14-O-Heterocyclic-substituted naltrexone derivatives as non-peptide mu opioid receptor selective antagonists: Design, synthesis, and biological studies

Article abstract of DOI:10.1016/j.bmcl.2008.12.093

Mu opioid receptor antagonists have clinical utility and are important research tools. To develop non-peptide and highly selective mu opioid receptor antagonist, a series of 14-O-heterocyclic-substituted naltrexone derivatives were designed, synthesized,

Full text of DOI:10.1016/j.bmcl.2008.12.093

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1825–1829
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
14-O-Heterocyclic-substituted naltrexone derivatives as non-peptide mu
opioid receptor selective antagonists: Design, synthesis, and biological studies
Guo Li a, , Lindsey C. K. Aschenbach a, , Hengjun He b, Dana E. Selley b, Yan Zhang a,
*
a Department of Medicinal Chemistry, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA 23298-0613, USA
b Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA 23298-0613, USA
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 clinical utility and are important research tools. To develop
non-peptide and highly selective mu opioid receptor antagonist, a series of 14-O-heterocyclic-substituted
naltrexone derivatives were designed, synthesized, and evaluated. These compounds showed subnanom-
olar-to-nanomolar binding affinity for the mu opioid receptor. Among them, compound 1 exhibited the
highest selectivity for the mu opioid receptor over the delta and kappa receptors. These results implicated
an alternative ‘address’ domain in the extracellular loops of the mu opioid receptor.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 25 September 2008
Revised 19 December 2008
Accepted 19 December 2008
Available online 29 December 2008
Keywords:
Opioid
Mu opioid receptor
Antagonist
Naltrexone
Opioid receptors were generally classified into three subtypes
based on the pharmacological, behavioral, and biochemical stud-
ies.1–3 Opioid antagonists have played very important roles in the
study of opioid receptors. In fact, an agonist is characterized as opi-
oid-receptor-mediated only if its effect is competitively inhibited
by an opioid antagonist.4,5 It is important to have receptor-selec-
tive opioid antagonists as tools to identify the receptor types
related to the interaction with opioid agonists.4–6 The mu opioid
receptor (MOR) is the major type that mediates opioid analgesic
effects of morphine, although all three opioid receptors can be
involved in analgesia. The characterization of the MOR structure–
function relationship is essential because it has been found that
morphine’s analgesic effect, addictive properties, and other major
side effects are abolished in MOR knock-out mice.7,8 Moreover, it
has been demonstrated that the analgesic effects and the adverse
side effects (including addiction and abuse liability) of morphine
are primarily due to its interaction with the MOR.4 In fact, naltrex-
one, an opioid antagonist with moderate selectivity for the MOR,
has been shown to block relapse and curb drug craving in post-
dependent opiate addicts.9,10 Recent research results also indicate
that MOR antagonists can be used in the treatment of obesity,
psychosis and Parkinson’s disease.11 Furthermore, highly selective
MOR antagonists can be used as probes to characterize the MOR-
binding pocket. Yet the lack of a non-peptidyl, highly selective,
and potent MOR antagonist limits our understanding of the struc-
ture–function relationship of the MOR, the interaction of non-
peptidyl MOR agonists with the receptor, and more specifically,
the activation mechanism of the receptor related to its role in drug
abuse and addiction.
Schwyzer et al. proposed the ‘message-address’ concept in his
analysis of the structure–activity relationship of ACTH, adrenocor-
ticotropic hormone, and related hormones.12 By applying the ‘mes-
sage-address’ concept, highly selective non-peptide antagonists for
the kappa opioid receptor (KOR) (e.g., norbinaltorphimine (norBNI)
and 50-guanidinonaltrindole (GNTI)),13,14 and for the delta opioid
receptor (DOR) (e.g., naltrindole (NTI))15 were designed and syn-
thesized several years ago (Fig. 1). Thus far no potent and highly
selective antagonist derived from morphinan’s structural skeleton
has been developed for the MOR, although some moderately po-
tent ligands, for example, cyprodime,16 are available. Compared
with the high selectivity of GNTI for the KOR (Ki value ratios are
mu/kappa ꢀ 120, delta/kappa ꢀ 250)14 and NTI for the DOR (Ki
value ratios are mu/delta ꢀ 152, kappa/delta ꢀ 276),15 cyprodime
only has a moderate selectivity for the MOR over the DOR and
KOR (Ki value ratios are kappa/mu ꢀ 45, delta/mu ꢀ 40).16a At the
same time, b-funaltrexamine (b-FNA), clocinnamox, and other
compounds, act as selective but irreversible antagonists for the
MOR.17 Therefore the development of a highly selective, non-pep-
tidyl, and reversible MOR antagonist is highly desired.
It was reported that the extracellular loop (EL) domains of the
MOR are critical for the binding of MOR-selective agonists, such
as morphine, sufentanil, lofentanil, and DAMGO.18 At the same
time, site-directed mutagenesis studies have revealed that certain
amino acid residues in this domain may be essential for ligand
* Corresponding author. Tel.: +1 804 828 0021; fax: +1 804 828 7625.
E-mail address: yzhang2@vcu.edu (Y. Zhang).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.093

1826
G. Li et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1825–1829
Figure 1. Morphinan derivatives as opioid selective antagonists.
(including agonist and antagonist) selectivity for the MOR over the
other two opioid receptor types.19 Therefore, a non-peptide ligand
with potential interaction with the EL domains of the MOR, would
be favorable for its selectivity for the MOR.
could act as hydrogen bonding donor/acceptors. This unique fea-
ture in the MOR antagonist-binding locus might form an alterna-
tive ‘address’ domain to differentiate the antagonist binding
mode of the MOR over the DOR and KOR. Therefore, a new com-
pound containing specific structural features to interact with these
amino acid residues might have increased selectivity for the MOR
over the DOR and KOR.
Based on this hypothesis, a series of novel 14-O-substituted nal-
trexone derivatives (Fig. 3) have been designed and synthesized.
The ester bond in these novel ligands was assumed to provide a
flexible conformation for the whole side chain. The nitrogen atom
in the hetero-aromatic moiety on the 14-O-position of naltrexone
was introduced to provide an opportunity for hydrogen bonding
and/or aromatic stacking interaction with the amino acid residues
Tyr212 and Trp320 in the MOR binding pocket (compounds 1–3
and 5–7). Compounds 4 and 8 were designed as control com-
pounds to test this hypothesis. These ligands could also be consid-
ered as derivatives of clocinnamox without the Michael acceptor
character.
Using naltrexone as the starting material, the syntheses of these
14-O-heterocyclic-substituted derivatives was straightforward
(Scheme 1). To be noticed, in the second step of the synthesis route,
K2CO3 aqueous solution was used to prepare the control com-
pounds 4 and 8 instead of using the acidic condition. All the final
compounds were obtained with reasonable yield and characterized
with NMR, IR, MS, and HPLC (see Supplementary information).
The primary biological studies of these ligands included com-
petitive radioligand-binding assays using mono-cloned opioid
receptors expressed in CHO cell lines. [3H] DAMGO, [3H] NTI and
[3H] norBNI were used to label the MOR, DOR, and KOR, respec-
tively. The binding affinities of these ligands for the MOR, DOR,
and KOR, and comparative selectivities were summarized in Table
1. These compounds showed binding affinities in the subnanomo-
lar-to-nanomolar range for the MOR.
Due to the lack of the crystal structure of the MOR, so far most
molecular design efforts directed toward development of selective
opioid ligands have been based on structure–activity relationship
studies. As a matter of fact, in the entire superfamily of GPCRs, only
the X-ray crystal structures of bovine rhodopsin,20–23 opsin,24 and
the human b2- 25–28 and b1-adrenergic receptors29 have been suc-
cessfully obtained with high resolution. Thus far, most of the
molecular models of other GPCRs have been constructed using rho-
dopsin’s structure as a template via homology modeling. Homol-
ogy modeling of GPCRs has been successfully applied to further
understand ligand–protein interactions, and to identify new and
potent ligands. It is believed that with all the lessons learned from
previous experience, GPCR homology modeling based on the bo-
vine rhodopsin X-ray crystal structure can aid in structure-based
drug design and virtual screening for therapeutic applications.30–37
For example, a homology model of the Angiotensin II Type 1
(AT1) receptor was used to further explore the binding sites of
several non-peptide AT1 receptor antagonists.38 A homology mod-
el of the M1 muscarinic acetylcholine receptor was applied to
understand the mechanism by which the agonist–receptor com-
plex activates G proteins.39
Recently, we reported the construction of a MOR homology
model based on the crystal structure of bovine rhodopsin.40 This
model contained not only the transmembrane helical domains,
but also the extracellular and intracellular loops so that the model
we obtained was integrated and complete. This model was further
optimized in a membrane-aqueous system by molecular dynamics
simulations. Similar homology models of the DOR and KOR were
then constructed (see Supplementary information for details). Nal-
trexone is an ideal template for the design of selective MOR antag-
onists, because it has subnanomolar-to-nanomolar affinity for all
three opioid receptor types and shows moderate selectivity for
the MOR over the other two opioid receptor types. Figure 2 shows
that in a representative binding mode of naltrexone in the MOR,
the 14-hydroxyl group of naltrexone is pointing to the EL3 loop
and the upper-level region of TM6/7. Compared to the amino acid
residues in the corresponding domains of the KOR and DOR, some
non-conserved residues, for example, Tyr212 and Trp320, in MOR
Also as shown above, all of these compounds exhibited different
levels of selectivity for the MOR over the KOR and DOR. Among
these, compound 1 had approximately 800-fold selectivity for the
MOR over the DOR and nearly 200-fold selectivity over the KOR.
Compound 5 also showed over 100-fold selectivity for the MOR
over the other two receptor types, although its binding affinity
for the MOR was significantly lower than compound 1. In addition,
all of these compounds acted as MOR antagonists in 35[S]GTP
cS

G. Li et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1825–1829
1827
Figure 2. Naltrexone in MOR-binding pocket: mu opioid receptor model: ribbon and in cyan color; the residues in mu opioid receptor: ball and stick and in atom color;
naltrexone molecular: ball and stick and carbon in yellow color, and oxygen red, nitrogen blue.
Figure 3. The designed ligand for primary study.
Scheme 1. The synthetic route for the 14-O-subsituted naltrexone derivatives.
functional assays except for compound 7, which was a partial
agonist.
To further characterize compound 1 as the lead for our next
generation molecular design, its antagonism was evaluated against
Compared to the control compounds 4 and 8, the MOR selectiv-
ity over DOR and KOR had been enhanced greatly in all of the other
compounds. This result suggested that the 14-O-substitutions
introduced onto the naltrexone skeleton might interact with the
proposed alternative ‘address’ domain in the MOR, and the nitro-
gen atom in the heterocyclic ring might act as a hydrogen bond
acceptor and play an important role for the selectivity. Among all
of these ligands, compound 1 showed the highest selectivity, which
suggested that it had the most favorable orientation of its side
chain towards this plausible ‘address’-binding domain in the
MOR. For compound 5, its side chain might confer selectivity for
the MOR, whereas the bulkiness of its side chain also might have
reduced its binding affinity for the MOR.
DAMGO in 35[S]GTP
cS functional assay. The concentration of com-
pound 1 was 1.5 nM while DAMGO was in the range of 10–
10,000 nM. The Ke value of compound was 0.20 0.04 nM and
apparent pA2 value was 9.72 0.10. This observation was consis-
tent with the binding affinity results and further verified that com-
pound 1 could be used as the lead for future molecular design.
It has been reported by Schmidhammer et al., that 14-alkoxy-
morphinans showed very high opioid receptor affinity. These com-
pounds exhibited significantly increased binding affinities at all
opioid receptors without any specific preference for any one recep-
tor type.41–43 Recently, Husbands et al., investigated the SAR of the
analogs of clocinnamox, 14-aminodihydromorphinones, and 14-
aminodihydrocodeinones, to explore the effect of changing the

1828
G. Li et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1825–1829
Table 1
Binding affinity and functional assay results for the 14-O-substituted naltrexone derivatives
Compound
Ki SEM (nM)
[3H] NTI (d)
Selectivity
Percent Max of DAMGO
[3H]DAMGO (
l)
[3H] norBNI (
j)
d/
l
j/l
Naltrexone
b-FNA
CTAP
0.26 0.02
0.41 0.04
2.02 0.71
0.14 0.03
1.59 0.61
5.58 1.34
123.23 38.23
68.40 6.04
1.44 0.32
117.00 8.90
27.78 4.60
5.15 0.26
0.94 0.05
1012.70 174.80
25.50 6.50
450
68
713
838
107
73
>81
>146
16
304
4
20
2
501
182
30
9
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
1441.00 106.10
117.38 17.97
170.30 12.64
405.32 234.68
>10,000.00
1
2
3
4
5
6
7
8
47.81 8.48
49.21 20.37
586.42 32.39
>10,000.00
67.15 36.72
148.23 55.53
46.57 13.53
5
>10,000.00
>146
47
55
<1
22.81 19.52
818.43 507.23
907.18 192.99
0.00
22.00 10.30
0.00
2.69 0.72
225.27 46.6
The Ki values for the mu, delta and kappa opioid receptors were n = 3. The averages were reported along with their standard error of the means, SEM, for each compound. The
comparison to percent stimulation of DAMGO was the Emax of the compound compared to the Emax of DAMGO (normalized to 100%). The DAMGO EC50 value was
45.1 6.63 nM and its Emax value was 366 23% stimulation over basal using a [35S]GTP
cS functional assay. Naltrexone, b-FNA and CTAP were tested along as positive
controls under the same conditions.
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chain linking and substitution in the aromatic ring of cinnamoyla-
minomorphinones and codeinones.44–46 These authors found that a
modest selectivity for the MOR over the DOR and KOR was
achieved when the side chain on the 14 positions was comparably
rotatable in these 14-aminiodihydromorphinone compounds.
Comparing to the compounds reported by Schmidhammer and
Husbands, the compounds reported here showed similar affinity
for the MOR, but much higher selectivity over the DOR and KOR.
One possible explanation might be that the introduction of a short-
er side chain and a more flexible ester bond in our compounds
might lead to a more favorable conformation and orientation of
the side chain to target the ‘address’ locus and thereby improve
selectivity for the MOR. Certainly this ‘address’ locus needs to be
further verified, for example, by site-directed mutagenesis, in fu-
ture studies.
Insummary, aseriesof 14-O-heterocyclic-substitutednaltrexone
derivatives were designed, synthesized, and evaluated as selective
MOR antagonists. Most of these novel ligands exhibited subnanom-
olar-to-nanomolar binding affinity for the MOR, with compound 1
showing the highest selectivity for the MOR over the DOR and
KOR. These results implicated a plausible ‘address’ domain in the
extracellular loops of the MOR. The knowledge gained from these
studies will enrich the ‘message-address’ concept that has been ap-
plied successfully in opioid research and may lead to the identifica-
tion of potent MOR-selective non-peptide antagonists.
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We thank Dr. Lee-Yuan Liu-Chen at Temple University and Dr.
Ping-Yee Law at the University of Minnesota for the generous gift
of opioid receptor expressing CHO cell lines. We appreciate the gen-
erous help from Mallinckrodt, Inc. for the gift of naltrexone sample.
The work was partially supported by PHS Grant DA10770 from NIH/
NIDA (D.E.S.), theResearchFund646920fromA.D. Williams Founda-
tion and PHS Grant DA24022 from NIH/NIDA (Y.Z.).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.12.093.
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