Structure selectivity relationship studies of 17-cyclopropylmethyl-3, 14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan derivatives toward the development of the mu opioid receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2011.06.135

Mu opioid receptor antagonists have been applied to target a variety of diseases clinically. The current study is designed to explore the structure selectivity relationship (SSR) of 17-cyclopropylmethyl-3,14β-dihydroxy-4, 5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan (NAP), a lead compound identified as a selective mu opioid receptor antagonist based on the previous study. Among a series of NAP derivatives synthesized, compounds 6 (NMP) and 9 (NGP) maintained comparable binding affinity, selectivity and efficacy to the lead compound. Particularly, the mu opioid receptor selectivity over kappa opioid receptor of NGP was considerably enhanced compared to that of NAP. Overall, the preliminary SSR supported our original hypothesis that an alternate 'address' domain may exist in the mu opioid receptor, which favors the ligands carrying a hydrogen bond acceptor and an aromatic system to selectively recognize the mu opioid receptor.

Full text of DOI:10.1016/j.bmcl.2011.06.135

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5625–5629
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure selectivity relationship studies of 17-cyclopropylmethyl-3,14b-dihy-
droxy-4,5a
-epoxy-6b-[(40-pyridyl)carboxamido]morphinan derivatives toward
the development of the mu opioid receptor antagonists
Yunyun Yuan a, Orgil Elbegdorj a, Jianyang Chen a, Shashidhar K. Akubathini a, Irina O. Beletskaya b,
Dana E. Selley b, Yan Zhang a,
⇑
a Department of Medicinal Chemistry, Virginia Commonwealth University, Biotech I, 800 E. Leigh Street, Richmond, VA 23298, United States
b Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Mu opioid receptor antagonists have been applied to target a variety of diseases clinically. The current
study is designed to explore the structure selectivity relationship (SSR) of 17-cyclopropylmethyl-
Received 25 April 2011
Revised 7 June 2011
Accepted 10 June 2011
Available online 18 July 2011
3,14b-dihydroxy-4,5a
-epoxy-6b-[(40-pyridyl)carboxamido]morphinan (NAP), a lead compound identi-
fied as a selective mu opioid receptor antagonist based on the previous study. Among a series of NAP
derivatives synthesized, compounds 6 (NMP) and 9 (NGP) maintained comparable binding affinity, selec-
tivity and efficacy to the lead compound. Particularly, the mu opioid receptor selectivity over kappa opi-
oid receptor of NGP was considerably enhanced compared to that of NAP. Overall, the preliminary SSR
supported our original hypothesis that an alternate ‘address’ domain may exist in the mu opioid receptor,
which favors the ligands carrying a hydrogen bond acceptor and an aromatic system to selectively rec-
ognize the mu opioid receptor.
Keywords:
Mu opioid receptor
Antagonist
NAP
Structure selectivity relationship
Published by Elsevier Ltd.
Opioid receptor selective antagonists not only serve as impor-
tant pharmacological probes in opioid receptor structural charac-
terization and functional studies of opioid agonists, but also
exhibit a variety of biological activities to treat different disorders
and diseases. For example, nalorphine (Fig. 1), the first important
mu opioid receptor (MOR) antagonist, was developed as opiate
antidote in 1954.1 It was also combined with morphine for pain
management to abolish respiratory depression. Since nalorphine
also possesses evident kappa opioid receptor (KOR) agonism, it
was eventually replaced by naloxone,2 the first neutral opioid
antagonist. Naloxone has a higher affinity for MOR and KOR over
sights to treat and prevent brain pathologies associated with
neuroinflammation.14 CTAP, one of the most highly selective,
reversible and peptidic MOR antagonists, was also found to block
interleukin-6 (IL-6) fever.15 KOR antagonists 50-guanidinonaltrin-
dole (GNTI), nor-binaltorphimine (norBNI), and (3R)-7-hydroxy-
N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidi-
nyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinoline-
carboxamide (JDTic) were demonstrated to have antidepressant
and anxiolytic activity.16–21 It was also suggested that kappa antag-
onists may find a place to treat alcoholism,22–24 cocaine25–28 and
nicotine29 addictions. As a selective DOR antagonist, naltrindole
(NTI) was reported to be able to attenuate the discriminative stim-
ulus properties of cocaine,30 reduce both alcohol and saccharin in-
take in rats bred for alcohol preference.31
d opioid receptor (DOR) (Ki value ratios, d/
l
ꢀ 96, d/
j
ꢀ 69).3 How-
ever, due to its extremely short duration of action, naloxone is pri-
marily used to treat opiate overdose. Later on, naltrexone4 was
identified and showed greater potency and longer duration of ac-
tion than naloxone.5 Those features of naltrexone are advanta-
geous in its application to treat opiate dependence where a long-
term opioid receptor blockade is preferred. Naltrexone is now
being used as an adjunct therapy in opiate addiction management
and for treating alcohol dependence as well.6–13 Apart from the
above utilities, b-funaltrexamine (b-FNA), an irreversible MOR
antagonist, showed dose-dependent inhibition of cytokine-in-
duced nitric-oxide synthase (iNOS) expression, which provides in-
Because the addiction/abuse liability of many opiates and alco-
holism primarily involves MOR agonism,32 naltrexone represents a
potentially viable strategy to treat alcohol and opiate addiction.
However, naltrexone is subjected to significant first pass metabo-
lism.33 Moreover, compared with the high selectivity of GNTI for
KOR (Ki value ratios,
l
/
j
j
ꢀ 120, d/
j
ꢀ 250)34 and NTI for DOR (Ki
value ratios,
l
/d ꢀ 152,
/d ꢀ 276),35 naltrexone only has a moder-
ate selectivity for MOR over KOR (Ki value ratios, d/
l
ꢀ 450,
j/
l
ꢀ 20).36 Another commercial available ligand cyprodime37 car-
ries a moderate selectivity for the MOR over the DOR and KOR
(Ki value ratios are
affinity for the MOR than naloxone and naltrexone, which
j
/
l
ꢀ 45, d/ ꢀ 40) while it has much lower
l
⇑
Corresponding author. Tel.: +1 804 828 0021; fax: +1 804 828 7625.
E-mail address: yzhang2@vcu.edu (Y. Zhang).
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2011.06.135

5626
Y. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5625–5629
N
N
N
N
O
H
OH
OH
OH
OMe
HN
H
O
OH
O
O
O
O
O
O
OH
OH
OH
OH
Naloxone
Naltrexone
β
-FNA
Nalorphine
N
N
S
S
OH
OH
O
D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH
2
N
H
N
OMe
O
O
CTAP
OH
OH
Cyprodime
NAP
NH
N
N
O
HN
N
O
N
NH2
OH
OH
HO
OH
HO
N
O
N
H
N
H
N
O
O
H
NH
OH
N
HO
OH
H
OH
norBNI
GNTI
NTI
JDTic
Figure 1. Examples of opioid receptor modulators.
generally limits its application.38 Hence, the need to develop small
molecule MOR antagonists with enhanced selectivity for alcohol
and opiate addiction treatment still remains.
at the DOR and KOR.40 This information encouraged us to apply
NAP as the lead for our next generation of molecular design for
the development of MOR selective neutral antagonists. The aim
of the current study is to further explore the structure selectivity
relationship (SSR) of NAP for its MOR selectivity. Ten derivatives
with different modifications toward 4-pyridyl side chain in NAP
were designed and synthesized based on the following consider-
ations: (1) the electronic/steric character of the aromatic ring sys-
tem; (2) the amide spacer between the C(6) side chain and the
morphinan skeleton; (3) the necessity of an aromatic system. Bio-
logical evaluations of this series of derivatives were then carried
out. Two ligands with comparable binding affinity, selectivity and
efficacy to NAP were identified and selected for future in vivo study
to further characterize their pharmacological profiles.
Based on our previous studies, a derivative of naltrexone, 17-
cyclopropylmethyl-3,14b-dihydroxy-4,5a
-epoxy-6b-[(40-pyri-
dyl)carboxamido]morphinan (NAP, Fig. 2) was identified as a po-
tent and selective MOR antagonist.36 Moreover, it was suggested
that an alternate ‘address’ domain may be present in MOR, which
may recognize a ligand (e.g., NAP) bearing an aromatic system
and a hydrogen bond acceptor to achieve high MOR binding affin-
ity and selectivity.36,39 The docking study of NAP to the homology
model of MOR also showed that the nitrogen atom on the pyridyl
ring may serve as a hydrogen bond acceptor.36 Further pharmaco-
logical characterization of NAP indicated that it can act as a com-
petitive, high affinity MOR antagonist while carrying low efficacy
Using naltrexamine as the starting material, the syntheses of
these designed ligands were straightforward. First, the stereo-
N
N
N
Ty
N
OH
r210
O
1) RCOOH, EDCI, HOBt,
TEA, 4Å MS, DMF
OH
OH
O
N
H
Trp318
O
NH2 2) K2CO3, MeOH
3) HCl/Et2O
R
N
H
O
O
•2HCl
OH
xHCl
•
OH
NAP
OH
44~88%
Figure 2. NAP and its interaction with the proposed alternative MOR ‘address’
domain.
Scheme 1. Synthetic route for NAP derivatives.

Y. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5625–5629
5627
selective synthesis of 6b-naltrexamine dihydrocholoride salt was
successfully achieved according to the literature.41 Then a variety
of acids, either commercially available or prepared following re-
ported protocols (see Supplementary data), were coupled with
6b-naltrexamine dihydrochloride salt via EDCI/HOBt method. The
6-monosubstituted target compounds were eventually obtained
with reasonable yields after treating the coupling mixture under
basic condition (Scheme 1).
tives using monocloned opioid receptor expressing CHO cells.
[3H]naloxone, [3H]NTI, and [3H]norBNI were used to label MOR,
DOR and KOR, respectively. Table 1 shows that all NAP derivatives
retained subnanomolar affinity for the MOR, while there were some
dramatic selectivity differences (MOR over KOR and DOR, respec-
tively) for some of them. Because the binding pocket in both MOR
and KOR can form aromatic stacking interaction with the ligand,36
most of the derivatives displayed very low selectivity for MOR over
KOR, except for compounds 6 (NMP) and 9 (NGP). Introduction of
substitutions with different electronic and steric characteristics
The competitive radioligand binding assay was first applied to
determine the binding affinity and selectivity of these NAP deriva-
Table 1
The binding affinity and selectivity of NAP derivatives (n = 3)a
N
OH
O
N
R
H
O
xHCl
•
OH
Compd
R
Ki SEM (nM)
KOR
Selectivity ratio
d/l
MOR
DOR
j/
l
NTX
b-FNA
CTAP
N/A
N/A
N/A
0.26 0.02
0.41 0.04
2.02 0.71
5.15 0.26
0.94 0.05
1012.7 174.8
117.06 8.94
27.78 4.60
1441.0 106.1
20
2
501
450
68
713
NAPb
0.37 0.07
0.10 0.04
60.72 5.58
0.15
277.51 7.97
602.2 22.33
163
747
N
N
N
N
Cl
1
1.5
6110.7
276.0
232.1
Br
2
3
0.63 0.18
0.39 0.20
0.18 0.03
0.58 0.12
173.7 134.9
90.1 17.1
0.3
1.5
CH3
Cl
Br
4
0.67 0.28
0.45 0.13
0.58 0.25
19.93 7.66
2.83 0.60
96.7 12.2
502.4 70.1
128.0 61.2
273.6 1.81
29.6
6.3
745.8
284.7
469.9
N
5
N
CH3
N
6 (NMP)
166.1
7
8
0.85 0.16
0.57 0.41
9.01 0.61
1.65 0.19
865.6 135.2
294.0 75.4
10.6
2.9
1016.9
516.1
N
N
O
9 (NGP)
0.73 0.59
0.87 0.38
203.2 67.0
6.49 2.36
526.1 78.3
2586 1704
277.6
7.5
718.8
N
H
N
10
2968.1
N
CH3
a
The average Ki values (n = 3) are reported standard error of the means (SEM) for each individual compound. Naltrexone, b-FNA, and CTAP were tested along as controls
under the same conditions.
b
Published data36 using the same protocol.

5628
Y. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5625–5629
Table 2
onto the pyridyl ring did not influence MOR binding affinity very
much, indicating non-affected hydrogen-bonding and aromatic
stacking interactions. Yet the selectivity of MOR over KOR was
achieved for compound 6 through a decreased KOR affinity. The
observation that meta-substituted compounds 4, 5, and 6 were less
selective than their ortho-substituted counterparts 1, 2, and 3 for
KOR (Ki value ratios, 4/1 ꢀ 133, 5/2 ꢀ 16, 6/3 ꢀ 167) suggests an im-
paired aromatic stacking interaction between ligands and KOR
caused by the steric hindrance of the meta-substitution. Adding
one or two methylene group(s) between the C(6) side chain and
the morphinan skeleton, as seen in compounds 7 and 8, did not sig-
nificantly affect on MOR affinity, but the selectivities for MOR over
KOR were decreased 15- and 56-fold, respectively, compared to
NAP. Whereas a considerable selectivity improvement for MOR over
KOR was observed as the amide spacer went one atom longer (com-
pound 9 vs 8). Taken together, the effect of the amide spacer on MOR
selectivity over KOR implies the aromatic stacking interaction be-
tween MOR and ligands is more flexible, while it prefers a certain
distance for KOR binding. As the hydrogen bonding is a crucial inter-
action in MOR binding mode, the replacement of an aromatic system
with a saturated cyclic ring (compound 10) still leads to high affinity
for MOR with relatively lower affinity to KOR. Actually, the nitrogen
atom in the piperidinyl ring is a much stronger hydrogen acceptor
than the nitrogen atom in the pyridyl ring.
Due to a lack of possible hydrogen bonding between the C(6)
side chain moiety and DOR, as well as the non-aromatic binding lo-
cus to which the C(6) side chain pointed in DOR,36 MOR over DOR
selectivity of NAP derivatives is much easier to achieve compared
to MOR over KOR selectivity. Among these NAP derivatives, only
compounds 2, 3, and 5 showed a slight increase in DOR binding
affinity, yet the selectivity ratios of MOR over DOR for all the deriv-
atives are still above 200-fold. Furthermore, compound 10 ap-
peared to be least potent for DOR in this series. Its binding
affinity is only about 10% of that of NAP, which means the intro-
duction of a hydrophilic moiety is unfavorable within the hydro-
phobic environment of DOR binding pocket.
The efficacy and potency of NAP derivatives in 35S-GTP[
cS]-binding assay in MOR
expressing CHO cells (n = 3)
Compd
EC50 SEM (nM)
% Max of DAMGO SEM
DAMGO
NTX
45.06 6.63
N.D.
N.D.
100.0 6.2
7.75 0.20 at 100 nM
1.99 0.92 at 100 nM
22.72 0.84
58.20 1.47
50.80 2.85
43.32 2.80
24.86 1.83
23.23 0.35
30.63 0.55
32.78 1.80
22.62 1.24
22.62 0.66
37.24 0.97
CTAP
NAPa
1.14 0.38
0.83 0.03
1.19 0.57
1.13 0.14
2.32 1.76
1.31 0.59
1.52 0.26
2.32 0.64
1.46 0.11
2.84 0.53
5.08 0.43
1
2
3
4
5
6 (NMP)
7
8
9 (NGP)
10
a
Published data36 using the same protocol. N.D. could not be determined.
lead to higher efficacy, as shown by compound 1, 2, and 3. The re-
sults from our modeling study36 indicated that the nitrogen atom
might act as a hydrogen bonding acceptor to interact with amino
acid residues Trp319 and/or Tyr210. Considering conformation
change of trans-membrane helix 7 of the G-protein Coupled Recep-
tors (where Trp319 locates in MOR) might induce the activation of
the receptor42,43 such adjacent substitution may further disturb
the hydrogen bonding interaction of the pyridine ring system with
Trp318 to induce potential agonism. The fact that compound 4, 5,
and 6 carried similar substitution at ortho position while showing
no significant change in their efficacy compared with NAP is in
agreement with this hypothesis. On the other hand, it seemed that
such hydrogen bonding might not be sensitive to the spacer of NAP
analogues since compound 7, 8, and 9 also showed comparable
agonism to that of NAP. Naturally the current effort is focusing
on the integration of structural features from compound 6 and 9
to further test the above hypothesis and to hopefully further re-
duce the agonism of the next generation ligands.
Because hydrogen bonding plays an essential role among the
interactions between ligands and MOR, all the NAP derivatives,
which contain a hydrogen bond acceptor in each of the structures,
still retained the high affinity for MOR (at the subnanomolar level).
The introduction of halogen atoms or methyl group onto the aro-
matic ring, different distances between C(6) and the morphinan
skeleton, and even the replacement of the aromatic system with
a saturated cyclic system are all well tolerated for MOR binding.
However, these modifications affected KOR binding affinity more
profoundly either due to the weakened or the enhanced aromatic
stacking interaction, which yields the varied MOR selectivity over
KOR. As for DOR, the lacking of hydrogen bonding and aromatic
stacking interaction in its binding pocket guaranteed all the NAP
derivatives had high selectivity for MOR over DOR.
Based on the binding and functional assay results, two NAP
derivatives, namely compounds 6 (NMP) and 9 (NGP), were se-
lected for further pharmacological evaluation. Both NMP and
NGP showed sub-nanomolar binding affinity to the MOR. Com-
pared with NAP, NMP’s selectivity for the MOR was similar while
the selectivity of NGP for MOR over KOR was considerably en-
hanced. Their efficacy at the MOR was also similar to that of
NAP. Based on the recent report of the potential peripheral nervous
system (PNS) activity of NAP,39 it would be interesting to exploit
both NMP and NGP for their application in PNS diseases treatment.
In summary, the important role of MOR antagonists in both the
opioid receptor study and their clinical values makes the develop-
ment of a non-peptidic, potent, selective, neutral, and reversible
MOR antagonists highly desirable. A series of NAP derivatives were
synthesized to explore its structure selectivity relationships (SSR) in
an effort to develop such a MOR antagonist. The preliminary SSR ob-
served for NAP derivatives provides solid evidence to support our
hypothesis that hydrogen bonding and aromatic stacking interac-
tions occurring between an alternative ‘address’ domain in MOR
and ligands may lead to MOR selectivity over DOR and KOR. The cur-
rently ongoing studies of the next generation of NAP derivatives
might shed light onto this aspect more comprehensively. Moreover,
some of these derivatives exhibited considerable efficacies as MOR
partial agonists in the in vitro study. These ligands may potentially
be applied to treat opioid dependence and addiction.
To determine whether each new ligand acts as an agonist, par-
tial agonist, or antagonist of MOR, the 35S-GTP[
cS] binding assay
was performed on the MOR-expressing CHO cells by determining
its efficacy for G-protein activation relative to a full agonist at
the MOR (Table 2). The results were interpreted as the relative effi-
cacy of each new ligand to the full agonist DAMGO in the ability to
produce the stimulation. Naltrexone (NTX; 0.1–100 nM) and CTAP
(1–300 nM) were tested as controls, and produced minimal stimu-
lation such that the concentration–effect curves could not be fit
using non-linear regression (data not shown). Their maximal stim-
ulation, observed at 100 nM of each ligand (Table 2), was less than
10% relative to DAMGO (100 5.4%). As shown in Table 2, all NAP
derivatives showed partial agonism for MOR in this in vitro assay,
with compounds 8 and 9 displaying the lowest relative efficacy. It
appeared that introducing some substitution at the meta position
to the nitrogen atom of the pyridine ring of the side chain would
Acknowledgments
We are grateful for the generous gift of the opioid receptor ex-
pressed CHO cell lines from Dr. Lee-Yuan Liu-Chen at Temple

Y. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5625–5629
5629
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at doi:10.1016/j.bmcl.2011.06.135.
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