Mixed k/μ opioid receptor agonists: The 6β-naltrexamines

Article abstract of DOI:10.1021/jm8015552

Ligands from the naltrexamine series have consistently demonstrated agonist activity at κ opioid receptors (KOR), with varying activity at the μ opioid receptor (MOR). Various 6β-cinnamoylamino derivatives were made with the aim of generating ligands with

Full text of DOI:10.1021/jm8015552

1546
J. Med. Chem. 2009, 52, 1546–1552
Mixed K/µ Opioid Receptor Agonists: The 6ꢀ-Naltrexamines
Gerta Cami-Kobeci,†,‡ Adrian P. Neal,†,‡ Faye A. Bradbury,§ Lauren C. Purington,§ Mario D. Aceto,| Louis S. Harris,|
John W. Lewis,‡ John R. Traynor,§ and Stephen M. Husbands*,‡
Department of Pharmacy and Pharmacology, UniVersity of Bath, ClaVerton Down, Bath, BA2 7AY, United Kingdom, Department of
Pharmacology, UniVersity of Michigan, Ann Arbor, Michigan, Department of Pharmacology and Toxicology, Virginia Commonwealth
UniVersity, Richmond, Virginia
ReceiVed December 9, 2008
Ligands from the naltrexamine series have consistently demonstrated agonist activity at κ opioid receptors
(KOR), with varying activity at the µ opioid receptor (MOR). Various 6ꢀ-cinnamoylamino derivatives were
made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with
this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired
high affinity, nonselective binding in vitro and in the functional assays were high efficacy KOR agonists
with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo,
with 12a acting as a KOR agonist and therefore somewhat similar to the previously evaluated analogues
3-6, while 12b displayed predominant MOR agonist activity.
Scheme 1a
Introduction
Various studies have demonstrated that κ opioid receptor
(KOR) agonists can reduce, or even prevent, some of the
behavioural effects caused by cocaine.1-4 Selective KOR
agonists are, however, unlikely to be seriously considered as
treatment agents as they themselves cause dysphoria, both in
drug na¨ıve individuals and in those with a history of drug use.5
Preclinical evidence suggests that a more effective approach
may be to target KOR-agonists that also display partial agonist
activity at the µ opioid receptor (MOR).4,6 Compounds of this
type, such as EKC, are more effective in reducing cocaine self-
administration, and display fewer side effects, than their more
selective counterparts such as enadoline and spiradoline.4
Derivatives of ꢀ-naltrexamine (ꢀ-NTA) have consistently
demonstrated KOR agonist properties. The most well-known
of this series is ꢀ-FNAa (1), a ligand widely utilized for its
irreversible MOR antagonist properties, but which also displays
short-lived KOR agonist effects.7-9 More recently, in a search
for potent KOR agonists from the ꢀ-NTA series, TRK-820 (2)
emerged as the lead compound identified from a comprehensive
study of such derivatives.10 However TRK-820 was the result
of optimization for high KOR selectivity and potency and
therefore is not an ideal candidate for further development
against cocaine. Independently, we found the cinnamoyl deriva-
tives (3-6) to have KOR agonist activity in vivo,11,12 but we
did not seek to optimize for KOR selectivity and found that
with no methyl group on the 6ꢀ-nitrogen (where a methyl group
is found in TRK-820) the ligands display equal affinity at MOR
and KOR and are therefore potentially more interesting. The
effect of the NMe group replicates the importance of having an
N-alkyl group (usually NMe) rather than NH in the arylaceta-
mide series of KOR agonists.13
a Reagents and conditions: (a) HNBn2, PhCOOH, TsOH then NaCNBH3,
EtOH, ∆, 20 h, (69%); (b) 10% Pd/C, 40 PSI, H2, MeOH/HCl, 3 days; (c)
10% Pd/C, 1:1 cyclohexene/MeOH, ∆, 24 h; (d) o-benzylhydroxylamine,
NaOAc, EtOH/H2O, ∆, 20h; (e) ZrCl4/NaBH4, THF, ∆, 24h, 42% (for R
) Bn).
KOR agonist effects and then substantial MOR antagonist
activity, while 3 and 4 were potent KOR agonists in both tail
withdrawal (TW) and antiwrithing (AW) assays.11,12 The aim
of the current work was therefore to increase the MOR efficacy
of this series to achieve the desired, mixed KOR/MOR profile.
In related series of 14-cinnamoylaminomorphinones,14 sub-
stitution at the 2′-position of the cinnamoyl aryl ring produced
ligands with significantly altered efficacy compared to their 4′-
substituted homologues and so the 2′-substituted analogues of
3-6 were targeted to see if a similar effect was observed in the
ꢀ-NTA series.
It has also become clear that introduction of substituents to
the C14-hydroxyl group can lead to an increase in MOR affinity
and efficacy. The effect is most robust when a three-carbon
chain, or substituted three-carbon chain is used. The most
dramatic example of this effect is provided by Schmidhammer
and colleagues,15 who converted the MOR antagonist naltrexone
The cinnamoyl derivatives (3-6) have KOR agonist activity
in vivo,11,12 with 6 and 5 similar to ꢀ-FNA, having short-lived
* To whom correspondence should be addressed. Phone: 44-1225 383103.
Fax: 44-1225 386114. E-mail: s.m.husbands@bath.ac.uk.
†
These authors contributed equally to the work.
Department of Pharmacy and Pharmacology, University of Bath.
Department of Pharmacology, University of Michigan.
Department of Pharmacology and Toxicology, Virginia Commonwealth
‡
§
|
University.
a Abbreviations: ꢀ-FNA, ꢀ-funaltrexamine; ꢀ-NTA, ꢀ-naltrexamine.
10.1021/jm8015552 CCC: $40.75
2009 American Chemical Society
Published on Web 03/02/2009

Mixed κ/µ Opioid Receptor Agonists: The 6ꢀ-Naltrexamines
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1547
Scheme 2a
a Reagents and conditions: (a) RC6H4CHdCHCOCl, NEt3, CH2Cl2, 25 °C, 0.5 h; (b) TBDMSCl, imidazole, CH2Cl2, (73%); (c) anhydride (R′OR′),
toluene, reflux, 24 h; (d) TBAF, THF, RT.
(7a) into a powerful MOR agonist by substitution of a
phenylpropyl group in the C14-hydroxyl (7b). In addition, the
14-phenylacetyloxy derivatives were targeted as introduction
of the phenylacetyl group in 14-amino analogues of naltrindole
(8) and in 14-aminodihydromorphinones and codeinones also
raised MOR efficacy.16,26
the pure ꢀ-NTA 10. It is proposed that in the course of the
reaction, the boron-complexed oxime mimics the bulky diben-
zyliminium formed during the preparation of 9 and exists in a
pseudochair conformation, hence exposing the R-face to pref-
erential reduction.17,18 Therefore, we chose to add bulk to the
oxime and synthesized ethers 11b, 11c by oximation of
naltrexone with the relevant alkoxylamines. Upon reduction of
the methyl oxime ether 11b with ZrCl4/NaBH4 (Scheme 1), the
stereoselectivity was improved to 13:1 in favor of the desired
ꢀ-diastereoisomer 10. Reducing the benzyl ether 11c gave
almost equal stereoselectivity (12:1). This new method, via 11c,
was adopted for the present study and gram quantities of 10
could be reproducibly obtained in two steps with one chromo-
graphic purification. The ꢀ-configuration of the 6-amino group
was confirmed by comparison with previously reported data on
this compound.17,18 In particular, a coupling constant of 6.8 Hz
was determined for H-5.
Synthesis of the target C-6ꢀ amides 3 and 12a-d was
achieved by acylation of ꢀ-NTA (10) with the relevant cin-
namoyl chlorides (Scheme 2). The 14-O-acyl targets (15) could
be accessed from 3 by protection of the 3-phenol and then
acylation of the C14-hydroxyl (Scheme 2).
Because of the low reactivity of the tertiary alcohol, alkylation
of the C14-hydroxyl required forcing conditions and protec-
tion of the 3-phenol as the methyl ether (Scheme 3). Introduction
of the 6ꢀ-amino group (17) was again accomplished using the
method of asymmetric reduction of the ketoxime (16).
Results
Chemistry. The synthesis of the target ligands relied on the
efficient production of the key intermediate ꢀ-NTA 10, which
can be achieved by reductive amination of naltrexone 7a with
dibenzylamine followed by hydrogenolysis of the benzyl group
(Scheme 1).17 Although this synthetic approach is well estab-
lished, in our hands removal of the benzyl group proved
problematic and we opted for an alternative method. Portoghese
and colleagues have reported a 9:1 mixture of ꢀ:R-diastereoi-
somers obtained from the reduction of naltrexone oxime (11a)
with BH3-THF.18 In our hands, using BH3-Me2S, the result was
7:1 and required rigorous silica gel chromatography to obtain
Binding affinities of the new compounds for MOR and KOR
were determined by competition with [3H]-diprenorphine bind-
ing in C6-rat glioma cells expressing recombinant rat MOR and
CHO cells expressing recombinant human KOR.19 DOR activity
of the new ligands was not determined as in no case has DOR
activity proved relevant to the pharmacological profile of ligands
with significant MOR and/or KOR efficacy. All of the ligands
bound with high to very high affinity to both KOR and MOR,
with little selectivity for either receptor (Table 1). Neither the
nature nor position of substituents on the phenyl ring of the

1548 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Cami-Kobeci et al.
Scheme 3a
a Reagents and conditions: (a) MeI, K2CO3, MeCOMe/H2O, (73%); (b) o-benzylhydroxylamine, NaOAc, EtOH/H2O; (c) ZrCl4/NaBH4, THF, ∆, 24 h,
(69%); (d) Cinnamoyl chloride, Et3N, CH2Cl2, RT, (83%); (e) R1Br, NaH, CH2Cl2; (f) BBr3, DCM, 0 °C.
Table 1. Binding Affinities Determined by Displacement of
[3H]Diprenorphine Binding to C6-µ and CHO-κ Membranesa
efficacy compounds (20b and 15c). Again 15b stood out for
having a substantially different profile to the other ligands, it
did not stimulate MOR and was in fact a high potency MOR
antagonist.
The unsubstituted 6ꢀ-cinnamoylnaltrexamine (3) has previ-
ously been evaluated in vivo in the warm water tail withdrawal
and acetic acid induced abdominal stretch assays and found to
be a potent and efficacious KOR agonist.12 For comparison,
two of the current series of ligands were chosen for preliminary
evaluation in the similar paraphenylquinone (PPQ) induced
abdominal stretch assay,21 an assay in which MOR and KOR
agonists of even relatively low efficacy would be expected to
show activity. 12b was chosen as it has a very similar profile
to 3 in vitro, while the second choice, 12a, had lower efficacy
in vitro at both MOR and KOR. 12a was found to be an agonist
of quite low potency (ED50 18.5 (13.2-26.1) mg/kg, sc), and
the effect of an ED80 concentration of 12a could be blocked by
norBNI (AD50 5.28 mg/kg, sc), a selective KOR antagonist but
not by the MOR antagonist ꢀ-FNA (up to 30 µg icv) or the
DOR antagonist naltrindole (NTI) up to 30 mg/kg sc. In contrast,
12b was significantly more potent (ED50 3.5 (1.6-7.7) mg/kg,
sc) and the effect of an ED80 dose was blocked by ꢀ-FNA (AD50
7.1 µg/icv), inconsistently by norBNI (38% at 1, 13% at 3 µg/
brain), and partially NTI (26% at 10, 23% at 30 mg/kg, sc),
indicating a predominantly MOR mediated mode of action for
12b.
Ki/nM
compd
type and substituent
µ
κ
3
A: R ) H
A: R ) o-NO2
0.17 ( 0.091
0.35 ( 0.13
0.043 ( 0.0022
0.30 ( 0.094
0.36 ( 0.32
0.27 ( 0.062
0.34 ( 0.16
0.86 ( 0.22
0.12 ( 0.014
0.59 ( 0.069
1.1 ( 0.097
0.26 ( 0.0098
12a
12b
12c
12d
20a
20b
15a
15b
15c
A: R ) m-NO2
A: R ) o-Cl
0.11 ( 0.036
0.079 ( 0.027
0.085 ( 0.033
0.16 ( 0.010
0.25 ( 0.074
0.21 ( 0.059
0.42 ( 0.19
A: R ) o-Me
B: R1 ) CH2C6H5
B: R1 ) CH2CHdCH2
B: R1 ) COCH3
B: R1 ) COC6H5
B: R1 ) COCH2C6H5
0.28 ( 0.055
a Values are an average ( SEM from three separate experiments.
cinnamoyl group substantially affected affinities and similarly,
introduction of substituents at C14 also had relatively little effect.
The in vitro assay used to determine opioid receptor functional
activity was the [35S]GTPγS binding stimulation assay, which,
like the binding assays, was performed on recombinant opioid
receptors transfected into C6-rat glioma cells (for MOR) and
CHO cells (for KOR). Assays were performed as previously
described by Traynor and Nahorski.20 Agonist efficacy at these
opioid receptors was determined in comparison to the standard
selective agonists DAMGO (MOR) and U69593 (KOR) (Table
2). The ligands were, as expected, agonists at the KOR,
efficacies mostly ranging from 76% to 120% relative to U69593,
the exception being 15b, which had only low efficacy and
potency KOR agonist activity; otherwise potencies were in the
low to subnanomolar range. The ring substituented analogues
(12a-12d) had very similar efficacy at KOR, although at 81%
stimulation 12a, the o-nitro analogue was somewhat lower than
the rest. There was slightly greater variation in the KOR efficacy
of the C14-substituted analogues, with the allyl substituted (20b)
displaying the highest efficacy of the compounds in this study.
All of the new ligands were low efficacy partial agonists at
MOR, with the 14-substituted series providing the highest
Discussion
The current series of 6ꢀ-naltrexamine derived ligands con-
firms our earlier finding that having a secondary amide at C6
results in compounds with no selectivity for any particular opioid
receptor. This effect is in contrast to the tertiary amides such
as TRK-820 (2), which are selective toward the KOR. The low
nanomolar to subnanomolar affinities seen here are entirely in
keeping with those observed with earlier members of the
series.11,12 The predominant activity in the [35S]GTPγS assay
of these new ligands is of high efficacy agonist activity at the
KOR. Again, this is in keeping with our earlier work in which
3 and p-substituted analogues were KOR agonists in the
electrically stimulated guinea pig ileal longitudinal muscle
(GPI)12 and the work of others.7,10 Compared to the p-methyl
and p-chloro derivatives, previously reported as partial ago-
nists,11 the o-analogues (12c, 12d) reported here seem to be of

Mixed κ/µ Opioid Receptor Agonists: The 6ꢀ-Naltrexamines
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1549
Table 2. Stimulation of [35S]GTPγS Binding to C6-µ and CHO-κ Membranesa
µ
κ
compd
type and substituent
EC50/nM
%DAMGO
EC50/nM
%U69593
3
A: R ) H
1.8 ( 0.79
0.69 ( 0.31
0.18 ( 0.062
12 ( 8.7
21 ( 1.5
6.7 ( 0.73
20 ( 3.4
17 ( 1.6
21 ( 1.4
19 ( 2.1
39 ( 1.8
19 ( 0.86
NSb
0.12 ( 0.037
1.9 ( 0.055
0.12 ( 0.039
0.40 ( 0.16
0.95 ( 0.69
0.78 ( 0.16
0.079 ( 0.012
2.4 ( 0.99
100 ( 4.5
81 ( 2.4
100 ( 3.3
97 ( 3.1
105 ( 6.0
97 ( 6.2
120 ( 3.0
97 ( 7.1
26 ( 6.0
76 ( 2.1
12a
12b
12c
12d
20a
20b
15a
15b
15c
A: R ) o-NO2
A: R ) m-NO2
A: R ) o-Cl
A: R ) o-Me
2.1 ( 2.0
B: R1 ) CH2C6H5
B: R1 ) CH2CHdCH2
B: R1 ) COCH3
B: R1 ) COC6H5
B: R1 ) COCH2C6H5
2.0 ( 0.38
0.60 ( 0.10
1.0 ( 0.15
9.8 ( 5.3
1.3 ( 0.21
41 ( 3.9
0.49 ( 0.053
a Values are an average ( SEM from three separate experiments. b NS ) No stimulation; 15b was evaluated as an antagonist at MOR, Ke (vs DAMGO)
0.41 ( 0.12 nM.
higher efficacy, certainly equivalent to the unsubstituted parent
compound (3).
been predicted from the in vitro data. Either the [35S]GTPγS
binding assay has overestimated efficacy at KOR or underes-
timated efficacy at MOR. The latter has been observed and
discussed previously in a related series of 14-cinnamoylami-
nomorphinones and may be related to the slower rate and extent
of receptor occupation by the ligands in vivo compared to in
the in vitro assays.14,23
Our previous studies with 3 indicated that it had little efficacy
at MOR in either the GPI (no reversal by the MOR antagonist
CTAP) or in vivo (antinociceptive effect not reversed by
ꢀ-FNA).12 The new results in the [35S]GTPγS assay confirm
its low MOR efficacy. Of the substituted analogues (12a-12d),
the o-Cl, o-Me, and m-NO2 substituted ligands (12b-12d) all
have similar low efficacy at MOR of around 20% of DAMGO’s
effect, whereas the MOR efficacy of 12a (o-NO2) is even lower
(7% of DAMGO). This is reminiscent of the effect of aryl
substitution in the cinnamoyl derivatives of the 14-aminomor-
phinones, where the effect of orientation with nitro substitution
was different to that with chloro and methyl.14
Substituents were added to the C14-oxygen in expectation
of increasing the MOR efficacy of the ligands. This approach
has shown partial success with both the allyl ether (20b) and
the phenylacetate (15c) having double the MOR efficacy of 3.
However, the effect was not consistent, both the benzyl ether
(20a) and the acetate (15a) displayed no change in efficacy
compared to 3, while the benzoate (15b) showed no stimulation
of [35S]GTPγS binding at MOR. Certainly the effect of
introducing a substituent at this position is much less dramatic
than seen in the somewhat related series of substituted 14-amino
analogues of oxymorphindole, where significant changes in
potency and efficacy could be seen.16 The effect of benzyl
substitution in this series can also be compared with the effect
of 14-O benzylation of naltrexone.22 With naltrexone, this
modification lead to an increase in affinity and antagonist
potency at KOR compared to naltrexone itself, which is in
contrast to the current findings where 20a has somewhat lower
affinity and potency at KOR compared to 3.
Experimental Section
Reagents and solvents were purchased from Aldrich or Lancaster
and used as received. Melting point: Gallenkamp MFB-595 melting
point apparatus; uncorrected. NMR spectra: Jeol Delta-270-MHz
instrument (1H at 270 MHz), and Varian Mercury-400-MHz in-
strument (1H at 400 MHz, 13C at 100 MHz); δ in ppm, J in Hz
with TMS as an internal standard. ESIMS: micrOTOF (BRUKER).
Microanalysis: Perkin-Elmer 240C analyzer. Ligands were tested
as their hydrochloride or oxalate salts, prepared by adding one
equivalent of (5 N hydrochloric acid in isopropyl alcohol) to an
ether solution and 1 equiv oxalic acid to an ethanolic solution of
the compound. Synthetic methods are detailed for one example in
each series. Full details for all experiments can be found in the
Supporting Information.
General Procedure A: Acylation of 6ꢀ-Naltrexamine. To a
stirring mixture of the appropriate cinnamic acid (2.7 mmol) in PhMe
(10 mL) was added oxalyl chloride (14 mmol), followed by DMF (4
drop) at 0 °C. The reaction mixture was stirred for 1 h and concentrated
under reduced pressure to yield the appropriate cinnamoyl chloride.
The crude cinnamoyl chloride (2.2 mmol) was added to a solution of
6-ꢀ-naltrexamine (2.2 mmol) in dry CH2Cl2 (15 mL) at 25 °C. Et3N
(11.2 mmol) was added, and the reaction mixture stirred for 1 h before
diluting with H2O (20 mL) and extraction with CH2Cl2 (3 × 20 mL).
The combined organic layers washed with (20 mL) brine, dried over
MgSO4, and concentrated under reduced pressure. Flash-chromatog-
raphy eluent (0.5/0.5/99 MeOH/Et3N/CH2Cl2) afforded the corre-
sponding cinnamoyl naltrexamine.
The activity of the two nitro-substituted cinnamoyl-6ꢀ-
naltrexamines (12a and 12b) in vivo is worthy of note. In the
[35S]GTPγS binding assay both appeared to be high efficacy
KOR agonists with some low level efficacy at MOR, with the
o-substituted analogue (12a) having somewhat lower efficacy
at both receptors compared to 12b. In the PPQ induced
abdominal stretch assay, 12a was found to be a KOR agonist,
correlating well with the in vitro data, while 12b, in the same
assay, had predominant MOR activity, which would not have
General Procedure B: 14-O-Acylation. To a stirred solution
of 3-O-tetrabutyldimethylsilyl-6ꢀ-cinnamoyl-naltrexamine (13) (0.25
mmol) in PhMe (14 mL) was added the appropriate anhydride (0.37
mmol). The reaction mixture was stirred at reflux for 24 h. After
cooling to room temperature, the suspension was diluted with (15
mL) of saturated NaHCO3 and extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. Flash-chroma-

1550 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Cami-Kobeci et al.
tography (10/90 EtOAc/hexane) gave the appropriate protected-6-
ꢀ-cinnamoyl-14-acyl naltrexamine (14).
was heated to reflux for 24 h. After evaporation to dryness, the
residue was diluted with H2O (20 mL), basified with Na2CO3 (pH
10), extracted into CHCl3 (3 × 20 mL), washed with brine (20
mL), dried over Na2SO4, and concentrated under reduced pressure.
Flash chromatography eluent (5/95 MeOH/CH2Cl2) afforded 11c
General Procedure C: TBDMS Deprotection. To a stirred
solution of the appropriate 3-O-tetrabutyldimethylsilyl-6-ꢀ-cin-
namoyl-14-acyl-naltrexamine (14) (0.12 mmol) in THF (3 mL) was
added TBAF (0.18 mmol) and the suspension stirred for 2 h. Flash-
chromatography (2/98 MeOH/CH2Cl2) afforded the appropriate 6-ꢀ-
cinnamoyl-14-acyl-naltrexamine derivatives (15).
General Procedure D: 14-O-Alkylation. Sodium hydride (5.28
mg 0.22 mmol), was added to a solution of 3-O-methyl-6-ꢀ-
cinnamoyl naltrexamine (18) (0.20 mmol) in DMF (anhydrous, 15
mL) at 0 °C. The reaction mixture stirred for 5 min and then allowed
to warm to RT and stirred for a further 20 min before adding alkyl
bromide (0.41 mmol) and stirring at RT for 6 h. Excess NaH was
destroyed carefully by addition of small pieces of ice and diluted
with H2O (50 mL) and the mixture extracted with CH2Cl2 (3 × 25
mL). The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. Flash chromatography (1/99
MeOH/CH2Cl2) afforded the products (19).
General Procedure E: 3-O-Demethylation. To a solution of
the appropriate (19) (0.38 mmol) in CH2Cl2 (1.2 mL) was added a
1 M solution of BBr3 in CH2Cl2 (2.4 mL) over 10 min at -15 °C.
After 5 min, ice (4.0 g) and concentrated NH4OH (1.8 mL) were
added and the resulting mixture was stirred at 0 °C for 30 min.
The organic layer was separated and the aqueous layers extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4, and concentrated
under reduced pressure. Flash chromatography (5/95 MeOH/
CH2Cl2) afforded pure material.
1
as a pale-cream foam (2.6 g, 89%); Rf 0.72. H NMR (270 MHz,
CDCl3): δ 7.55-7.28 (5H, m, CHAr), 6.60 (1H, d, J ) 8.0 Hz, H1),
6.51 (1H, d, J ) 8.0 Hz, H2), 5.35 (2H s, Ph-CH2-O), 5.00 (1H,
brs, OH14), 4.68 (1H, s, H5), 3.09 (1H, d, J ) 5.5 Hz, H9), 3.05
(1H, d, J ) 18.0 Hz H10ꢀ), 2.58-2.24 (6H, m), 1.87 (2H, d, J )
6.6 Hz, cyclopropylmethyl CH2), 1.59-1.58 (2H, m), 1.24-1.20
(1H, m), 0.86-0.83 (1H, m, cyclopropyl CH), 0.54 (2H, d, J )
8.0 Hz, cyclopropyl CH2 cis), 0.13 (2H, d, J ) 8.0 Hz, cyclopropyl
CH2 trans). ESIMS m/z: 447 [M + 1]+.
3-t-Butyldimethylsilyloxy-17-cyclopropylmethyl-14ꢀ-hydroxy-
4,5r-epoxy-6ꢀ-(cinnamoylamino)morphinan (13). To a stirred
solution of 3 (0.25 mmol) in CH2Cl2 (5 mL), imidazole (0.67 mmol),
and t-butyldimethylsilylchloride (0.25 mmol) were added at 0 °C.
The suspension was stirred at RT for 24 h. The reaction mixture
then was diluted with H2O (10 mL) and extracted with CH2Cl2 (3
× 10 mL). The combined organic extracts were washed with H2O
(20 mL), brine (20 mL), and then dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. Flash chroma-
tography (10/90 EtOAc/Hexane) gave 13 (126 mg, 86%) of white
powder; Rf 0.86 (5/95 MeOH/CH2Cl2). 1H NMR (270 MHz,
CDCl3): δ 8.03 (1H, brs, NH), 7.55 (1H, d, J ) 15.6 Hz, CH )
CH), 7.48-7.47 (2H, m, CHAr), 7.33-7.32 (3H, m, CHAr), 6.68
(1H, d, J ) 8 Hz, H1), 6.57 (1H, d, J ) 8 Hz, H2), 6.43 (1H, d, J
) 15.6 Hz, CHdCH), 4.40 (1H, d, J ) 6.8 Hz, H5), 4.07-4.03
(1H, m, H6), 3.10 (1H, d, J ) 5.5 Hz, H9), 3.03 (1H, d, J ) 18.0
Hz H10ꢀ), 2.65-2.60 (2H, m), 2.35 (2H, d, J ) 6.6 Hz, cyclopro-
pylmethyl CH2), 2.34-2.18 (2H, m), 1.72-1.46 (5H, m), 0.92 (9H,
s, Si-(CH3)3) 0.92-0.89 (1H, m, cyclopropyl CH), 0.51 (2H, d, J
) 8.0 Hz, cyclopropyl CH2 cis), 0.14 (6H, s, Si-(CH3)2), 0.12 (2H,
d, J ) 8.0 Hz, cyclopropyl CH2 trans). ESIMS m/z: 587 [M + 1]+.
17-Cyclopropylmethyl-3,14ꢀ-dihydroxy-4,5r-epoxy-6ꢀ-(cin-
namoylamino)morphinan (3). Compound 3 was prepared using
the general method A described above to obtain 675 mg (65%) of
1
pale-white solid; Rf 0.40 (1/5/94 NH3/MeOH/CH2Cl2). H NMR
(270 MHz, CDCl3): δ 7.59 (1H, d, J ) 15.6 Hz, CHdCH),
7.48-7.47 (2H, m, CHAr), 7.34-7.32 (3H, m, CHAr), 6.67 (1H, d,
J ) 8 Hz, H1), 6.55 (1H, d, J ) 8 Hz, H2), 6.39 (1H, d, J ) 15.6
Hz, CHdCH), 5.43 (1H, brs, OH), 5.28 (1H, s, OH), 4.43 (1H, d,
J ) 6.8 Hz, H5), 4.10-4.10 (1H, brm, H6), 3.09 (1H, d, J ) 5.6
Hz, H9), 3.00 (1H, d, J ) 18.0 Hz H10ꢀ), 2.66-2.63 (2H, m), 2.33
(2H, d, J ) 6.6 Hz, cyclopropylmethyl CH2), 1.83-1.79 (2H, m),
1.65-1.60 (2H, m), 1.50-1.47 (2H, m), 1.28-1.23 (1H, m),
0.84-0.82 (1H, m, cyclopropyl CH), 0.51 (2H, d, J ) 8.0 Hz,
cyclopropyl CH2 cis), 0.12 (2H, d, J ) 8.0 Hz, cyclopropyl CH2
trans). 13C NMR (CDCl3): δ 166.5, 145.8, 141.6, 139.0, 135.3,
130.8, 128.6, 128.4, 127.6, 127.1, 120.9, 118.0, 77.2, 71.8. 71.0,
61.9, 60.5, 48.4, 46.4, 32.5, 27.1, 22.2, 19.4, 9.2, 3.8, 3.7. ESIMS
m/z: 473 [M + 1]+. Anal. (C29H32N2O4 ·HCl·2H2O) CHN.
6ꢀ-Naltrexamine (10). To ZrCl4 (392 mg, 1.6 mmol) in dry THF
(15 mL) was added portion wise NaBH4 (132 mg, 5.5 mmol) at
0 °C. After the mixture had been stirred for 30 min, naltrexone
O-benzyl oxime (11c) (500 mg, 1.1 mmol) was added portion wise.
The reaction mixture was warmed to RT and then refluxed for 24 h
under N2. The suspension was concentrated to dryness before adding
2 M HCl at 0 °C (slowly) and then heated at 80 °C for at least 1 h.
The aqueous layer was basified with Na2CO3 and extracted with
EtOAc (3 × 30 mL), washed with brine (30 mL), dried with
MgSO4, and concentrated under reduced pressure. Flash chroma-
tography eluent (5/95 MeOH/CH2Cl2) afforded 10 as a white solid
161 mg (42%); Rf 0.24 (1/5/94 NH3/MeOH/CH2Cl2). 1H NMR (270
MHz, CDCl3): δ 6.60 (1H, d, J ) 8.0 Hz, H1), 6.51 (1H, d, J )
8.0 Hz, H2), 5.21 (3H brs, OH, NH2), 4.23 (1H, d, J ) 6.8 Hz,
H5), 3.04 (1H, d, J ) 5.5 Hz, H9), 2.96 (1H, d, J ) 18.0 Hz H10ꢀ),
2.60-2.56 (4H, m), 2.33 (2H, d, J ) 6.6 Hz, cyclopropylmethyl
CH2), 2.22-2.08 (2H, m), 1.80-1.72 (2H, m), 1.65-1.35 (2H, m),
0.80-0.79 (1H, m, cyclopropyl CH), 0.48 (2H, d, J ) 8.0 Hz,
cyclopropyl CH2 cis), 0.10 (2H, d, J ) 8.0 Hz, cyclopropyl CH2
trans). ESIMS m/z: 343 [M + 1]+.
14ꢀ-Acetoyloxy-3-t-butyldimethylsilyloxy-17-cyclopropyl-
methyl-4,5r-epoxy-6ꢀ-(cinnamoylamino)morphinan (14a). Com-
pound 14a was prepared using the general method B described
above to obtain 90 mg (56%) of white solid; Rf 0.33 (5/95 MeOH/
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.56 (1H, d, J ) 15.6
Hz, CHdCH), 7.49-7.46 (2H, m, CHAr), 7.36-7.34 (3H, m, CHAr),
6.62 (1H, d, J ) 8 Hz, H1), 6.53 (1H, d, J ) 8 Hz, H2), 6.36 (1H,
d, J ) 15.6 Hz, CH ) CH), 4.46 (1H, d, J ) 6.8 Hz, H5), 4.33.
(1H, d, J ) 5.5 Hz, H9), 3.78-3.66 (1H, m, H6), 3.02 (1H, d, J )
18.0 Hz H10ꢀ), 2.70-2.40 (2H, m), 2.36-2.23 (4H, m), 2.11 (3H,
s CO-CH3), 2.06-1.36 (5H, m), 0.92 (9H, s, Si-(CH3)3) 0.75-0.68
(1H, m, cyclopropyl CH), 0.43 (2H, d, J ) 8.0 Hz, cyclopropyl
CH2 cis), 0.12 (6H, s, Si-(CH3)2), 0.05-0.04 (2H, m, cyclopropyl
CH2 trans). 13C NMR (CDCl3): δ 169.9, 140.9, 129.6, 128.8, 127.7,
122.2, 120.6, 118,8, 91.3, 83.0, 77.3, 77.0, 76.6, 59.3, 55.7, 52.3,
48.1, 44.1, 30.0, 25.6, 24.1, 23.1, 22.3, 9.6, 3.82, 3.5, -4.5, -4.6.
ESIMS m/z: 629 [M + 1]+.
14ꢀ-Acetoyloxy-17-cyclopropylmethyl-4,5r-epoxy-3-hydroxy-
6ꢀ-(cinnamoylamino)morphinan (15a). Compound 15a was
prepared using the general method C described above to obtain 60
1
mg (93%) of white solid; Rf 0.27 (5/95 MeOH/CH2Cl2). H NMR
(400 MHz, CDCl3): δ 8.03 (1H, brs, NH), 7.56 (1H, d, J ) 15.6
Hz, CHdCH), 7.49-7.46 (2H, m, CHAr), 7.36-7.34 (3H, m, CHAr),
6.62 (1H, d, J ) 8 Hz, H1), 6.53 (1H, d, J ) 8 Hz, H2), 6.36 (1H,
d, J ) 15.6 Hz, CH ) CH), 4.77 (1H, d, J ) 6.8 Hz, H5), 4.25
(1H, d, J ) 4.2 Hz, H9), 3.62-4.03 (1H, m, H6), 2.93 (1H, d, J )
18.0 Hz H10ꢀ), 2.62-2.61 (1H, m), 2.51-2.44 (1H m), 2.38-2.23
(3H, m), 2.107 (3H, s, CO-CH3) 2.07-1.86 (2H, m), 1.78-1.72
(1H, m), 1.28-1.18 (2H, m), 0.92 (1H, t, J ) 5.0 Hz), 0.76-0.68
(1H, m, cyclopropyl CH), 0.44 (2H, d, J ) 8.0 Hz, cyclopropyl
CH2 cis), 0.6-0.2 (2H, m, cyclopropyl CH2 trans). 13C NMR
(CDCl3): δ 170.8, 166.4, 141.2, 140.9, 139.9, 134.4, 129.7, 128.6,
127.7, 120.7, 119.6, 82.7, 59.3, 55.7, 52.3, 48.1, 44.1, 29.7, 26.1,
24.0, 22.9, 22.2, 9.5, 3.8, 3.5. ESIMS m/z: 515 [M + 1]+. Anal.
(C31H34N2O5 ·HCl) CHN.
Naltrexone O-Benzyl Oxime (11c). To a solution of naltrexone
benzoate (3.02 g, 6.5 mmol) and sodium acetate (1.58 g, 19.2 mmol)
in EtOH/H2O (80 mL:5 mL) was added O-benzyl hydroxylamine
hydrochloride (1.57 g, 9.8 mmol). The suspension of white solid

Mixed κ/µ Opioid Receptor Agonists: The 6ꢀ-Naltrexamines
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1551
ꢀ-Naltrexamine-3-O-methyl Ether (17). Compound 17 was
prepared from 3-O-methylnaltrexone following the same procedure
for formation of 6ꢀ-naltrexamine 10, to obtain 2.41 g (69%) of
medium (DMEM) supplemented with 10% fetal bovine serum
(FBS), 90 units/mL penicillin, 90 µg/mL streptomycin, and 0.5 mg/
mL Geneticin. Chinese hamster ovary cells stably expressing the
human κ-opioid receptor (CHOκ)24 were maintained similarly,
except that DMEM-F12 was used. Both cell lines were grown under
5% CO2 at 37 °C.
1
white solid; Rf 0.31 (1/5/94 NH3/MeOH/CH2Cl2). H NMR (400
MHz, CDCl3): δ 6.73 (1H, d, J ) 8.0 Hz, H1), 6.60 (1H, d, J )
8.0 Hz, H2), 5.56 (2H brs, NH2), 4.48 (1H, d, J ) 6.8 Hz, H5),
3.88 (3H, s, OCH3), 3.49 (1H, d, J ) 5.5 Hz, H9), 3.23-3.20 (1H,
m, H6), 3.02 (1H, d, J ) 18.0 Hz H10ꢀ), 2.77-1.38 (11H, m),
0.86-0.83 (1H, m, cyclopropyl CH), 0.54 (2H, d, J ) 8.0 Hz,
cyclopropyl CH2 cis), 0.19 (2H, d, J ) 8.0 Hz, cyclopropyl CH2
trans). ESIMS m/z: 357 [M + 1]+.
17-Cyclopropylmethyl-4,5r-epoxy-14ꢀ-hydroxy-3-methoxy-
6ꢀ-(cinnamoylamino)morphinan (18). Compound 18 was pre-
pared using the general method A described above, to obtain 192
mg (18%) of white powder; Rf 0.66 (1/5/94 NH3/MeOH/CH2Cl2).
1H NMR (400 MHz, CDCl3): δ 8.03 (1H, brs, NH), 7.41 (1H, d, J
) 15.6 Hz, CHdCH), 7.47-7.35 (2H, m, CHAr), 7.34-7.33 (3H,
m, CHAr), 6.70 (1H, d, J ) 8 Hz, H1), 6.60 (1H, d, J ) 8 Hz, H2),
6.41 (1H, d, J ) 15.6 Hz, CH ) CH), 5.29 (1H, brs, OH14), 4.45
(1H, d, J ) 6.8 Hz, H5), 4.14-4.09 (1H, m, H6), 3.83 (3H, s, OCH3),
3.11 (1H, d, J ) 5.5 Hz, H9), 3.00 (1H, d, J ) 18.0 Hz H10ꢀ),
2.68-2.61 (2H, m), 2.35 (2H, d, J ) 6.6 Hz, cyclopropylmethyl
CH2), 2.19-2.03 (2H, m), 1.73-1.24 (5H, m), 0.85-0.83 (1H, m,
cyclopropyl CH), 0.52 (2H, d, J ) 8.0 Hz, cyclopropyl CH2 cis),
0.12 (2H, d, J ) 8.0 Hz, cyclopropyl CH2 trans). ESIMS m/z: 487
[M + 1]+.
14ꢀ-Allyloxy-17-cyclopropylmethyl-4,5r-epoxy-3-methoxy-
6ꢀ-(cinnamoylamino)morphinan (19b). Compound 19b was
prepared using the general method D described above, to obtain
4.7 mg (43%) of white powder; Rf 0.46 (1/5/94 NH3/MeOH/
CH2Cl2). 1H NMR (270 MHz, CDCl3): δ 8.16 (1H, brs, NH), 7.66
(1H, d, J ) 15.6 Hz, CHdCH), 7.45-7.31 (5H, m, CHAr),
6.77-6.67 (3H, m, H1, H2, CHdCH), 6.04-5.92 (1H, m, allyl
CHdCH2) 5.44-5.13 (1H, m, allyl CH2 cis), 4.79-4.65 (1H, m,
allyl CH2 trans), 4.24-4.20 (2H, q, H5 H6), 3.85 (3H, s, OCH3),
3.70-3.68 (2H, s, CH2-CHdCH2), 3.09-3.05 (2H, m, H9 H10ꢀ),
2.65-2.58 (2H, m, cyclopropylmethyl CH2), 2.37-2.22 (3H, m),
1.63-1.42 (5H, m), 1.27-1.26 (1H, m), 0.87-0.83 (1H, m,
cyclopropyl CH), 0.51 (2H, d, J ) 8.0 Hz, cyclopropyl CH2 cis),
0.14 (2H, d, J ) 8.0 Hz, cyclopropyl CH2 trans). ESIMS m/z: 527
[M + 1]+.
Preparation of Membranes from C6 µ or CHOK Cells. Cells
were washed three times with 1× PBS and detached from plates
using 37 °C harvesting buffer (20 mM HEPES, pH 7.4, 150 mM
NaCl, and 0.68 mM EDTA). After centrifugation at 200g for 3
min, the cell pellet was resuspended in 50 mM Tris-HCl, pH 7.4,
and homogenized with a Tissue Tearor (Biospec Products, Inc.)
10 times at setting 4. The homogenate was pelleted at 20000g for
20 min at 4 °C and the pellet was resuspended in 50 mM Tris-
HCl, pH 7.4 and homogenized with a Tissue Tearor 5 times at
setting 2. The final pellet was resuspended in 50 mM Tris-HCl,
pH 7.4 and frozen in aliquots at -80 °C. The protein concentrations
of the aliquots were determined using the BCA protein assay.
[3H]Diprenorphine Competitive Binding Assay. Because of
the stickiness of the compounds, plasticware was precoated with
Sigma Cote. Membranes (20 µg) were incubated in 50 mM Tris-
HCl, pH 7.4, with 0.2 nM [3H]diprenorphine in the absence or
presence of varying concentrations of unlabeled compound for 60
min in a shaking water bath at 25 °C. Nonspecific binding was
measured using 10 µM naloxone. Samples were filtered through
GF/C glass-fiber filtermats mounted on a Brandel cell harvester
and rinsed four times with 4 °C 50 mM Tris-HCl, pH 7.4 buffer.
Filtermats were dried and 0.1 mL of EcoLume scintillation cocktail
was added to each sample area to soak the filter. Each filter mat
was placed in a polyethylene bag, heat sealed, and radioactivity
retained in each sample area was counted in a Wallac 1450
MicroBeta liquid scintillation and luminescence counter. Ki values
were determined using GraphPad Prism.
[35S]GTPγS Binding Assay. Because of the stickiness of the
compounds, plasticware was precoated with Sigma Cote. As
described previously,20 membranes (20 µg) were incubated in 20
mM Tris-HCl, pH 7.4, 5 mM MgCl2, 100 mM NaCl, 2.2 mM
dithiothreitol (prepared freshly), 30 µM GDP, 0.1 nM [35S]GTPγS,
and 10 µM compound or Super Q H2O. The membranes were
incubated for 60 min in a shaking water bath at 25 °C. Samples
were filtered through GF/C glass-fiber filter mats mounted on a
Brandel cell harvester and rinsed four times with 4 °C 50 mM Tris-
HCl, pH 7.4, 5 mM MgCl2, and 100 mM NaCl. Filter mats were
then processed as described above. EC50 and relative efficacy values
were calculated using GraphPad Prism.
14ꢀ-Allyloxy-17-cyclopropylmethyl-4,5r-epoxy-3-hydroxy-6ꢀ-
(cinnamoylamino)morphinan (20b). Compound 20b was prepared
using the general method E described above to obtain 76 mg (39%)
1
of white powder; Rf 0.61 (1/5/94 NH3/MeOH/CH2Cl2). H NMR
(400 MHz, CDCl3): δ 8.08 (1H, brs, NH), 7.57 (1H, d, J ) 15.6
Hz, CHdCH), 7.57-7.54 (1H, m, CHAr), 7.45-7.43 (1H, m, CHAr),
7.41-7.32 (3H, m, CHAr), 6.95 (1H, d, J ) 15.6 Hz, CHdCH),
6.75 (1H, d, J ) 8 Hz, H1), 6.65 (1H, d, J ) 8 Hz, H2), 6.09-5.94
(1H, m, allyl CHdCH2) 5.41 (1H, d, J ) 17.0 Hz, allyl CH2 cis),
5.32-5.14 (1H, m, allyl CH2 trans), 4.68 (1H, d, J ) 7 Hz, H5),
4.32-4.00 (3H, m, H6, CH2-CHdCH2), 3.14 (1H, d, J ) 5.5 Hz,
H9), 3.08 (1H, d, J ) 18.7 Hz H10ꢀ), 2.72-2.62 (2H, m), 2.42 (2H,
d, J ) 6.6 Hz, cyclopropylmethyl CH2), 2.31-2.12 (2H, m),
1.65-1.24 (5H, m), 0.93-0.88 (1H, m, cyclopropyl CH), 0.54 (2H,
d, J ) 8.0 Hz, cyclopropyl CH2 cis), 0.16 (2H, d, J ) 8.0 Hz,
cyclopropyl CH2 trans). 13C NMR (CDCl3): δ 168.2, 143.4, 143.0,
142.5, 140.3, 139.9, 135.1, 134.8, 129.7, 129.3, 128.8, 127.9,
127.8, 119.0, 118.7, 118.4, 117.2, 70.0, 62.3, 62.1, 59.1, 47.8,
47.7, 43.9, 43.8, 30.6, 30.3, 22.7, 22.6, 9.4, 3.8, 3.7. ESIMS
m/z: 513 [M + 1]+. Anal. (C31H35N2O4 · HCl · H2O) CHN.
Biology. Materials. [3H]diprenorphine and [35S]GTPγS were
from Perkin-Elmer Life and Analytical Sciences (Boston, MA).
BCA protein assay reagents were from Pierce (Rockford, IL). Cell
culture reagents were from Invitrogen (Carlsbad, CA). Sigma Cote,
U69593, DAMGO, and GDP were from Sigma-Aldrich (St. Louis,
MO). EcoLume scintillation cocktail was from ICN (Aurora, OH).
Whatman GF/C glass-fiber filtermats were from Brandel (Gaith-
ersburg, MD).
Acknowledgment. This work was funded by NIDA grant
no. DA07315.
Supporting Information Available: 1H NMR, 13C NMR, mass
spectra, and microanalysis data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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