Discovery of Potent and Selective Agonists of δ Opioid Receptor by Revisiting the "message-Address" Concept

Article abstract of DOI:10.1021/acsmedchemlett.5b00423

The classic "message-address" concept was proposed to address the binding of endogenous peptides to the opioid receptors and was later successfully applied in the discovery of the first nonpeptide δ opioid receptor (DOR) antagonist naltrindole. By revisiting this concept, and based on the structure of tramadol, we designed a series of novel compounds that act as highly potent and selective agonists of DOR among which (-)-6j showed the highest affinity (K_i = 2.7 nM), best agonistic activity (EC₅₀ = 2.6 nM), and DOR selectivity (more than 1000-fold over the other two subtype opioid receptors). Molecular docking studies suggest that the "message" part of (-)-6j interacts with residue Asp128^3.32 and a neighboring water molecule, and the "address" part of (-)-6j packs with hydrophobic residues Leu300^7.35, Val281^6.55, and Trp284^6.58, rendering DOR selectivity. The discovery of novel compound (-)-6j, and the obtained insights into DOR-agonist binding will help us design more potent and selective DOR agonists.

Full text of DOI:10.1021/acsmedchemlett.5b00423

Letter
pubs.acs.org/acsmedchemlett
Discovery of Potent and Selective Agonists of δ Opioid Receptor by
Revisiting the “Message-Address” Concept
Qing Shen,† Yuanyuan Qian,† Xiaoqin Huang,‡ Xuejun Xu,§ Wei Li,*,† Jinggen Liu,*,§ and Wei Fu*,†
†Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, P. R. China
‡Center for Theoretical Biological Physics and Center for Research Computing, Rice University, Houston, Texas 77005, United States
§Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China
S
* Supporting Information
ABSTRACT: The classic “message-address” concept was proposed to address the binding of endogenous peptides to the opioid
receptors and was later successfully applied in the discovery of the first nonpeptide δ opioid receptor (DOR) antagonist
naltrindole. By revisiting this concept, and based on the structure of tramadol, we designed a series of novel compounds that act
as highly potent and selective agonists of DOR among which (−)-6j showed the highest affinity (Ki = 2.7 nM), best agonistic
activity (EC50 = 2.6 nM), and DOR selectivity (more than 1000-fold over the other two subtype opioid receptors). Molecular
docking studies suggest that the “message” part of (−)-6j interacts with residue Asp1283.32 and a neighboring water molecule, and
the “address” part of (−)-6j packs with hydrophobic residues Leu3007.35, Val2816.55, and Trp2846.58, rendering DOR selectivity.
The discovery of novel compound (−)-6j, and the obtained insights into DOR-agonist binding will help us design more potent
and selective DOR agonists.
KEYWORDS: δ opioid receptor, agonist, affinity, selectivity, molecular docking
pioid analgesics are widely used as treatments to relieve
moderate-to-severe pain, and most of them (e.g.,
naltrindole (NTI) and the DOR agonist SIOM (Figure 1).12,13
The morphinan fragment of these two compounds was
envisaged as the “message” part, and the aromatic group
(e.g., indole group of NTI) as “address” part for DOR
selectivity.
( )-cis-Tramadol (4, Figure 1), a commonly prescribed
medicine to treat moderate pain, is actually an agonist of MOR
with Ki = 2400 nM.14 Its O-metabolite M1 was found to be
much more potent (Ki = 11.0 nM) than tramadol. (1R,2R)-M1
stereoisomer was identified as its active form.14 We found that
the nitrogen atom and phenol fragment of both (1R, 2R)-M1
and SIOM overlapped very well (Figure 2A) after super-
imposing them together with morphine. This indicates that the
(1R,2R)-M1 shares similar pharmacophore features of
morphine and SIOM. According to the “message-address”
concept, the nitrogen atom and phenol fragment of these
compounds could be viewed as the “message” part for DOR
O
morphine) are μ opioid receptor (MOR) agonists (Figure 1).
The observed side effects of these MOR agonists include
respiratory depression, constipation, addiction, and physical
dependence. Recently, the δ opioid receptor (DOR) has been
confirmed as an attractive target for the development of novel
analgesic drugs, with less side effects and more significant
analgesia in animal models of inflammatory1−3 and neuropathic
pain.3−5 It has also been shown that DOR agonists can possibly
be used as potential therapeutics for depression,6,7 affective
disorder,7,8 organ protection,9 and neurodegenerative dis-
eases.10
The classic “message-address” concept11 was proposed to
explore how the opioid receptors bind with their endogenous
peptide ligands (e.g., DOR and enkephalin). Residues at the
headgroup of these peptides were identified as the “message”
part responsible for the recognition and affinity for the
receptor, while residues at the middle or tail group of these
peptides were viewed as “address” part to enhance the
specificity and/or potency. This concept was then successfully
applied in the discovery of the first nonpeptide DOR antagonist
Received: November 3, 2015
Accepted: February 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00423
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Figure 1. Structures of morphine, maltrindole, SIOM, ( )-cis-tramadol, and ( )-cis-M1.
Figure 2. (A) Structural superimposition of (R,R)-M1 with the structures of morphine and SIOM. Different parts for these compounds are labeled
according to the “message-address” concept.11 (B) The DOR compounds designed by adding the biphenyl substituent as the “address” part to the
skeleton of tramadol structure.
activity, and aromatic groups at the C ring of morphinan
skeleton could function as “address” for DOR selectivity.
Inspired by the discovery of NTI and SIOM, we wanted to add
an “address” part to the tramadol structure, i.e., incorporating a
biphenyl group to the cyclohexane group of tramadol, in order
to design novel DOR agonists. We hypothesized that adding an
“address” part to tramadol structure would improve DOR
activity and selectivity. We also wanted to know which group
(−OCH3 or − OH) at the “message” part of tramadol would
possibly enhance DOR affinity. For these purposes, we
designed and synthesized a series of novel DOR compounds
for biological evaluation based on the structure of tramadol
(Figure 2B).
The synthetic route for preparation of the designed
compounds was shown in Scheme 1. Compound 7 was
prepared from 6-hydroxy-1-tetralone through a novel three-step
one-pot Smiles rearrangement process.15 The amino group of 7
was transformed to a bromo substituent by Sandmeyer reaction
in the presence of HBr and CuBr to give compound 8. Suzuki
coupling of 8 with various substituted phenylboronic acids in
the presence of tetrakis(triphenylphosphine) palladium(0), and
potassium carbonate led to compounds 9a−9l. The ketones
9a−9l were condensed with N-methyl-N-methylenemethana-
minium to afford 10a−10l. Addition of organolithium reagent
prepared by halogen-metal exchange between n-butyl lithium
and 3-bromoanisole to the carbonyl group of 10a−10h
provided 6a−6h. Addition of organolithium reagent prepared
by halogen-metal exchange between n-butyl lithium and (3-
bromophenoxy) (tert-butyl)dimethylsilane to the carbonyl
group of 10a−10h gave 6i−6t after removal of the tert-butyl-
dimethylsilane group with Cs2CO3 dissolved in DMF/H2O.
The binding affinities of compounds 6a−6t with opioid
receptors (MOR, DOR, and κ opioid receptor (KOR)) were
measured using a radio-ligand displacement assay. The radio-
ligands [3H]DAMGO, [3H]DPDPE, and [3H]U69,593 were
used for competitive inhibition assay on the MOR, DOR, and
KOR, respectively. Then the representative compounds were
evaluated for receptor activation using the standard [35S]GTP-
γ-S binding assay. The results of these assays are summarized in
Table 1 and Table 2, respectively.
SARs of Newly Designed DOR Agonists. As shown in
Table 1, tramadol has very low affinity for MOR, but its O-
desmethyl metabolite M1 exhibited much higher affinity for
MOR, which agrees with the reported affinity data of tramadol
and M1.14 Interestingly, all the new compounds have no affinity
for MOR, except that 6i showed very low MOR affinity and
moderate KOR affinity (Ki = 140 nM). All the methoxyl
substituent (R1 = Me) at the “message” part of compounds 6a−
6h showed very low affinity for either DOR or KOR. However,
the phenolic substituent (R1 = H) in 6i−6t generally exhibited
higher affinities for DOR, or for KOR than those of 6a−6h.
The effect of different R1 substituents on binding affinity
suggests that the R1-substituted phenyl group at the “message”
part is critical for DOR affinity. At the “address” part, the newly
added phenyl group does help to increase the DOR affinity for
these compounds. More interestingly, for the newly added
phenyl group at “address” part, introduction of ortho-
substitution (−F, −Cl, −CH3, −CF3, −OCF3, −OCH3)
B
DOI: 10.1021/acsmedchemlett.5b00423
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a
Scheme 1
a
Reagents and conditions: (a) NaOH, N,N-dimethylacetamide, 2-bromo-2-methylpropanamide, yield: 63%; (b) HBr, CuBr, NaNO2, H2O, yield
85%; (c) Pd(PPh3)4, phenylboronic acids, K2CO3, toluene 90°C, yield 78% for 9a as example; (d) N-methyl-N-methylenemethanaminium, MeCN
rt, without purification for next step; (e) n-BuLi, 3-bromoanisole, −78 °C, THF, yield 54% for 6a as example; (f) n-BuLi, (3-bromophenoxy) (tert-
butyl)dimethylsilane, −78°C, THF; Cs2CO3, DMF/H2O 10:1, rt, yield 39% for 6i as example.
dramatically enhanced both the affinity and selectivity for
compounds 6j and 6p−6t toward DOR, while the meta- or
para-substitutions (e.g., compounds 6k−6o) did not exhibit any
DOR affinity. Among these new compounds, 6j displayed very
high DOR affinity (Ki = 4.7 nM) and high DOR/KOR
selectivity (over 1000-fold). We separated the enantiomers of
compound 6j and measured their affinities with DOR. The
(−)-6j is 2-fold more potent than the racemic mixture 6j (Ki =
2.7 nM), while (+)-6j did not exhibit DOR affinity at all.
As shown in Table 2, compounds 6j (also (−)-6j) and 6p−6t
turned out to be selective full DOR agonists in the [35S]GTP-γ-
S binding assay, while compound 6i is a KOR agonist. Among
them, the (−)-6j is the most potent agonist with EC50 = 2.6
nM. Thus, by adding the new “address” part to the basic
structure of tramadol, we obtained highly potent and selective
DOR agonists.
SIOM. We used the GOLD 5.0.1 program16 to dock these
compounds into the binding site of the X-ray structure of DOR
(PDB entry as 4eji with resolution of 3.40 Å).17 The results of
molecular docking are shown in Figure 3. We found that
(1R,2R)-isomer of 6j fits the binding site of DOR very well
(Figure 3A). At the subsite of “message” part in (1R,2R)-6j, the
protonated nitrogen atom formed a strong salt bridge with
residue Asp1283.32 of DOR, and the distance for the −N···OD1
hydrogen bonding is 2.90 Å. The phenolic group at the
“message” part of (1R,2R)-6j formed a strong hydrogen bond
with the neighboring water molecule. The binding mode of
(1R, 2R)-6j with DOR (Figure 3A) explains why the −OH
substituted phenyl group at the “message” part of our newly
designed compounds was able to significantly enhance the
DOR affinity and selectivity (Table 1, Table 2). The mode of
binding between DOR and (1R, 2R)-6j is consistent with
reported binding modes of morphinan derivatives with opioid
receptors.17−19 As shown in Figure 3A for the “address” part of
our newly designed compounds, the 6-ortho-methoxyphenyl
Structural Determinants of DOR Selectivity. In order to
see how these newly designed compounds bind with DOR,
molecular docking operations were performed on 6j and
C
DOI: 10.1021/acsmedchemlett.5b00423
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Table 1. Binding Affinities of Compounds 6a−6t for the Opioid Receptors MOR, DOR, and KOR, Reported as Ki, or
Percentage for the Displacement of Each of the Radio-Labeled Ligands at 1.0 μM, or the Testing Concentration if Totally
Inactive
Ki ( SEM, nM) or inhibition (%)
a
b
c
compd
R1
R2
MOR
DOR
>104
KOR
d
6a
6b
6c
6d
6e
6f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
>104
37 1%
>104
o-OCH3
m-OCH3
p-OCH3
p-CF3
>104
>104
>104
>104
>104
>104
>104
37.9 0.2%
>104
>104
>104
>104
>104
>104
p-Cl
>104
>104
6g
6h
6i
m,p-diCl
o-CH3
H
>104
>104
13 2%
22 1%
4.7 0.1
43 1%
32 2%
>104
16.2 0.3%
20 1%
>104
140
9
6j
H
o-OCH3
m-OCH3
p-OCH3
p-CF3
17.7 0.1%
15 1%
>104
6k
6l
H
>104
H
>104
6m
6n
6o
6p
6q
6r
6s
6t
H
>104
>104
H
p-Cl
>104
17 1%
>104
8.9 0.2%
>104
H
m,p-diCl
o-CH3
o-F
>104
H
>104
140
4
>104
H
>104
720 89
160 58
>104
H
o-Cl
>104
>104
H
o-CF3
>104
65
4
>104
H
o-OCF3
o-OCH3
o-OCH3
>104
260 26
>104
>104
(+)-6j
H
>104
>104
(−)-6j
H
>104
2.7 0.6
>104
>104
(
)-tramadol
9.6 0.4%
>104
(
)-M1
13.0 0.5
>104
>104
a
b
Displacement of [3H]DAMGO from CHO cell membranes expressing human MOR. Displacement of [3H]DPDPE from CHO cell membrane
c
d
expressing human DOR. Displacement of [3H]U69593 from CHO cells expressing human KOR. No binding affinity could be determined up to
104 nM. The binding-assay was performed three times for each compound, and the result was reported as mean standard error of the mean.
Table 2. Standard [35S]GTP-γ-S Binding Assay for the Selected Compounds with Measurable Ki from Table 1
MOR
DOR
KOR
a
compd
EC50 (nM)
Emax
%
EC50 (nM)
Emax
230
%
EC50 (nM)
580 84
Emax
187
%
6i
6j
b
2
9.3 0.5
2.6 0.3
7
(+)-6j
(−)-6j
6p
205
199
172
216
217
215
3
7
1
3
5
7
490
9
6q
1600 240
950 63
6r
6s
900 190
1000 120
6t
(
(
)-tramadol
)-M1
1000 120
240 24
220
220
225
7
9
1
DAMGO
30
2
DPDPE
0.12 0.02
216
2
a
b
the basal activity level of G-protein was defined as the Emax% = 100%. [35S]GTP-γ-S binding activity was not able to be determined. The assay was
performed three times for each compound, and the result was reported as mean standard error of the mean.
D
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Figure 3. Binding structures of DOR-6j and DOR-SIOM obtained from molecular docking. (A) The binding mode of (1R,2R)-6j (colored in
orange) at the agonist-binding site of DOR. (B) The binding mode of (1S,2S)-6j (colored in yellow) at agonist-binding site of DOR. (C) The
binding mode of SIOM (blue color) at DOR binding site. (D) The superimposed binding structures of (1R,2R)-6j and SIOM with DOR,
respectively.
group of (1R,2R)-6j stretched into the hydrophobic pocket
formed by residues Leu3007.35, Val2816.55, and Trp2846.58 of
DOR and form cation−π interaction with Lys2145.39 (i.e., the
distance from the center of phenyl group of (1R, 2R)-6j to the
positive charged nitrogen atom at Lys2145.39 side chain is 5.5 Å)
(Figure 3A). Meanwhile, the 6-ortho-methoxyphenyl group of
(1R,2R)-6j packs perpendicularly with the side chain of
Leu3007.35 of DOR. Based on the binding structure, we
would predict that, if Leu3007.35 is replaced by a residue with a
larger side chain, the hydrophobic interaction between the
affinity. This docking result suggested that, like tramadol, the
(1R,2R)-6j must be the (−)-6j isomer, the active compound.
The docked DOR-SIOM binding structure (Figure 3C)
shows that the “message” part of SIOM also formed a
conserved interaction with Asp1283.32 and a water molecule at
the agonist-binding site of DOR. The “address” part (i.e., 7-
spiroindanyl group) of SIOM interacted with Ile3047.39
,
Leu3007.35, and Trp2846.58 through hydrophobic packing.
When superimposing these two binding structures (Figure
3D), we found that the “message” part of each of these two
compounds adopts a similar orientation at the agonist-binding
site of DOR. The only difference is the orientation of the
“address” part of these two agonists, i.e., SIOM has hydro-
phobic packing with residue Ile3047.39, but no cation−π
interaction with Lys2145.39 of DOR.
“address” part of (1R,2R)-6j and residues Leu3007.35, Val2816.55
,
and Trp2846.58 will probably be weakened. Such specific
packing between the “address” part of (1R, 2R)-6j and DOR
can be used to explain why the newly designed active
compounds are selective agonists of DOR. Actually, residue
Leu3007.35 of DOR corresponds to Trp3187.35 of MOR and to
Tyr3127.35 of KOR. The much larger side chain of Trp3187.35 at
the agonist-binding site of MOR will not be able to form
optimal contact points with the “address” part of (1R,2R)-6j as
that of Leu3007.35 of DOR. Similarly, the Tyr3127.35 side chain
at the agonist-binding site of KOR is not compatible with the
“address” part of (1R, 2R)-6j as that of Leu3007.35 of DOR.
This is consistent with the reported observation that Leu3007.35
is responsible for the DOR selectivity of compound NTI17 as
shown in the X-ray crystal structure. The binding structure of
DOR with (1S,2S)-isomer of 6j (Figure 3B) shows that (1S,
2S)-6j could not form a salt bridge with Asp1283.32 and that the
“address” part of (1S,2S)-6j has much worse packing with
In summary, we designed and synthesized a series of novel
compounds showing high affinity and good selectivity for δ
opioid receptor. Starting from the structure of tramadol, we
revisited the classic “message-address” concept and added the
biphenyl group as the “address” part in our newly designed
compounds. Among these compounds, we found that
compound 6j was the most potent and selective DOR agonist,
and we also identified that the steroisomer (−)-6j is the actual
active component of the racemic 6j. Through molecular
docking operations, we found that the “message” part of
(−)-6j formed a salt bridge with Asp1283.32 of DOR and a
hydrogen bond with the neighboring water molecule. The
“address” part of (−)-6j has cation−π interaction with
Lys2145.39 and is packed with hydrophobic residues
Leu3007.35, Val2816.55, and Trp2846.58. The interaction with
residue Leu3007.35 is responsible for the DOR selectivity of
(−)-6j. Taken together, our newly discovered (−)-6j can be
used as a lead compound for further pharmacological studies.
hydrophobic residues Leu3007.35, Val2816.55, and Trp2846.58
,
although (1S,2S)-6j keeps hydrogen bonding with the
neighboring water molecule. Overall, the limited contact points
of (1S,2S)-6j with DOR must lead to very low or no obvious
E
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ASSOCIATED CONTENT
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* Supporting Information
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Chemical synthesis and structural characterization of the
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AUTHOR INFORMATION
■
Corresponding Authors
*Fax: +86-21-51980010. Phone: +86-21-51980010. E-mail:
wfu@fudan.edu.cn.
*E-mail: jgliu@mail.shcnc.ac.cn. Phone: +86-21-50807588.
*E-mail: weili_at@126.com.
Author Contributions
W.F., W.L., and Q.S. designed the research; Q.S. and Y.Q.
synthesized the compounds; X.X. and J.L. performed the
pharmacological assay; and Q.S., X.H., and W.F. wrote the
paper. Q.S. and Y.Q. equally contributed to the work.
Funding
This work was supported by the National Natural Science
Foundation of China (No. 81473136 and 81172919) and
Shanghai Science and Technology Development Funds
(14431900500).
Notes
The authors declare no competing financial interest.
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