Discovery of novel triazole-based opioid receptor antagonists

Article abstract of DOI:10.1021/jm0601250

We report the computer-aided design, chemical synthesis, and biological evaluation of a novel family of δ opioid receptor (DOR) antagonists containing a 1,2,4-triazole core structure that are structurally distinct from other known opioid receptor active l

Full text of DOI:10.1021/jm0601250

4044
J. Med. Chem. 2006, 49, 4044-4047
Letters
Discovery of Novel Triazole-Based Opioid
Receptor Antagonists
Qiang Zhang,‡,† Susan M. Keenan,‡ Youyi Peng,‡
Anil C. Nair,|,# Seong Jae Yu,|,§ Richard D. Howells, and
William J. Welsh*,‡
Department of Pharmacology, Robert Wood Johnson Medical
School, UniVersity of Medicine and Dentistry of New Jersey
(UMDNJ) and UMDNJ Informatics Institute, Piscataway,
New Jersey 08854, Department of Chemistry and Biochemistry,
UniVersity of MissourisSt. Louis, St. Louis, Missouri 63121, and
Department of Biochemistry and Molecular Biology,
Figure 1. Comparison of the structures of naltrindole and the present
1,2,4-triazoles.
New Jersey Medical School, UMDNJ, Newark, New Jersey 07101
ReceiVed February 3, 2006
Abstract: We report the computer-aided design, chemical synthesis,
and biological evaluation of a novel family of δ opioid receptor (DOR)
antagonists containing a 1,2,4-triazole core structure that are structurally
distinct from other known opioid receptor active ligands. Among those
δ antagonists sharing this core structure, 8 exhibited strong binding
affinity (Ki ) 50 nM) for the DOR and appreciable selectivity for δ
over µ and κ opioid receptors (δ/µ ) 80; δ/κ > 200).
Figure 2. Up-regulation results of compounds 2 and 8.
paradigm is the proprietary Shape Signatures computational tool
that provides unique capabilities for scaffold hopping in the
search for new lead compounds.14,15
Opioid analgesics are the mainstay for treatment of moderate
to severe pain. Research on opioids and their receptors has
remained active over the past decade.1 Three opioid receptor
subtypes, designated as δ, κ, and µ, have been identified in the
central nervous system (CNS) and periphery2,3 and are products
of three distinct and extensively studied genes. Recent evidence
suggests that subtype-selective opioid receptor agonists and
antagonists offer great potential as therapeutic agents devoid
of the numerous adverse side effects (e.g., respiratory depression,
physical dependence, and gastrointestinal effects) associated with
morphine.4 In particular, δ-selective antagonists have been
shown to modulate the development of tolerance5,6 and depen-
dence on µ agonists such as morphine,7 to offset the behavioral
effects of drugs of abuse such as cocaine,8 and to elicit favorable
immunomodulatory9 and emotional effects.10 On the other hand,
δ-selective agonists have been shown to elicit the prototypical
analgesic effects of clinically available opioids.4 They may also
provide unique benefits as cardioprotective and neuroprotective
agents11 and as treatments for depression and anxiety.12,13
In view of their broad range of pharmacological applications,
the δ-selective opioids have attracted interest in our laboratory
and elsewhere. Given the paucity of high-quality X-ray crystal
structure data for GPCRs such as the opioid receptor, our drug
design strategy has relied on ligand-based molecular modeling
approaches. An additional component of our drug discovery
A three-point pharmacophore was extracted by overlaying a
series of high-affinity opioid receptor ligands including the
δ-antagonist naltrindole.16 This pharmacophore model (Figure
1, gray) comprised the basic nitrogen atom, the centroid of the
phenol ring (A), and the centroid of the hydrophobic ring (B).
Virtual screening of an in-house database of ∼1.2 million
commercially available small-molecule chemicals was conducted
to identify structures matching this three-point pharmacophore.
Additional molecular models were developed for a distinct series
of DOR-selective agonists17 and antagonists18 to demonstrate
the structural requirement for δ selectivity. Promising chemical
entities were then subjected to filters using an expanded Lipinski
rule of five19 hierarchical scheme. The substituted 1,2,4-triazoles
(Figure 1) emerged from this scheme as an interesting core
structural framework for our DOR active agents. In selecting
appropriate substitution patterns for the 1,2,4-triazole ring to
confer δ binding affinity and selectivity, we exploited the
“message-address” concept20,21 associated with classical mor-
phine-like opioids. For instance, a sterically bulky group (e.g.,
tert-butyl) was attached to the B aryl group to mimic the δ
“address” in our 1,2,4-triazoles. Several di- and trisubstituted
1,2,4-triazoles (Table 1) were selected for chemical synthesis
and biological evaluation. Structural alignment of naltrindole
and 8 in the conformation adopted in its X-ray crystal structure
reveals good overlap between the tert-butyl group of 8 and the
δ “address” of naltrindole (Figure 2, Supporting Information).
Three separate reaction schemes were developed for the
synthesis of the 1,2,4-triazoles (Scheme 1) with thioamides as
key intermediates. In most cases, thioamides were synthesized
from the corresponding amides.22,23 For 1, 2, 10, and 16, a
coupling reaction of arylmagnesium reagents with isothiocy-
anates was conducted to synthesize the thioamides.24,25 Amidra-
zones could be efficiently prepared by reaction of thioamides
* To whom correspondence should be addressed. Phone: 732-235-3234.
Fax: 732-235-3475. E-mail: welshwj@umdnj.edu.
‡ University of Medicine and Dentistry of New Jersey and UMDNJ
Informatics Institute.
† Present address: Intra-Cellular Therapies, Inc., 3960 Broadway, New
York, NY 10032.
| University of MissourisSt. Louis.
# Present Address: Sanofi-Aventis Pharmaceuticals, Inc., 1580 E. Hanley
Boulevard, Oro Valley, Tucson, AZ 85737.
§ Present Address: FMC Corporation, Agricultural Products Group,
Princeton, NJ 08543.
New Jersey Medical School.
10.1021/jm0601250 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/21/2006

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4045
Table 1. Structures and Opioid Receptor Binding Affinities for Substituted 1,2,4-Triazoles
% inhibitiona
Ki (nM)b
selectivity ratio
compd
R1
R2
R3
δ
µ
κ
δ
µ
κ
δ/µ
na
3.70
na
δ/κ
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
3-OCH3
3-OH
3-OCH3
3-OH
3-OH
3-OH
3-OH
3-OH
3-OCH3
3-OH
3-OH
3-OH
3-OH
4-OH
3-OH
3-OH
3-OH
3-OH
3-tert-butyl
3-tert-butyl
4-tert-butyl
4-tert-butyl
3-phenyl
H
H
H
H
H
H
H
31
91
8
11
78
9
5
66
8
16
42
46
27
6
3
6
8
11
27
21
12
10
9
>10000
230
>10000
∼10000
140
>10000
850
>10000
>10000
1000
>10000
>10000
4000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
1500
6.52
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
54
84
75
68
94
28
76
86
82
68
27
18
65
88
90
16
84
60
48
32
50
19
23
15
48
8
na
7.14
>6.66
>4.76
80
>71.4
>6.66
>4.76
>200
4-phenyl
1500
2100
50
3,4-(CHdCH)2
4-tert-butyl
4-tert-butyl
3-tert-butyl
3-phenyl
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH2CH2)2NCH3
CH2N(CH3)2
CH2N(CH3)2
(CH2)2N(CH3)2
>10000
1050
150
130
480
>10000
>10000
2600
460
na
>9.5
>66.6
>76.9
>20.8
na
>9.5
>66.6
>76.9
>20.8
4-phenyl
3,4-(CHdCH)2
4-tert-butyl
4-tert-butyl
3-tert-butyl
4-tert-butyl
4-tert-butyl
5
na
27
20
23
>3.86
>21.6
>11.1
>3.86
>21.6
>11.1
19
900
a Compounds, initially screened at 10 µM, are expressed as percentage inhibition of the reference compound which is normalized to 100%. (-)-
[9-3H]bremazocine was used as the radiolabeled ligand. b Inhibitory effect to (-)-[9-3H]bremazocine on membranes isolated from HEK 293 cells stably
transfected with mouse (δ and µ) or rat (κ) opioid receptors. Ki values are the average of two to three independent experiments.
Scheme 1. General Synthesis of Substituted 1,2,4-Triazolesa
Several of the subject compounds (e.g., 5, 8, 11, 12) exhibited
selectivity for the δ over µ and κ opioid receptors, which concurs
with our initial design strategy to confer δ selectivity. The
inhibitory activity was much greater at all three opioid receptors
for compounds with R1 ) OH (2 and 4) compared with R1 )
OCH3 (1 and 3). In fact, the latter compounds showed very
limited inhibitory activity for any of the opioid receptors even
at 10 µM. Comparison of 8 and 14 indicates that the binding
affinity for all three opioid receptor subtypes was virtually
abolished when the hydroxyl substituent at R1 is moved from
the meta to para position on the aromatic ring. Although this
single example precludes making generalizations, the strong
preference for the meta over para phenolic moiety is consistent
with the familiar SAR of morphine-like opioids.30-33
For 1-7, R2 substitutions were preferred at the meta position
over the para position (e.g., Ki(δ) ) 230 nM for 2 vs ∼10 000
nM for 4). For compounds with R3 substitutions, namely 8-17,
the opposite trend was observed in cases exhibiting an ap-
preciable affinity difference (see 8 vs 10). Compound 8
(Ki(δ) ) 50 nM), with R2 ) p-tert-butyl and R3 ) N(CH3)2,
yielded the best results overall among this first generation of
triazole-based opioid receptor active agents in terms of δ binding
affinity and subtype selectivity. It is worth noting that introduc-
tion of groups more highly constrained than tert-butyl at R2
failed to increase binding affinity for the δ receptor. For
example, the δ binding affinity was poorer for 11, 12 and 13
(Ki ) 150, 130, and 480 nM, respectively) than for 8 (Ki )
50 nM).
The functional activity of our substituted 1,2,4-triazoles on
the opioid receptors was determined by receptor up-regulation
assays. Incubation of the δ opioid receptor with 2 and 8
produced a sharp increase in receptor expression, suggesting
that the subject compounds are δ opioid antagonists (Figure
2). Interestingly, 8 exhibited >3-fold up-regulation of the δ
opioid receptor in this assay. The pharmacological significance
of this observation is currently under investigation in our
laboratory.
In fact, a N,N-dimethylamino group at R3 did produce a sharp
increase in binding affinity to the δ receptor. Compare, for
example, the Ki(δ) of 8 (50 nM, R3 ) N(CH3)2) with its simple
homologue 4 (∼10 000 nM, R3 ) H). One might reasonably
attribute the greater activity of 8 over 4 to the strong basicity
a See Table 1 for examples of R1, R2, and R3. (a) Viehe’s salts, DCM,
room temp, 5 h; (b) BBr3, DCM, room temp, 3 h; (c) trimethyl orthoformate,
HOAc/DMF, room temp, 3 h; (d) Eschenmoser’s salt, DMF, 80 °C, 8 h;
(e) N,N-dimethylaminopropionic acid hydrochloride, DCC, toluene, room
temp; (f) reflux, 8 h.
with excess hydrazine at room temperature. Cyclization of
amidrazones with different reagents led to products with
methoxyl groups at the R2 positions. 1-7 were obtained using
trimethyl orthoformate as the cyclization reagent,26 while 8-15
involved cyclization of amidrazones with phosgeninium salts
(Viehe’s salts), which were easily synthesized from the corre-
sponding amines.27 Compounds 16 and 17 were synthesized
from 1 and 3, respectively, through reaction with Eschenmoser’s
salt.28,29 Compound 18 was prepared directly by condensation
of amidrazone with 3-N,N-dimethylaminopropionic acid hydro-
chloride in the presence of dicyclohexyldiimide (DCC) (Scheme
1). For most of the products, the final step of cleaving methoxyl
groups at R2 was completed easily by reaction with BBr3 in
dichloromethane. Where hydrolysis of the methoxyl group was
incomplete using the above BBr3 procedure, excess NaSH was
added to achieve ether cleavage in acceptable yields.
Initially, 1-4 were synthesized to evaluate the feasibility of
our approach (Table 1). Radioligand binding assays revealed
that 2 binds to all three opioid receptors with Ki values of 230
(δ), 850 (µ), and 1500 (κ) nM, respectively. As anticipated, it
exhibited some subtype selectivity for the δ over µ and κ opioid
receptors. Structural analogues (5-18) were synthesized in order
to increase the δ binding affinity and selectivity (Table 1).

4046 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Letters
Table 2. Relative Energies of Protonationa Obtained from HF/6-31G**
ab Initio Calculations on Compound 8 Assuming Vacuum and Aqueous
Conditions
modeling and in vitro assays, and the X-ray crystal structure of 8
together with the crystallographic structural data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Acknowledgment. Funding for this research was provided
to W.J.W. by the Biotechnology Research & Development
Corporation (Peoria, IL) and to R.D.H. by the National Institute
on Drug Abuse (Grant DA09113). The authors also thank Dr.
John Duchek of Tyco-Mallinckrodt, Inc. (St. Louis, MO) for
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