Structural determinants of opioid activity in derivatives of 14-aminomorphinones: Effect of substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones

Article abstract of DOI:10.1021/jm0604777

In recent years there has been substantial interest in the 14-aminodihydromorphinone derivatives methoclocinnamox (MC-CAM) and clocinnamox (C-CAM). To investigate the importance of the cinnamoyl ring substituent, a series of analogues have been prepared w

Full text of DOI:10.1021/jm0604777

J. Med. Chem. 2006, 49, 5333-5338
5333
Structural Determinants of Opioid Activity in Derivatives of 14-Aminomorphinones: Effect of
Substitution in the Aromatic Ring of Cinnamoylaminomorphinones and Codeinones
Nick P. R. Nieland,† Humphrey A. Moynihan,† Simon Carrington,† Jillian Broadbear,‡ James H. Woods,‡ John R. Traynor,‡
Stephen M. Husbands,§ and John W. Lewis*,§
School of Chemistry, UniVersity of Bristol, Bristol, BS8 1TS, U.K., Department of Pharmacy and Pharmacology, UniVersity of Bath,
Bath, BA2 7AY, U.K., and Department of Pharmacology, UniVersity of Michigan, Michigan 48109
ReceiVed April 24, 2006
In recent years there has been substantial interest in the 14-aminodihydromorphinone derivatives
methoclocinnamox (MC-CAM) and clocinnamox (C-CAM). To investigate the importance of the cinnamoyl
ring substituent, a series of analogues have been prepared with chloro, methyl, and nitro substituents in the
2′ and 4′ positions. Despite some discrepancies between the in vitro and in vivo data, a clear SAR could be
observed where the 2′-chloro and 2′-methyl ligands consistently displayed higher efficacy than their 4′-
substituted analogues. The new series also followed the well-established SAR that 17-methyl ligands have
greater efficacy at the µ opioid receptor than their 17-cyclopropylmethyl counterparts.
Introduction
Synthesis
The starting material for the synthesis of codeinones (5) and
morphinones (6) was 14-amino-17(N)-cyclopropylmethyl-7,8-
dihydronorcodeinone (4a), while for codeinones (7) and mor-
phinones (8) it was 14-amino-7,8-dihydrocodeinone (4b).10,11
Acylation of the 14â-amino group was achieved readily using
freshly prepared acid chlorides. 3-O-Demethylation of dihy-
drocodeinones (5) to dihydromorphinones (6) was carried out
with boron tribromide.12,13
The 14-substituted 7,8-dihydromorphinone and derived series
of opioid ligands have provided a greater range of therapies,
therapeutic opportunities, and pharmacological tools than any
other opioid chemical series (Chart 1). The oxymorphone
derivatives (1) include the parent (1a) and its codeinone
equivalent oxycodone which are important opiate analgesics,
and the prototype opioid antagonists naloxone (1b) and nal-
trexone (1c). The last, though predominantly a µ opioid receptor
(MOR) ligand, was the starting material for the first selective
antagonist for δ opioid receptors (DOR), naltrindole (NTI, 2a),1
and the prototype selective antagonists for the κ opioid receptor
(KOR), norbinaltorphimine (norBNI, 3)2 and GNTI (2b).3 The
14-O-phenylpropyl ethers (1d, 1e) of naloxone (1b) and
naltrexone (1c) have recently been shown to be high potency
and high efficacy MOR agonists in vivo,4 whereas other 14-O
ethers and esters of naloxone (1b) and naltrexone (1c) had
previously been found to be antagonists themselves.5
Results
Because of the poor ability of in vitro assays to predict the
in vivo activity of ligands from these series,14,15 only some of
the new ligands were evaluated in opioid receptor binding assays
and in the [35S]GTPγS stimulation functional assay,16 in both
cases using recombinant human MOR, DOR, and KOR trans-
fected into Chinese hamster ovary (CHO) cells.17 All of the
new ligands tested had subnanomolar MOR affinity in the
binding assay and also high affinity for DOR and KOR so that
no significant selectivity for any receptor type was apparent
(Table 1).
In the [35S]GTPγS assays the 17-methyldihydrocodeinones
and dihydromorphinones (7, 8) showed agonist or partial agonist
activity for MOR, DOR, and KOR (Table 2). MOR potency
was higher than DOR or KOR potency, but only in the case of
the dihydrocodeinone 7c was there substantial selectivity for
MOR. Dihydromorphinones 8e and 8f had exceptionally high
MOR efficacy and potency; they also had high DOR and KOR
agonist potency. The equivalent dihydrocodeinones (7e, 7f) had
efficacy for MOR, DOR, and KOR similar to that of the
morphinones, but potency was an order of magnitude reduced,
though still high. The only 17-methyl-14-cinnamoylamino
derivatives tested that lacked MOR agonist efficacy were 8c18
and 8d,10 but 4c18 with the dihydrocinnamoylamino side chain
also lacked MOR efficacy. Both 8c and 4c were MOR
antagonists of subnanomolar potency and moderately potent
KOR antagonists, but whereas 8c was also a DOR antagonist,
4c was a DOR partial agonist (Table 3). 8d was almost identical
in profile to 8c in this assay. The 17-cyclopropylmethyl ligands
with 2′-chloro or 2′-methyl substitution were MOR antagonists
Our own interest in this field has been primarily in the 14-
amino analogues (4) of the oxymorphones, particularly the 14-
cinnamoylaminodihydromorphinones C-CAM (6b)6 and M-
CAM (6c)7 and the equivalent codeinones MC-CAM (5b)8 and
MM-CAM (5c).9 6b and 6c have been shown to be pseudo-
irreversible MOR selective antagonists functionally equivalent
to and superior to â-FNA, respectively.7 5b and 5c are MOR
partial agonists with agonist and antagonist activity of long
duration so that they could be regarded as similar to buprenor-
phine,8 the MOR partial agonist used as a treatment for opioid
dependence and as an analgesic. We here report extended
structure-activity data in this series, particularly concerning the
effect of substitution and orientation in the cinnamoyl aromatic
ring. Some major effects have been discovered, particularly
differences resulting from substitution in the ortho and para
positions.
* To whom correspondence should be addressed. Phone: 44 (0)1225
383103. Fax: 44 (0)1225 386114. E-mail: prxjwl@bath.ac.uk.
† University of Bristol.
‡ University of Michigan.
§ University of Bath.
10.1021/jm0604777 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/29/2006

5334 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Nieland et al.
Chart 1
Table 1. Binding Affinities Ki to Opioid Receptorsa
Ki ( SEM, nM
morphinones (6e, 6f) were also DOR and KOR antagonists,
whereas dihydrocodeinones (5e, 5f) were partial DOR and KOR
agonists.
[3H]DAMGO
MOR
[3H]Cl-DPDPE
DOR
[3H]U69,593
KOR
The new ligands were investigated in several in vivo
antinociceptive assays. Two thermal assays, in which heat is
applied to the tails of groups of mice, were used. In the tail
flick assay an infrared beam is used,19 while in the tail
withdrawal assay the source is warm water that is maintained
at either 50 or 55 °C.7 In both assays the time to removal of the
tail from the heat is a measure of antinociceptive effect. Activity
in these assays is indicative of relatively high efficacy opioid
agonist activity, most likely mediated by MOR agonist effects.20
In tail flick a number of the new ligands were very potent
antinociceptive agents. In this category were found the 4′-
chlorodihydrocodeinone and 4′-methyldihydrocodeinone (7b,
7c), the 2′-chlorodihydromorphinone and 2′-methyldihydromor-
phinone (8e, 8f), and the 17-cyclopropylmethyl-2′-methyldihy-
drocodeinone (5f) (Table 4). Other than 5f the 17-cyclopropyl-
methyl ligands tested were inactive as agonists in the tail flick,
but in this assay they showed potent ability to antagonize the
antinociceptive actions of morphine. None of the new MOR
antagonists were as potent as C-CAM (6b) and M-CAM (6c),
but the 17-methyl-4′-methyldihydromorphinone (8c) had no
agonist activity in tail flick and as a MOR antagonist in this
assay was only 3-fold less potent than its N-cyclopropylmethyl
congener 6c (Table 4). However, the equivalent dihydrocin-
namoyl derivative (4c) in tail flick was a potent agonist without
4c
5e
5f
6e
6f
7b
7c
7e
7f
8c
8d
8e
0.35 ( 0.04
0.60 ( 0.05b
0.20 ( 0.01b
0.71 ( 0.02
0.72 ( 0.02
0.60 ( 0.01
0.49 ( 0.09
0.68 ( 0.11
0.40 ( 0.01
0.34 ( 0.03
0.20 ( 0.03
0.15 ( 0.005
0.21 ( 0.05
4.78 ( 0.58
2.98 ( 0.22
1.1 ( 0.05
1.25 ( 0.04
7.2 ( 2.7b
2.3 ( 1.0b
1.3 ( 0.19
1.25 ( 0.21
1.0 ( 0.04
2.9 ( 0.45
0.58 ( 0.08
0.42 ( 0.05
4.0 ( 1.1
0.54 ( 0.10
0.08 ( 0.02
0.11 ( 0.07
4.8 ( 0.73
2.7 ( 0.23
140 ( 1.5
10.8 ( 3.0
0.57 ( 0.08
2.4 ( 0.55b
2.1 ( 0.2b
2.4 ( 0.53
1.50 ( 0.34
6.4 ( 2.0
9.9 ( 1.8
2.5 ( 0.32
2.3 ( 0.41
1.5 ( 0.05
5.5 ( 0.96
0.54 ( 0.20
0.23 ( 0.03
16.4 ( 2.5
1.4 ( 0.52
46.9 ( 14.5
0.40 ( 0.1
8f
MC-CAM, 5b
C-CAM, 6b
morphine
naltrexone
0.20 ( 0.0
a Binding to cloned human opioid receptors transfected into Chinese
hamster ovary (CHO) cells. All data provided through NIDA Abuse
Treatment Discovery Program (ATDP). Data are the average from two
experiments, each carried out in triplicate. b Binding to guinea pig brain
membranes.
(dihydromorphinones 6e, 6f; Table 3) or low-efficacy MOR
partial agonists (dihydrocodeinones 5e, 5f; Table 2). Dihydro-

Structural Determinants of Opioid ActiVity
Table 2. Stimulation of [35S]GTPγS Binding in Recombinant Human Opioid Receptors by Test Ligandsa
MOR DOR
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5335
KOR
compd
EC50, nM
% stimulationb
EC50, nM
% stimulationc
EC50, nM
% stimulationd
5e
5f
7b
7c
7e
7f
8e
8f
3.80 ( 0.31
2.60 ( 0.09
0.90 ( 0.45
2.5 ( 1.5
0.50 ( 0.20
0.50 ( 0.30
0.04 ( 0.005
0.04 ( 0.005
15.6 ( 0.5
24
17
28
17.5 ( 5.9
20.9 ( 7.8
5.0 ( 1.2
36
39
50
9.0 ( 1.48
1.8 ( 0.78
35 ( 11
55
47
26
51
78
83
59
81
62
68
76 ( 21
86
84 ( 4.7
108
96.5
126
111
93
2.2 ( 0.95
4.6 ( 0.95
0.10 ( 0.005
0.40 ( 0.22
316 ( 4.9
110
108
115
71
8.5 ( 1.6
5.6 ( 1.1
0.1 ( 0.03
0.2 ( 0.03
484 ( 213
morphine
103
a Data provided through NIDA (ATDP). Values are the mean of five or six experiments. b Compared to DAMGO. c Compared to DPDPE. d Compared
to U69593.
Table 3. Reversal of the Stimulation of [35S]GTPγS Binding, in
Table 5. Agonist and Antagonist Activity of the Ligands in the Mouse
Hot Water Tail-Withdrawal (TW) Assay
Recombinant Human Opioid Receptors Transfected into CHO Cells, by
Test Ligandsa
TW agonist
activitya
TW morphine
antagonisma
compd
4c
5b
6b
6e
6f
8c
8d
MOR Ke,b nM
DOR Ke,c nM
KOR Ke,d nM
compd
R
R1
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
6d
6e
6f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
4′-Cl
++
+++
+++
++
++
+
0.32 ( 0.02
0.97 ( 0.15f
0.53 ( 0.13f
0.45 ( 0.01
0.29 ( 0.01
0.30 ( 0.01
0.13 ( 0.04
0.59 ( 0.04
e
4.9 ( 0.29
9.8 ( 0.88f
0.10 ( 0.006f
0.38 ( 0.01
0.16 ( 0.01
4.10 ( 0.75
3.3 ( 0.73
1.9 ( 0.16
7.2 ( 0.57f
0.19 ( 0.02f
0.67 ( 0.07
0.40 ( 0.05
2.2 ( 0.14
1.4 ( 0.37
5.4 ( 0.75
0
4′- CH3
4′-NO2
2′-Cl
2′- CH3
2′-NO2
H
+
++++b
++++b
++++c
+
++
0
0
0
++
naltrexone
4′-Cl
++++
++++
++++
+++
a Data provided through NIDA (ATDP). Values are the mean of five or
six experiments. b Versus DAMGO. c Versus DPDPE. d Versus U69593.
e Partial agonist, EC50 ) 4.97nM, 45% stimulation compared to DPDPE.
f Data from ref 29.
4′- CH3
4′-NO2
2′-Cl
++
0
0
H
2′- CH3
+++
a Effect as % of maximum possible effect at a dose of 32 mg/kg sc
(administered 24 h pretest for antagonism): (0) 0-10%; (+) 10-25%; (++)
40-55%; (+++) 65-85%; (++++) >90%. b At 10 mg/kg. c At 1 mg/
kg.
Table 4. Agonist and Antagonist Activity of the Ligands in Mouse
Antinociception Testsa
b
EC50
c
AD50
compd
R
R1
R2
4′-CH3 CH3
CH3 4′-Cl CH2cC3H5 >30 0.2
TF PPQ
0.5 0.09
TF vs M
series is a MOR antagonist without opioid agonist activity,
comparable to naloxone and naltrexone in this respect.23
Investigation of the in vivo activity of an extended series of
17-cyclopropylmethyldihydrocodeinones (5) and dihydromor-
phinones (6) was undertaken in the tail withdrawal assay (Table
5). The potent agonist activity of the 2′-methyldihydrocodeinone
(5f) in tail flick was confirmed, and similar activity for the 2′-
chloro- (5e) and 4′-nitro- (5d) dihydrocodeinones was found.
Substantial but lesser agonist activity in tail withdrawal was
also discovered for the unsubstituted cinnamoylaminodihydro-
codeinone (5a), the 2′-nitrodihydrocodeinone (5g), and as the
only 17-cyclopropylmethyldihydromorphinone with substantial
antinociceptive effect in tail withdrawal, the 4′-nitro derivative
(6d). The ability of these N-cyclopropylmethyl ligands to
demonstrate long-lasting (g24 h) pseudo-irreversible morphine
antagonist activity was investigated in tail withdrawal. Such
activity for 6b and 6c had previously been reported.6,7 Equivalent
activity was found for the 4′-nitro analogue (6d), and similar
though somewhat less pronounced activity was also shown by
the unsubstituted dihydrocodeinone and dihydromorphinone (5a,
6a), 2′-chloro- and 2′-methyldihydromorphinones (6e, 6f), 4′-
chloro- and 4′-methyldihydrocodeinones (5b, 5c), and the 4′-
nitrodihydrocodeinone (5d). The 2′-chloro-, 2′-methyl-, and 2′-
nitrodihydrocodeinones (5e, 5f, 5g), which had substantial
agonist activity in tail withdrawal, showed no delayed morphine
antagonism in this assay.
e
4c
5b
5c
5f
6a
6b
6c
6f
7b
7c
8b
8c
8e
8f
9
H
>30
>6.0
5.7
CH3 4′- CH3 CH2cC3H5 >30 0.1
CH3 2′- CH3 CH2cC3H5 0.03 0.03
H
H
H
H
>30
H
CH2cC3H5 >30 66% @ 0.3 1.3
CH2cC3H5 >30 69% @ 30 0.12
4′-Cl
4′-CH3 CH2cC3H5 >30 >30
2′-CH3 CH2cC3H5 >30 3.17
0.2
50% @ 3
>30
>30
3.8
CH3 4′-Cl
CH3 4′-CH3 CH3
CH3
0.04 0.02
0.06 0.40
>30 1.2
H
H
H
H
H
4′-Cl
4′-CH3 CH3
2′-Cl CH3
2′-CH3 CH3
4′-Cl CH3
CH3
>30 57% @ 1
0.12 0.04
0.08 0.03
0.5
1.92 0.4
>10 inactive
>10 inactive
0.6
>30
>30
>30
morphined
naloxoned
naltrexoned
inactive
0.04
0.007
a Data provided through DEC. b Agonist activity determinations in tail-
flick (TF) and phenylquinone abdominal stretching (PPQ) assays. Values
are ED50, mg/kg sc or % change. c Antagonist activity determinations in
tail flick versus morphine (TF vs M). Values are AD50, mg/kg sc or
percentage change. d Data from ref 23. e Dihydrocinnamoyl.
MOR antagonist activity. The 17-methyldihydromorphinone
(8b)18 was inactive as an agonist and was a moderately potent
MOR antagonist, whereas the equivalent morphinone (9)21 was
a potent antinociceptive agent in tail flick with no MOR
antagonist activity. The ligands with MOR antagonist activity
but no antinociceptive activity in tail flick, including the
unsubstituted cinnamoylaminodihydromorphinone (6a),22 with
only one exception, 6c, had some antinociceptive activity in
the phenylquinone-induced writhing assay in which the chemical
nociceptor provides less intensive nociceptive stimulus than the
thermal stimulus in tail flick (Table 4). Thus, only 6c in this
Structure-Activity Relationships (SARs) and Discussion
The main purpose of the present study was to establish SAR
for the orientation of substitution in the cinnamoyl aromatic
ring in analogues of 6b and 6c. The in vitro functional and in
vivo data show very clear distinction between the effects of

5336 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Nieland et al.
substitution in the 4′ and 2′ positions, but there were discrep-
ancies for some of the new ligands between their in vitro and
in vivo profiles. The 4′-chlorodihydrocodeinone (7b) was a low-
efficacy partial MOR agonist in the [35S]GTPγS assay (Table
2), but in tail flick it was a very potent full agonist without the
morphine antagonist effect (Table 4). In the antinociceptive
assay it showed the Straub tail effect characteristic of a high-
efficacy MOR agonist, and in withdrawn morphine-dependent
rhesus monkeys it fully suppressed withdrawal with potency
50 times greater than that of morphine.24 Similarly, the
17-cyclopropylmethyl-2′-methyldihydrocodeinone (5f) had very
low efficacy MOR partial agonist activity in vitro (Table 2)
and yet was a potent full agonist in tail flick (Table 4) with
Straub tail effect in mice and complete suppression of abstinence
in withdrawn morphine-dependent rhesus monkeys.24 Further
light was thrown on these discrepancies by the report that 7b,
when administered icv in tail withdrawal, had no antinociceptive
activity and had MOR antagonist activity that was delayed in
onset, peaked at 24 h, and lasted beyond 48 h.25 The delay in
onset of antagonism was dependent on the dose of 7b, with
higher doses substantially reducing the delay time. The cin-
namoylaminodihydrocodeinones behave as irreversible MOR
antagonists, but it is thought that they exert their receptor
blockade effects icv only after binding to a significant portion
of the receptor reserve; the delay could result from limitation
of the number of receptors available for binding by the rate of
receptor turnover.25 The predominant MOR agonism observed
after peripheral administration would result from there being
insufficient brain concentrations to effect any significant receptor
blockade. In the in vitro situation of the [35S]GTPγS assay for
MOR efficacy, the test ligand is present in sufficient concentra-
tion to bind “irreversibly” at a substantial rate so that its efficacy
appears to be quite low.
addition to its impressive antinociceptive activity in tail
withdrawal, 6d was also an effective delayed MOR antagonist.
Since the SAR for methyl and chloro substitution in the
cinnamoyl group is basically similar, it is unlikely that electronic
factors are responsible for the difference between these sub-
stituents and nitro substitution. Though the nitro group is
somewhat larger than chloro and methyl, and this may have
some effect, it seems more likely that the main factor is
lipophilicity because both the chloro and methyl groups have
positive π values indicating substantial lipophilicity whereas
the nitro group has a negative π value to indicate more
hydrophilicity in its character.26
Comparison of the 17-cyclopropylmethyl series (5, 6) with
the 17-methyl series (7, 8) might be expected to comply with
well-established SAR in the morphinan and epoxymorphinan
series of opioids. When 17-methyl is replaced by 17-cyclopro-
pylmethyl, MOR efficacy is very much reduced but KOR
efficacy is relatively little affected so that in vivo KOR agonist
effects usually predominate.27,28 In the in vitro assays, the current
series generally show greater loss of MOR efficacy than KOR
efficacy when 17-methyl is replaced by 17-cyclopropylmethyl.
In the antinociceptive assays in which relative MOR and KOR
efficacy was not determined, there was no overt evidence of
predominant KOR agonist effects for any 17-cyclopropylmethyl
ligands tested. However, in the thermal (tail flick, tail with-
drawal) assays, clear evidence of lower MOR efficacy for the
17-cyclopropylmethyl ligands when compared to their 17-methyl
equivalents was observed. Thus, in tail flick the only 17-
cyclopropylmethyl ligand tested that showed antinociceptive
activity was the 2′-methylcodeinone (5f). The equivalent activity
of 5f in tail withdrawal was fully reversed by naltrexone (data
not shown), and in the acetic acid induced writhing assay, the
antinociceptive effect of 5f was fully reversed by the MOR-
selective antagonist M-CAM (6c) but not by the KOR-selective
antagonist norBNI or by the DOR selective antagonist naltrin-
dole (Broadbear, personal communication). The overall conclu-
sion can be drawn that the 14-cinnamoylamino group in this
series predominantly affects MOR activity and that its lipophilic
nature, particularly with 4′-chloro and 4′-methyl substitution,
is associated with low MOR efficacy and irreversible binding.
Despite discrepancies between in vitro and in vivo activity
in certain cases as described above, in both the [35S]GTPγS
and the antinociceptive assays the 2′-chloro- and 2′-methyl-
substituted dihydrocodeinones (5e, 5f, 7e, 7f) and dihydromor-
phinones (8e, 8f) consistently showed very much higher efficacy
for MOR, DOR, and KOR in the in vitro assay and for MOR
in the antinociceptive assays than the 4′-substituted equivalents
(5b,8 5c,9 7b, 7c, 8b,18 8c18). Only in the 17-cyclopropylmeth-
yldihydromorphinones (6e, 6f, 6b, 6c) including the unsubsti-
tuted parent (6a) was there less differentiation between the
effects of 2′ and 4′ substitution. Nevertheless, the evidence from
the 17-cyclopropylmethyl series in vivo (Tables 4 and 5) is that
the 2′-substituted dihydrocodeinones (5e, 5f) have higher
antinociceptive efficacy than the unsubstituted cinnamoylami-
nodihydrocodeinone (5a), which in turn has higher efficacy than
the 4′-substituted derivatives (5b, 5c).
Experimental Section
Column chromatography was performed under gravity, over silica
gel 60 (35-70µm) purchased from Merck. Analytical TLC was
performed using aluminum-backed plates coated with Kieselgel 60
F254, from Merck. The chromatograms were visualized using 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
The more limited in vivo data on the 17-cyclopropylmethyl-
2′-nitro and -4′-nitro derivatives (5d, 5g, 6d) suggest that the
effect of orientation with nitro substitution is different from
chloro and methyl substitution. Thus, the 4′-nitrodihydroco-
deinone (5d) had (MOR) antinociceptive activity in tail with-
drawal substantially greater than that of the 2′-isomer (5g). It
also had significant delayed antagonist activity comparable to
that of the 4′-methyl analogue (5c) (Table 5). This profile is
similar to that reported for 5d by McLaughlin et al.25 using icv
administration. In the present study the 4′-nitrodihydromorphi-
none (6d), though with no 2′-isomer for comparison, had higher
efficacy in tail withdrawal than any other 17-cyclopropylmeth-
yldihydromorphinone tested, including the unsubstituted parent
(6a) and the 2′-chloro and 2′-methyl derivatives (6e, 6f). In
1
with a Fisons autosampler. H NMR and 13C NMR spectra were
recorded using a JEOL 270 (operating at 270 MHz for 1H and 67.8
MHz for 13C) spectrometer. Chemical shifts (δ) are measured in
ppm. Spectra were referenced internally using TMS as the standard.
Only diagnostic peaks have been quoted for proton NMR. Mi-
croanalysis was performed with a Perkin-Elmer 240C analyzer.
Infrared spectroscopy was performed on a Perkin-Elmer 782
instrument. Chemicals and solvents were purchased from Aldrich
Chemical Company. Compounds were submitted for testing as their
oxalate salts, formed by adding 1 equiv of oxalic acid to an ethanolic
solution of the ligand. Compound recrystalization was from ethanol.
General Procedure A. A suspension of the appropriate car-
boxylic acid (1.1 molar equiv) in anhydrous toluene was refluxed
with oxalyl chloride (8.8 molar equiv) for 1 h. Solvent was removed

Structural Determinants of Opioid ActiVity
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5337
in vacuo, and the residue was taken up in CH2Cl2 before adding to
a solution of codeinone (4a or 4b: 1 molar equiv) and NEt3 (1.1
molar equiv) in anhydrous CH2Cl2, which was stirred under N2 for
18 h. Removal of the solvent in vacuo, silica gel column
chromatography, and recrystallization from methanol yielded the
codeinones.
General Procedure B. To a solution of codeinone (1 molar
equiv) in anhydrous CH2Cl2 at -30 °C under N2 was slowly added
BBr3 (6 molar equiv, 1 M in CH2Cl2), and the solution was warmed
to room temperature over 1 h. A 1:1 mixture of ice/concentrated
ammonia was added, and the organic layer was isolated. The
aqueous layer was extracted with CHCl3/MeOH (3:1, 3×). The
organic layer washed with brine and dried (Na2SO4). Removal of
the solvent in vacuo and silica gel chromatography yielded the
morphinones.
N-Cyclopropylmethyl-14â-cinnamoylamino-7,8-dihydronor-
codeinone (5a). 10 (0.24 g, 0.67 mmol) was treated as in general
procedure A to give 5a as a clear oil (0.29 g, 88%). Anal.
(C30H32N2O4‚oxalate‚2H2O) C, H, N.
N-Cyclopropylmethyl-14â-(4′-nitrocinnamoylamino)-7,8-di-
hydronorcodeinone (5d). 10 (0.85 g, 2.4 mmol) was treated as in
general procedure A to give 5d as a white solid (0.69 g, 54%).
Anal. (C30H31N3O6‚oxalate‚2H2O) C, H, N.
N-Cyclopropylmethyl-14â-(2′-chlorocinnamoylamino)-7,8-di-
hydronorcodeinone (5e). 10 (0.35 g, 1.0 mmol) was treated as in
general procedure A to give 5e as a white solid (0.35 g, 69%).
Anal. (C30H31N2O4Cl‚oxalate‚1.5H2O) C, H, N.
N-Cyclopropylmethyl-14â-(2′-methylcinnamoylamino)-7,8-di-
hydronorcodeinone (5f). 10 (0.33 g, 0.90 mmol) was treated as
in general procedure A to give 5f as a white solid (0.23 g, 50%).
Anal. (C31H34N2O4‚oxalate‚H2O) C, H, N.
N-Cyclopropylmethyl-14â-(2′-nitrocinnamoylamino)-7,8-di-
hydronorcodeinone (5g). 10 (0.92 g, 2.9 mmol) was treated as in
general procedure A to give 5g as a white solid (0.39 g, 28%).
Anal. (C30H31N3O6‚oxalate‚1.5H2O) C, H, N.
Acknowledgment. This work was funded through NIDA
Grants DA00254 and DA07315, and the in vitro characterization
of compounds was carried out through the NIDA Abuse
Treatment Discovery Program (ATDP). Tail flick, phenylquino-
ne abdominal stretching, and tail flick vs morphine in vivo
assays were performed by the Drug Evaluation Committee
(DEC) of the College on Problems of Drug Dependence
(CPDD).
Supporting Information Available: 1H NMR, 13C NMR, mass
spectra, infrared, melting point, and microanalysis data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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