Mixed κ agonists and μ agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: Synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan

Article abstract of DOI:10.1016/S0960-894X(01)00543-1

A series of new N-substituted derivatives of morphinan was synthesized and their binding affinity for the three opioid receptors (μ, δ, and κ) was determined. A paradoxical effect of N-propargyl (MCL-117) and N-(3-iodoprop-(2E)-enyl) (MCL-118) substituents on the binding affinities for the μ and κ opioid receptors was observed. All of these novel derivatives showed a preference for the μ and κ versus δ binding.

Full text of DOI:10.1016/S0960-894X(01)00543-1

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2735–2740
Mixed ꢀ Agonists and ꢁ Agonists/Antagonists as Potential
Pharmacotherapeutics for Cocaine Abuse: Synthesis and Opioid
Receptor Binding Affinity of N-Substituted Derivatives of
Morphinan
John L. Neumeyer,a,* Xiao-Hui Gu,a L. Alexander van Vliet,a Nicholas J. DeNunzio,b
Daniela E. Rusovici,b Dana J. Cohen,b S. Stevens Negus,a Nancy K. Melloa
and Jean M. Bidlackb
aAlcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
bDepartment of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
Received 7 June 2001; accepted 3 August 2001
Abstract—A series of new N-substituted derivatives of morphinan was synthesized and their binding affinity for the three opioid
receptors (m, d, and k) was determined. A paradoxical effect of N-propargyl (MCL-117) and N-(3-iodoprop-(2E)-enyl) (MCL-118)
substituents on the binding affinities for the m and k opioid receptors was observed. All of these novel derivatives showed a pref-
erence for the m and k versus d binding. # 2001 Elsevier Science Ltd. All rights reserved.
The abuse of cocaine and other stimulant drugs is
becoming a significant social and public health concern
in the world.1 Drug abuse has contributed greatly to the
increasing spread of HIV and HBV.2 Currently there
are no efficacious medications for the treatment of
cocaine abuse.3,4 Although the mesolimbic dopamine
pathway is believed to play a primary role in mediating
the locomotor, discriminative stimulus and reinforcing
effects of cocaine,5À8 other neurotransmitter systems
have also been implicated in the reinforcing effect of
cocaine.9À15
drug-taking behavior in an animal model of relapse.26,29
Taken together, these findings suggest that activation of
k opioid receptors may functionally antagonize some
abuse-related effects of cocaine, possibly by inhibiting
the release of dopamine from dopaminergic neurons,
and thus offers a novel and effective pharmacological
approach to treat cocaine abuse.
In recent studies, we found that the nonselective k ago-
nist ethylketocyclazocine (EKC), which possesses m
receptor-mediated effects in addition to its k agonist
effects, decreased cocaine self-administration more
effectively and with fewer undesirable side effects than
highly selective k agonists.27 This suggested that non-
selective k opioid receptor agonists with additional
activity at m opioid receptors may be especially useful
for the treatment of cocaine abuse.
There is increasing evidence that opioid receptor ago-
nists are able to modulate the neurochemical and beha-
vioral effects of cocaine. For example, kappa (k)
receptor agonists attenuated cocaine-induced increases
in dopamine levels in the nucleus accumbens.16,17
Administration of k opioid receptor agonists has also
been reported to attenuate the discriminative stimulus
properties,18À20 conditioned reinforcing effects,21À23 and
self-administration of cocaine.24À28 Further, k opioid
agonists attenuated the reinstatement of extinguished
Our initial efforts to develop mixed k agonists and m
agonists/antagonists focused on the morphinan and
benzomorphan nucleus, because derivatives of morphi-
nan and benzomorphan such as cyclorphan and cycla-
zocine are known to have potent mixed activity at m and
k opioid receptors. As part of these efforts, we synthe-
sized and pharmacologically evaluated some analogues
of cyclorphan and cyclazocine.30,31 From that study, we
*Corresponding author. Tel.: +1-617-855-3388; fax: +1-617-855-
2519; e-mail: neumeyer@mclean.harvard.edu
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00543-1

2736
J. L. Neumeyer et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2735–2740
observed that morphinans with a cyclobutylmethyl or
(S)-tetrahydrofurfuryl group on the nitrogen atom had
k agonist activity. In order to systematically study the
effects of N-substituents in the morphinan nucleus on
binding affinity, selectivity, and efficacy at m and k
opioid receptors, we introduced a variety of substituents
on the nitrogen atom in morphinan. Herein, we report
on the synthesis and preliminary biological evaluation
of a series of N-substituted derivatives of morphinan.
catalyst followed by column separation of the two iso-
mers.34 Another efficient route to the (E)-tributyltin
precursor 32 involved alkylation of norlevorphanol with
3-(tributylstannyl)prop-(2E)-enyl chloride, which was
prepared by chlorination of 3-(tributylstannyl)prop-
(2E)-en-1-ol with PPh3 and CCl4. The (E)-stannyl alco-
hol was obtained by hydrostannylation of propargyl
alcohol using the literature procedure.35 The structures
and physical properties of these new N-substituted
derivatives are shown in Table 1.
The target derivatives 3–13 and 20–31 were synthesized
from norlevorphanol 2 by one of the three methods as
depicted in Scheme 1. Demethylation of levorphanol 1
was accomplished according to the procedure reported
by DeGraw and Engstrom.32 Thus, levorphanol was
treated with ethyl chloroformate in refluxing chloro-
form in the presence of K2CO3 followed by partial
hydrolysis of the product with 10% NaOH in methanol.
Norlevorphanol 2 was obtained in good yield after
hydrolysis of the resulting carbamate (structure not
shown) intermediate in a mixture of hydrochloric acid
and glacial acetic acid. Direct alkylation of norlevor-
phanol with various alkyl halides in DMF using K2CO3
or NaHCO3 as base provided N-substituted derivatives
3–1333 in good to excellent yields. Alternatively, acyla-
tion of norlevorphanol with acid chlorides followed by
reduction of the intermediate amides, 14–19 with
LiAlH4 in THF afforded the tertiary amines 20–25.
Alkylation of norlevorphanol with 1-aryl-3-(dimethyla-
mino)-1-propanone methiodide in DMF in the presence
of Na2CO3 yielded ketones 26–28, which were then
reduced with NaBH4 to afford the alcohols 29–31 as a
mixture of hydroxy diastereomers. The N-(3-iodoprop-
(2E)-enyl) and N-(3-iodoprop-(2Z)-enyl) derivatives 34
and 35 were obtained by iododestannylation of com-
pounds 32 and 33 by treatment with iodine in chloro-
form (Scheme 2). The tributyltin precursors 32 and 33
were prepared by hydrostannylation of the N-propargyl
derivative 9 with HSnBu3 in the presence of Et3B as
The binding affinities of compounds 3–13, 20–31, and
34–35 for the m, d, and k opioid receptors were assessed
using competitive binding assays in guinea pig brain
membranes employing [3H]DAMGO (m agonist),
[3H]naltrindole (d antagonist) and [3H]U69593 (k ago-
nist) as radioligands as described previously.30 The
results are summarized in Table 2. For comparison
purposes the binding data for U50,488, Mr2033, EKC,
levorphanol, and cyclorphan are also included.
As noted, the N-substituent had a significant effect on
both the opioid receptor binding affinity and selectivity
of these morphinan derivatives. Replacement of the
methyl group in levorphanol with a cyclopropylmethyl
resulted in greatly increased affinity at the d and k
opioid receptors (20-fold and 40-fold, respectively),
while the affinity at the m opioid receptor increased just
2-fold.30 The interesting pharmacology of the cyclopro-
pylmethyl group is not confined to the morphinan series
but is also true for the corresponding benzomorphan
and morphine series.30 The N-cyclobutylmethyl deriva-
tive MCL-101 showed 30-fold increase in binding affi-
nity at the k opioid receptor but the increase for the m
and d opioid receptors is less pronounced (2-fold and 3-
fold, respectively). MCL-101 possessed almost the same
affinity for the m and k opioid receptors as cyclorphan
but MCL101 had greater k/d selectivity (18-fold vs 4-
fold).30 Further increasing the size of the ring led to a
Scheme 1. Reagents and conditions: (a) ethyl chloroformate, K2CO3, CHCl3, reflux; 10% NaOH, MeOH; glacial HOAc, HCl (12 N), reflux; (b)
RBr, K2CO3 or NaHCO3, DMF, rt or 90 ꢀC; (c) RCOCl, Et3N, CH2Cl2, 0 ꢀC–rt; (d) LiAlH4, THF, rt; (e) ArCOCH2CH2NMe3I, DMF, Na2CO3, rt;
(f) NaBH4, MeOH, rt.

J. L. Neumeyer et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2735–2740
2737
Scheme 2. Reagents and conditions: (a) Bu3SnH, Et3B, THF; column separation; (b) I2, CHCl3.
Table 1. Physical properties of N-substituted derivatives of morphinan
Compd
R
Molecular formula
C19H26NOF
Yield (%)
83
Mp (ꢀC)
215–216b
Anal.a
3
MCL-107
MCL-108
MCL-109
MCL-110
MCL-111
MCL-113
MCL-117
MCL-124
MCL-125
MCL-126
MCL-127
MCL-104
C, H, N
.
C20H29NO 0.25H2O
4
62
69
95
95
61
55
45
61
75
56
68
164–165c
164–166
181–183
165–167
172–174
203–204 (dec)
Foam
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
.
C20H29NO2 0.5H2O
5
.
C19H27NO2 0.75H2O
6
.
C23H27NO 0.25H2O
7
.
C19H59NO 0.25H2O
8
9
C19H23NO
10
11
12
13
20
C19H24F3NO
Foamd
.
C19H24N2O 0.45H2O
.
C20H26N2O 0.25H2O
158–160
130–132
229–230e
.
C24H29NO 0.25H2O
C22H31NO
C, H, N
(continued)

2738
J. L. Neumeyer et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2735–2740
Table 1 (continued)
Compd
R
Molecular formula
C23H33NO
Yield (%)
73
Mp (ꢀC)
242–243e
Anal.a
21
22
23
24
26
27
28
29
30
31
34
35
MCL-105
C, H, N
.
C29H33NO2 0.75H2O
MCL-119
MCL-120
MCL-112
MCL-114
MCL-115
MCL-123
MCL-122
MCL-121
MCL-128
MCL-118
MCL-116
33
38
39
82
76
74
64
79
51
32
15
105–110e
218–220
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
.
C21H25NOS 0.25H2O
.
C24H29NO 0.25H2O
233–235
.
C25 H29NO2 0.25H2O
Foam
C25H29NO2
166–168 (dec)
Foam
.
C23H27NO3 1.25H2O
.
C23H29NO2S 1.75H2O
Foam
.
C25H31NO2 0.5H2O
218–220 (dec)
Foam
C23H29NO3
.
C19H24INO 0.25H2O
165–167 (dec)
210–214 (dec)
.
C19H24INO 0.25H2O
aThe C, H, N analyses are within Æ0.4% of theoretical values.
bL-Tartrate salt recrystallized from MeOH.
cRecrystallized from EtOAc.
dJacobson et al.38 reported that the free base is an oil and the mp of its HCl salt was 188 ꢀC (softening at 160 ꢀC).
e(S)-Mandelate salt recrystallized from MeOH–iPrOH.
loss in binding affinity. The N-cyclohexylmethyl deriva-
tive 21 (MCL-105) displayed very low affinity for the
three opioid receptors. The N-isopropyl derivative 4
(MCL-108) showed much higher (14-fold) affinity for
the k receptor but lower (2-fold) affinity for the m
receptor than levorphanol. Replacement of the methyl
with an allyl group 8 (MCL-113, levallorphan) resulted
in 15-fold increase in affinity for the k opioid receptor
and almost no changes in affinity for both of the d and m
opioid receptors. Surprisingly, the N-propargyl deriva-
tive 9 (MCL-117) and the N-(3-iodoprop-(2E)-enyl)
derivative 34 (MCL-118) exhibited unexpectedly high
affinity for the m and k opioid receptors with Ki values in
the picomolar range. In fact, these two compounds are
some of the most potent ligands for the m and k opioid
receptors identified to date. Compounds 9 and 34 had
the same high affinity for the m opioid receptor but 34
displayed 10-fold decreased affinity for the k and 43-
fold decreased affinity for the d opioid receptor in com-
parison to 9. The N-(3-iodoprop-(2Z)-enyl) derivative
35, however, displayed dramatically decreased (100-fold
and 17-fold) affinity for the m and k receptors relative to
34. Recently, May et al. reported the effect on opioid
receptor affinity and efficacy of several N-alkenyl and N-
alkynyl substituents in normetazocine.36 The N-(3-
fluoropropyl) derivative 3 (MCL-107) also displayed
very high affinity for all three opioid receptors
(Ki=0.18, 0.85, and 0.083 nM for the m, d, and k
receptor, respectively). The N-methoxyethyl derivative 6
(MCL-110) was found to have high affinity for the k
and m opioid receptors (Ki=0.094 nM and 0.11 nM,
respectively). Replacement of methoxyethyl with ethoxy-
ethyl resulted in a 2-fold and 4-fold loss in affinity for
the m and k opioid receptors, respectively. The N-phe-
noxyethyl derivative 13 (MCL-127) exhibited decreased
affinity for all three opioid receptors relative to the
methoxyethyl derivative 6. It appears that the size of the
ether chain affects the affinity for the three opioid
receptors. The N-methoxymethyl and N-fluoropropyl
derivatives of normetazocine were found to bind non-
selectively, with high affinity for the m and k receptors.37
The N-furanylmethyl derivative 22 (MCL-119) dis-
played high affinity for the m and k receptors (Ki=0.54
nM and 0.13 nM, respectively). Replacement of the
furanylmethyl group with thienylmethyl resulted in
decreased affinity for all three opioid receptors but this

J. L. Neumeyer et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2735–2740
2739
Table 2. Opioid receptor binding affinity and selectivity for N-substituted derivatives of morphinan
Ki (nM)ÆSEM
Selectivity
Compd
[3H]DAMGO (m)
[3H]Naltrindole (d)
[3H]U69,593 (k)
k/m
610
2
1
0.09
2
2
5
12
2
3
0.8
1
11
0.092
2
0.06
0.04
0.6
1
0.13
4
k/d
U 50,48
Mr2033
220Æ5.6
0.40Æ0.07
0.78Æ0.10
0.21Æ0.017
0.092Æ0.005
0.12Æ0.012
0.96Æ0.13
18Æ1.3
2500Æ170
4.5Æ0.70
3.4Æ0.41
4.2Æ2.3
0.22Æ0.01
1.3Æ0.06
6.9Æ0.68
69Æ5.3
0.36Æ0.056
0.21Æ0.044
0.62Æ0.11
2.3Æ0.26
6900
20
5
(À)EKC
Levorphanol
(À) Cyclorphan
MCL-101
2
4
0.053Æ0.003
0.073Æ0.012
0.21Æ0.014
1.5Æ0.19
18
33
46
10
35
16
6
220
2
26
2
20 (MCL-104)
21 (MCL-105)
3 (MCL-107)
4 (MCL-108)
5 (MCL-109)
6 (MCL-110)
7 (MCL-111)
24 (MCL-112)
8 (MCL-113)
26 (MCL-114)
27 (MCL-115)
35 (MCL-116)
9 (MCL-117)
34 (MCL-118)
22 (MCL-119)
23 (MCL-120)
30 (MCL-121)
29 (MCL-122)
28 (MCL-123)
10 (MCL-124)
11 (MCL-125)
12 (MCL-126)
13 (MCL-127)
31 (MCL-128)
0.18Æ0.025
0.54Æ0.15
0.26Æ0.02
0.11Æ0.007
20Æ2.9
0.85Æ0.021
5.6Æ0.70
5.6Æ0.040
0.54Æ0.05
420Æ77
0.083Æ0.002
0.16Æ0.25
0.33Æ0.015
0.094Æ0.001
1.9Æ0.19
0.12Æ0.015
0.34Æ0.008
0.27Æ0.035
0.43Æ0.11
0.42Æ0.15
0.0032Æ0.001
0.0048Æ0.001
0.54Æ0.04
1.5Æ0.16
3.1Æ0.88
4.1Æ0.50
10.0Æ2.1
23Æ2.6
1.3Æ0.26
0.16Æ0.031
4.5Æ0.82
9.9Æ1.2
2
33Æ6.2
0.65Æ0.06
0.0030Æ0.0005
0.037Æ0.007
0.13Æ0.004
0.32Æ0.015
57Æ2.1
51
210
730
65
160
2
4
5
21
11
8
0.62Æ0.19
27Æ4.9
8.5Æ1.1
51Æ6.3
5
21Æ8.8
130Æ16
0.4
0.2
0.035
2
1.4
0.42
0.06
0.35
4.1Æ0.27
110Æ9.5
42Æ5.4
25Æ0.62
0.28Æ0.06
2.3Æ0.44
7.9Æ0.26
27Æ1.7
1.3Æ0.10
0.33Æ0.01
0.16Æ0.02
0.92Æ0.29
4.2Æ0.36
2.6Æ0.95
3.1Æ0.38
33Æ1.6
0.23Æ0.05
0.38Æ0.008
15Æ3.6
2
2
29Æ2.4
12Æ1.9
decrease was most pronounced for the d opioid receptor
(6-fold vs 2-fold). Thus, the N-thienylmethyl derivative
23 (MCL-120) displayed good selectivity for the m and k
receptors versus d receptor (k/d=160, m/d=14). The N-
benzyl derivative 7 (MCL-111) showed dramatically
decreased affinity at all three opioid receptors relative to
22 and 23. Adding one more carbon between the nitro-
gen and the phenyl ring (the phenethyl derivative 24) led
to a great increase in binding affinity. The increase is
130-fold and 16-fold for the d and m opioid receptors,
respectively. The N-cyanoethyl derivative 11 (MCL-
125), prepared by Jacobson et al. two decades ago,38
displayed increased affinity (10-fold) for the k opioid
receptor as compared with levorphanol (the N-methyl
derivative). Replacement of the 2-cyanoethyl with a 3-
cyanopropyl group caused few changes in binding affi-
nity for all three opioid receptors. However, the N-tri-
fluoropropyl derivative 12 had decreased affinity for the
m and d receptors and similar affinity for the k receptor
relative to levorphanol. The three Mannich base deri-
vatives 26–28 showed similar binding profiles with good
affinity for the m opioid receptor and low affinity for
both the k and d opioid receptors. Reduction of the keto
group to secondary alcohol resulted in loss in binding
affinity for the three opioid receptors. It seems that a
hydroxyl group in the N-substituent interferes with the
interaction of the ligand with the opioid receptors,
probably due to its hydrogen-donating property.
Finally, it is important to point out that the k/d selec-
tivity of most of these derivatives was considerably
better than that of levorphanol and EKC.
In conclusion, this study demonstrated that the N-sub-
stituent of morphinan had significant effect on the
binding affinity and selectivity for the three opioid
receptors. These N-substituted derivatives exhibited a
strong preference for m and k versus d binding. The N-
cyclopropylmethyl (cyclorphan), N-(S)-tetrahydro-
furfuryl,30 N-cyclobutylmethyl (MCL-101),30 N-(3-
fluoropropyl) 3 (MCL-107), N-methoxyethyl 6 (MCL-
110), the N-propargyl 9 (MCL-117), and the N-(3-iodo-
prop-(2E)-enyl) 34 (MCL-118) derivatives possessed
high affinity for the m and k opioid receptors. In parti-
cular, the N-propargyl analogue 9 (MCL-117) and the
N-(3-iodoprop-(2E)-enyl) analogue 34 (MCL-118)
showed surprisingly high affinity for the m and k opioid
receptors with Ki values in the picomolar range. Further
syntheses of other N-substituted derivatives of morphi-
nan and GTPgS functional assays on selected com-
pounds are in progress and will be reported in due
course.
Acknowledgements
This work was supported by National Institute on Drug
Abuse (K05-DA00360, U-19-DA11007 and K05-
DA00101). Levorphanol tartrate was generously dona-
ted by Mallinckrodt Inc. We thank Jim Hilbert for
excellent technical assistance.

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J. L. Neumeyer et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2735–2740
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