (v) PPh3, imidazole, Br2, DCM, rt, 1.5 h, 79%.
3
Chart 1. 14-Substituted 7,8-Dihydromorphinones and Codeinones
Scheme 2a
with peak effect (at 3.2 mg/kg), reaching about two-thirds
of the maximum possible (Figure 1). In AS, 9a at a dose of
0.32 mg/kg totally inhibited the stretching response. This
effect was reversed by the selective MOR antagonist methcin-
namox (M-CAM, 2b) but not by naltrindole (DOR) and
partially by norBNI (KOR) (Table 2).
All of the arylpropiolylamino ligands were able to antag-
onize the antinociceptive effects of morphine in TW (Table 3).
When a high dose of the test ligand (32 mg/kg) was admini-
stered 30 min before morphine, 8a, 8b, and 9b all flattened the
morphine dose-response curve and were shown to retain
antagonist activity beyond 48, 144, and 24 h, respectively. 9a,
which had agonist activity in TW, was only tested at 24 h and
beyond; it was active as an MOR antagonist at 24 h (Table 3).
The most impressive in vivo morphine antagonist among
the new ligands was thus the p-chlorophenylpropiolylamino
a (i) R0C6H4CCCOCl, NEt3, DCM, rt, overnight, 27-71%; (ii) BBr3,
morphinone (8b). Its OR antagonist selectivity was investi-
DCM, -30 °C to rt, 0.5 h, 72-75%; (iii) ClC6H4CCCH2Br, K2CO3,
DMF, 90 °C, 3 h, 63-74%.
gated in AS against ED100 doses of the selective agonists
morphine (MOR), bremazocine (KOR), and BW373U86
(DOR). At a dose of 3.2 mg/kg of 8b, the inhibitory effect
of each of the selective agonists was fully reversed; 1 mg/kg 8b
was also substantially effective, with the MOR and DOR
activity showing superiority over KOR activity (Figure 2).
With 24 h pretreatment, 3.2 mg/kg 8b still showed substantial
OR antagonist activity; this activity was significantly MOR
selective (Figure 3).
The arylpropiolylamino derivatives (8a, 8b, 9a, 9b) were
evaluated in vivo in mouse antinociceptive assays using
thermal (50 °C water tail withdrawal; TW) and chemical
(acetic acid induced stretching; AS) nociceptors.10 Only the
phenylpropiolylamino codeinone (9a) had any antinocicep-
tive activity in these assays. In TW, it was a partial agonist

6928 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21
Nieland et al.
Table 1. Binding Affinities (Ki) of New Compounds to Opioid Receptors and Antagonist Activity (Ke) in the [35S]GTPγS Binding Assay
Ki/nMa
Ke/nMd
MOR
DOR
KOR
MOR
DOR
KOR
8a
8b
10
9a
9b
11
2ab
3ab
4c
1.31 ( 0.27
3.75 ( 0.15
0.97 ( 0.12
1.46 ( 0.31
7.43 ( 2.7
9.68 ( 2.0
2.98 ( 0.22
4.78 ( 0.58
0.32 ( 0.03
0.70 ( 0.10
1.60 ( 0.08
5.41 ( 1.2
3.26 ( 0.32
28.3 ( 2.0
65.2 ( 5.6
136 ( 17
2.69 ( 0.23
4.79 ( 0.73
0.63 ( 0.08
44.5 ( 4.6
1.12 ( 0.06
2.73 ( 0.36
2.89 ( 0.53
7.86 ( 1.8
13.7 ( 1.0
74.4 ( 9.4
1.41 ( 0.52
16.4 ( 2.5
0.91 ( 0.12
53.6 ( 0.95
0.37 ( 0.07
0.52 ( 0.08
0.25 ( 0.02
4.60 ( 0.61
1.16 ( 0.06
4.24 ( 0.43
0.53 ( 0.13
0.97 ( 0.15
NT
0.38 ( 0.03
0.73 ( 0.04
1.43 ( 0.18
agoniste
agonistf
0.29 ( 0.03
2.50 ( 0.09
agonistg
agonisth
106 ( 12
0.10 ( 0.006
9.81 ( 0.88
NT
29.5 ( 1.4
152 ( 27
0.19 ( 0.02
7.16 ( 0.57
NT
5c
NT
NT
NT
a Ki/nM vs [3H]DAMGO (MOR), [3H]U69593 (KOR) and [3H]DPDPE (DOR). Data are the mean of two experiments, each carried out in triplicate.
b Data from Nieland et al.1 c Data from Rennison et al.2 d Ke/nM vs the standard agonists DAMGO (MOR), U69593 (KOR) and DPDPE (DOR). e Agonist
activity, EC50 75.1 ( 16.9 nM, 47% stimulation relative to DPDPE. f Agonist activity, EC50 0.30 ( 0.09 nM, 21% stimulation relative to U69593. g Agonist
activity, EC50 3.18 ( 0.73 nM, 77% stimulation relative to U69593. h Agonist activity, EC50 20.0 ( 2.78 nM, 25% stimulation relative to U69593. NT: not tested.
Data supplied by the NIDA Addiction Treatment Discovery Program.
Figure 1. Antinociceptive activity of 9a in the mouse warm water
tail withdrawal assay.
Figure 2. Antagonist activity of 8b in the mouse abdominal stretch
(AS) assay vs fully effective doses of standard opioid receptor
agonists. ** p < 0.01 compared to morphine (MOR) or BW373-
U86 (DOR) alone. ¼ p < 0.05, ¼¼ p < 0.01 compared to control
(8b alone), which was not different from vehicle (saline). One way
ANOVA with Dunnett’s posthoc test.
Table 2. Agonist Selectivity of 9a (0.32 mg/kg, sc) in the Mouse AS
Assay
treatment
control
9a
no. of stretches
10.0 ( 1.3
0a
9a þ MCAM
12.0 ( 1.5
(1.8 mg/kg, 1 h pretreatment)
9a þ naltrindole
Discussion
0a
The data obtained from the evaluation of the new ligands
synthesized in the present study conform to the pattern of
structure-activity relationships established for the analogous
14-cinnamoylamino derivatives.1 That is, the arylpropiolyl-
amino morphinones (8a, 8b) behave as pseudoirreversible
MOR antagonists of long duration and that p-chloro sub-
stitution in the side chain aromatic ring eliminates agonist
activity, enhances MOR antagonist activity, and increases the
duration of the latter effect. Comparison with the equivalent
cinnamoylaminomorphinones (2a, 2c) reveals substantial
similarity between 2a and 8b in binding and in vitro assays
(Table 1). Comparison of the binding of the 14-propiolyl-
amino codeinones (9) with the corresponding morphinones
(8) shows little difference in MOR binding affinity but greater
difference in KOR and particularly DOR binding. Similar
effects were seen in comparison of the 14-cinnamoylamino
morphinones (2) with codeinones (3). This confirms that for
MOR binding the lipophilic C14 side chain is the dominant
structural motif, whereas for KOR and DOR binding, the
C3 phenolic group is also required. In vivo it appears that
the arylpropiolylamino derivatives (8a, 8b) have somewhat
longer duration of morphine antagonist activity than the
(10 mg/kg, 15 min pretreatment)
9a þ norBNI
5.0 ( 2.0a
(32 mg/kg, 24 h pretreatment)
a Significantly different from controls.
Table 3. Antagonist Activity in the Mouse Tail-Withdrawal (50 °C)
Test
pretreatment
morphine ED50 mg/kg, ip
shift
control
9a, 32 mg/kg
9.3 (7.3-11.8)
38.3 (12.2-119)a
17.1 (10.7-27.2)
.100a,b
24 h
48 h
4.1
1.8
d
9b, 32 mg/kg
30 min
24 h
118.5 (99.4-141.2)a
25.0 (8.2-76.1)
.100a,b
12.7
2.7
d
4 days
2.5 h
48 h
8a, 32 mg/kg
8b, 32 mg/kg
65.1 (28.1-150)a
.100a,b
7
30 min
3 day
4 day
6 day
d
.100a,c
d
112.9 (43.6-292)a
40.8 (28.1 - 59.3)a
12.1
4.4
a Significantly different from control. b 0% effect, 100 mg/kg. c 20%
effect, 100 mg/kg. d Shift was too large to determine.

Brief Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21 6929
Experimental Section
Reagents and solvents were purchased from Aldrich or
Lancaster and used as received. NMR Spectra: Jeol Lambda-
270-MHz instrument: 1H at 270 MHz, with TMS as an internal
standard. Only representative examples of the synthesis are
shown. Oxalate salts were formed prior to pharmacological
evaluation. Tested compounds had purity g95%.
N-Cyclopropylmethyl-14β-[phenylpropioloylamino]-7,8-dihy-
dronorcodeinone (9a). Oxalyl chloride (8.8 equiv) and phenyl-
propiolic acid (1.1 equiv) in anhydrous toluene were heated at
reflux for 1 h. The solvent was removed, the residue dissolved in
anhyd CH2Cl2, added dropwise to a solution of 18b (1 equiv)
and triethylamine (1.1 equiv) in anhyd CH2Cl2, and stirred at rt
overnight. The solvent was removed and the crude residue
purified by column chromatography to yield a white solid
(71%); Rf (CH2Cl2:MeOH, 50:1) 0.26. 1H NMR (CDCl3) 0.21
(2H, m), 0.60 (2H, m), 0.89 (1H, m), 2.32-2.52 (2H, m), 3.10
(1H, d), 3.88 (3H, s), 4.95 (1H, s), 6.63 (1H, d), 6.74 (1H, d), 7.30
(1H), 7.35-7.61 (5H, m).
N-Cyclopropylmethyl-14β-[phenylpropioloylamino]-7,8-dihy-
dronormorphinone (8a). To the codeinone (9a) in anhyd
CH2Cl2 at -30 °C under N2, was added BBr3 (6 equiv, 1 M in
CH2Cl2) slowly. The reaction was allowed to reach rt over 1 h
before adding a 1:1 mixture of ice:ammonia (concd). The
organic phase was isolated, the aqueous layer washed (ꢀ3) with
CHCl3:MeOH (3:1), the combined organic fractions washed
with brine, dried, and evaporated to dryness. Column chroma-
tography gave 8a as a white solid (72%); Rf (CH2Cl2: MeOH,
20:1) 0.47. 1H NMR (DMSO) 0.25 (2H, m), 0.62 (2H, m), 0.92
(1H, m), 3.10 (1H, d), 5.01 (1H, s), 6.61 (1H, d), 6.80 (1H, d), 7.38
(5H, m).
Figure 3. Antagonist selectivity of 8b (3.2 mg/kg) against ED100
doses of the selective agonists morphine (MOR), BW373U86
(DOR) and bremazocine (KOR) in the mouse abdominal stretch
(AS) assay after 24 h pretreatment. ** p < 0.01 compared to
morphine. ¼¼ p < 0.01 compared to control (8b alone), which
was not different from vehicle (saline). One way ANOVA with
Dunnett’s posthoc test.
cinnamoylamino equivalents (2a, 2c).1 When the morphine
dose-response curve was determined 4 days after admini-
stration of a 32 mg/kg dose of the test antagonist, 2a shifted
the dose-response curve about 5-fold to the right,11 whereas
in the present study, the same dose of 8b in the same protocol
resulted in a 12-fold shift (Table 3).
N-Cyclopropylmethyl-14β-[30-(400-chlorophenyl)-propargyl-
amino]-7,8-dihydronormorphinone (10). 18a was treated with
3-(40-chlorophenyl)propargyl bromide (17, 1.1 equiv) in the
presence of potassium carbonate (5 equiv) in dimethylforma-
mide at 90 °C for 12 h. The solvent was removed and the crude
residue was purified by column chromatography to afford 10 as
There is perhaps greater difference in in vivo activity
between the arylpropiolylamino codeinones (9a, 9b) and the
corresponding cinnamoylamino codeinones (3a, 3c). Whereas
9b had no antinociceptive activity in TW or AS, 3a, though
having no agonist activity in TW, has potent antinociceptive
activity in AS, being fully effective at 0.2 mg/kg.1,12,13 Simi-
larlytheMOR partialagonism shown in vivoby3cisofhigher
efficacy than that of 9a in the present study.1 Thus it appears
that the conformationally linear side chains of the arylpro-
piolylamino derivatives (8, 9) are associated with lower MOR
efficacy and more profound MOR antagonism than the
equivalent cinnamoylamino derivatives (2, 3). This suggests
that for antagonism, the optimum position for the lipoph-
ilic aryl moiety is further from C14 than is achieved in
the cinnamoyl derivatives. Rennison et al.2 showed that the
14β-phenylbutylamidomorphinone (12), with a longer spacer
between C14 and the aryl group, was more effective than
C-CAM in flattening the dose-response curve of DAMGO in
a [35S]GTPγS binding assay.
1
a white solid (63%); Rf 0.42 (CH2Cl2:MeOH, 20:1). H NMR
(CDCl3) δ 0.18 (2H, m), 0.54 (2H, m), 0.89 (1H, m), 3.06 (1H, d),
3.57 (2H, s), 4.70 (1H, s), 6.60 (1H, d), 6.71 (1H, d), 7.29 (2H, d),
7.37 (2H, d).
Acknowledgment. NIDA grants DA00254 and DA07315.
In vitro evaluation through the NIDA Abuse Treatment
Discovery Program (ATDP).
Supporting Information Available: Full experimental details,
including biological assay methods and microanalysis data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
In the present study, there was pronounced similarity in
OR binding and in vitro profiles between the p-chlorophenyl-
propiolylamino derivatives (8b, 9b) and the p-chlorophenyl-
propargylamino derivatives (10, 11). In this respect, the SAR
followed that established by Rennison et al.2 for a range
of 14-acylamino- (6) and 14-alkylaminomorphinones and
codeinones (7).
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