Discovery and pharmacological evaluation of a diphenethylamine derivative (HS665), a highly potent and selective κ opioid receptor agonist

Article abstract of DOI:10.1021/jm301258w

Here we report on the design, synthesis, and biological characterization of novel κ opioid (KOP) receptor ligands of diphenethylamines. In opioid receptor binding and functional assays, the N-cyclobutylmethyl substituted derivative 4 (HS665) showed the hi

Full text of DOI:10.1021/jm301258w

Brief Article
pubs.acs.org/jmc
Discovery and Pharmacological Evaluation of a Diphenethylamine
Derivative (HS665), a Highly Potent and Selective κ Opioid Receptor
Agonist
Mariana Spetea,† Ilona P. Berzetei-Gurske,‡ Elena Guerrieri,† and Helmut Schmidhammer*,†
†Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of
Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria
‡Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025, United States
S
* Supporting Information
ABSTRACT: Here we report on the design, synthesis, and biological characterization of novel κ opioid (KOP) receptor ligands
of diphenethylamines. In opioid receptor binding and functional assays, the N-cyclobutylmethyl substituted derivative 4 (HS665)
showed the highest affinity and selectivity for the KOP receptor and KOP agonist potency. Compound 4 inhibited acetic acid
induced writhing after subcutaneous administration in mice via KOP receptor-mediated mechanisms, being equipotent as an
analgesic to the KOP agonist U50,488.
was reported revealing important features of the ligand-binding
pocket that contribute to the high affinity and selectivity of
JDTic for the human KOP receptor.16 The pharmacology of
currently available selective KOP antagonists shows a delay in
onset of action and extremely long-lasting effects in vivo, which
might limit their therapeutic utility.17,18
The development of KOP receptor ligands with improved
pharmacokinetic and pharmacodynamic properties and safety
profile is an important direction in pharmaceutical research
toward the discovery of useful clinical agents. Earlier
observations were made on the dopamine D2 receptor agonist
1 (RU 24213, Figure 1),19 a diphenethylamine derivative,
INTRODUCTION
■
The κ opioid (KOP) receptor belongs to the family of seven-
transmembrane G-protein-coupled receptors (GPCRs), and it
plays a significant role in a broad range of physiological
functions.1,2 Stimulation of the KOP receptor results in
significant analgesia, while it is not involved in the unwanted
side effects of respiratory depression, inhibition of gastro-
intestinal motility, dependence, or abuse liability, as in the case
of the μ opioid (MOP) receptor.2 KOP agonists appear to have
some advantages over the widely used MOP analgesics. On the
other hand, the therapeutic utility of KOP agonists is associated
with dose-limiting effects including dysphoria, sedation, and
psychotomimetic effects.1,2 Besides the analgesic activity,3 KOP
agonists have also shown other beneficial actions such as
antipruritic,4 antiarthritic,5,6 anti-inflammatory,5,6 and neuro-
protective effects.7 At present, the main classes of available
chemically distinct KOP receptor agonists include peptides
(e.g., dynorphin analogues),8 benzomorphans (e.g., bremazo-
cine, pentazocine),9 morphinans (e.g., TRK-820),9 arylaceta-
mides (e.g., U50,488, U69,593),9 diazabicyclononanones (e.g.,
HZ2),9 neoclerodane diterpenes (e.g., salvinorin A),9,10
benzodiazepines (e.g., tifluadom).9 Several of such compounds
are employed as research tools or are in clinical use. Recent
reviews on small molecule and peptide ligands as agonists at the
KOP receptor and their potential for drug development have
been published.8−10
Figure 1. Structures of investigated compounds. CPM, cyclo-
propylmethyl; CBM, cyclobutylmethyl.
reported to display moderate affinity to KOP receptors and to
act as KOP antagonist.20 Moreover, its n-pentyl analogue 2
(Figure 1) also exhibited moderate affinity to the KOP receptor
and showed KOP antagonist activity in vivo. Compound 2
antagonized diuresis and antinociceptive effects in rats after
subcutaneous (sc) administration produced by the KOP
receptor agonist U50,488.21 Therefore, such simple molecules
Inhibiting KOP receptors has been proposed to be useful for
the treatment of stress-related conditions (e.g., depression and
anxiety), drug addiction, and eating disorders.1,8,11,12 The first
competitive KOP receptor antagonist was norbinaltorphimine
(nor-BNI),13 followed later by 5′-guanidinonaltrindole
(GNTI),14 both derived from naltrexone. The structurally
distinct JDTic, a trans-3,4-dimethyl-4-(3-hydroxyphenyl)-
piperidine derivative, was discovered as a highly potent and
selective KOP receptor antagonist.15 Recently, the crystal
structure of the human KOP receptor in complex with JDTic
Received: August 31, 2012
© XXXX American Chemical Society
A
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Journal of Medicinal Chemistry
Brief Article
represent useful lead structures for the design of novel ligands
for KOP receptors.
Scheme 3. Alternative Synthesis of Compound 4 via
Acetamide 16
a
In the present study, we describe further chemical
derivatization of diphenethylamines by targeting the substitu-
tion at the nitrogen. Several N-substituted diphenethylamine
analogues (3−6) have been synthesized (Figure 1) and
biologically characterized. In this work, we have also
investigated the character of the N-substituent on opioid
receptor activities to understand the role of the substitution
pattern at the nitrogen on the interaction with the KOP
receptor. Additionally, the effect of different substitution
patterns on binding and functional activity at dopamine (D1,
D2, and D3) receptors was examined.
a
Reagents and conditions: (a) EDCI, HOAt, CH2Cl2, rt; (b) 1 M
BH3·THF, THF, reflux; (c) cyclobutylmethyl bromide, NaHCO3,
CH3CN, reflux.
RESULTS AND DISCUSSION
■
Chemistry. Starting material for the synthesis of 1−6 was 2-
(3-methoxyphenyl)-N-phenethylethaneamine (7), which is
readily available from 2-(3-methoxyphenyl)ethaneamine (8)
by alkylation with phenethyl bromide.20 Compounds 1 and 2
were prepared from 7 essentially as earlier described.20,21 N-
Alkylation of 7 with the respective alkyl bromide in DMF in the
presence of potassium carbonate afforded 9−12, which were in
turn transformed by ether cleavage with sodium ethanethiolate
in DMF into the respective phenols 3−6 (Scheme 1).
membranes from Chinese hamster ovary (CHO) cells
expressing one of the human opioid receptors.22 The lead
compounds N-n-propyl (1) and N-n-pentyl (2) substituted
derivatives showed Ki in the low nanomolar range to KOP
receptors while having 2−3 orders of magnitude decreased
affinities at MOP and DOP receptors (Table 1). Our findings
support earlier observations on the binding to the KOP
receptor of the two derivatives (IC50 of 57 nM for 1 and 2),
based on binding assays in guinea pig brain with [3H]-
ethylketocyclazocine as KOP receptor specific radioligand.20,21
Replacement of the n-propyl group by an n-butyl group at
the nitrogen (1 and 5) resulted in comparable affinity to KOP
receptors and a minor increase in affinities to MOP and DOP
receptors and as a consequence in a 2-fold decrease in KOP
receptor selectivity (Table 1). A similar profile was revealed
when the n-butyl group in 5 was replaced by an n-pentyl group
in 2. With further extension of the N-substituent by one
methylene group resulting in the n-hexyl analogue 6, a more
than 10-fold decrease in KOP receptor affinity and selectivity
was observed, paralleled by lower interaction with MOP and
DOP receptors.
We also evaluated the effect on opioid receptor binding of
cyclopropylmethyl (CPM) and cyclobutylmethyl (CBM)
groups at the nitrogen, derivatives 3 and 4 (HS665),
respectively. Interestingly, the N-CBM substituted analogue 4
showed a remarkable >1100-fold selectivity for KOP vs MOP
receptors, and >20000-fold selectivity for KOP vs DOP
receptors, being the most selective derivative in the new series
of compounds. Compared to analogues 1 and 2 described
earlier,20,21 compound 4 displayed considerably higher KOP
receptor affinity and selectivity (Table 1).
a
Scheme 1. Synthesis of Compounds 9−12 and 3−6
a
Reagents and conditions: (a) respective alkyl bromide, K2CO3, DMF,
80 °C; (b) sodium ethanethiolate, DMF, 130 °C.
Two alternative routes have been employed for the synthesis
of 4. First, 7 has been prepared from phenylacetaldehyde (13)
by reductive amination with 2-(3-methoxyphenyl)ethaneamine
(8) using NaBH3CN in MeOH (Scheme 2), while the
following steps remained unchanged to give 4 in an overall
yield of 26% in comparison to the lower overall yield of 17% of
the original procedure.
Scheme 2. Alternative Synthesis of Compound 7 from
a
Phenylacetaldehyde
The presence of an N-CPM group in 3 also resulted in
increased binding at the KOP receptor and greater MOP/KOP
and DOP/KOP selectivity ratios than 1 and 2 and also than the
other new alkyl derivatives 5 and 6. From the opioid binding
data, it is apparent that a CPM or CBM substitution at the
nitrogen is more favorable for interaction with KOP receptors
than n-alkyl groups by causing a notable increase in KOP
receptor affinity and selectivity, thus indicating that cyclo-
alkylalkyl groups are superior over n-alkyl groups in this respect.
The functional activity of all diphenethylamine analogues 1−
6 was evaluated using the guanosine 5′-O-(3-[35S]thio)-
triphosphate ([35S]GTPγS) binding assays with membranes
from CHO expressing human KOP receptors.22 It was
observed that the overall rank order of potencies (EC50) in
a
Reagents and conditions: (a) NaBH3CN, Et3N, MeOH, rt.
The second route started from 3-hydroxyphenylacetic acid
(14), which was reacted with 2-phenethylamine 15 in CH2Cl2
in the presence of EDCI and HOAt to afford amide 16. BH3
reduction in THF yielded amine 17, which was N-alkylated
with cyclobutylmethyl bromide in CH3CN in the presence of
NaHCO3 to give 4 in an overall yield of 21% (Scheme 3).
Biological Evaluation. Diphenethylamine analogues 3−6
(Figure 1) were examined for their affinity and selectivity for
KOP, MOP, and DOP receptors in binding assays using
B
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Journal of Medicinal Chemistry
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Table 1. Binding Affinities and [35S]GTPγS Stimulation at Human Opioid Receptors
a
a
binding (Ki, nM)
selectivity
stimulation of [35S]GTPγS binding
b
compd
KOP
MOP
DOP
MOP/KOP
DOP/KOP
EC50 (nM)
% stim
1
2
3
4
5
6
8.13 0.32
12.6 1.9
5.90 3.00
0.49 0.20
10.9 2.4
141 42
594 101
325 26
826 98
542 239
412 19
788 175
290 14
1145 335
3713 1266
1315 364
>10000
73
457
49.1 8.8
86.4 4.6
35.0 5.3
3.62 1.87
46.2 11.4
647 88
21.2 0.1
36.2 2.7
53.4 8.1
90.0 3.7
45.5 5.9
24.0 1.3
93 11
26
104
140
1106
38
>1700
>20000
223
>10000
2429 837
3572 222
>10000
5.6
25
c
c
U50,488
U69,593
0.2 0.05
1450
3817
>50000
>30000
9.31 2.54
26.1 10.7
0.3 0.0
>10000
100
a
b
c
Data are the mean SEM. Percentage stimulation (% stim) relative to U69,593 (KOP). From ref 23.
Table 2. Binding Affinities and Activities in Stimulation of Mitogenesis at Human Dopamine Receptors
a
a
binding (Ki, nM)
stimulation of mitogenesis
b
b
compd
D1
D2
D3
D2, EC50 (nM) D2, % stim
39.0 9.8 99.7 4.7
D2, IC50 (nM) D3, EC50 (nM) D3, % stim
D3, IC50 (nM)
1
2
3
4
5
6
>10000
>10000
>10000
>10000
>10000
>10000
4470 1598
>10000
64.4 7.5
1420 13
118 16
450 28
1233 433
831 18
422 9.2
21.8 0.4
1098 161
168 30
5.32 0.2
74.2 8.6
181
8
63.8 1.1
32.2 8.2
>10000
84.5 3.7
282 34
>10000
1647 297
1252 25
953 74
1148 273
1147 32
20.0 1.2
43.0 19.7
>10000
65 15
19 16
c
dopamine
90
6.1 0.4
8.4 5.7
100
100
c
quinpirole
1185 265
100
a
b
c
Data are the mean SEM. Percentage stimulation (% stim) relative to quinpirole. From ref 23.
the functional assays correlated with affinities (Ki) at the KOP
receptor derived from the binding studies (Table 1). At human
KOP receptors, derivatives 1 and 2 showed moderate potency
and low efficacy, acting as weak partial agonists with only 21%
and 36% stimulation relative to U69,593. Examination of the
chemical structure and functional activities revealed certain
SAR in this series of differently N-substituted diphenethylamine
analogues. The targeted alkyl modifications at the nitrogen, i.e.,
n-butyl and n-hexyl, resulted in partial agonists at the KOP
receptor with efficacies roughly similar to those of the parent
compounds 1 and 2. The n-butyl substituted 5 exhibited a
potency comparable to that of the n-propyl 1, while the n-hexyl
derivative 6 had substantially reduced potency at the KOP
receptor compared with the n-pentyl 2, observations that are in
line with the binding data (Table 1). Replacement of the n-alkyl
groups with cycloalkylalkyl substituents resulted in increased
potency and efficacy at the KOP receptor, especially for the
CBM derivative 4. This compound was 14- and 24-fold more
potent than derivatives 1 and 2, respectively, and was up to
179-fold more potent than the diphenethylamine analogues 3,
5, and 6. It also had significantly higher efficacy (90%) acting as
a full KOP receptor agonist compared to all compounds in the
series. The highly selective KOP ligand 4 was 2.5- and 7-fold
more potent than the prototypical KOP receptor agonists.
Compounds 3 and 5 did not antagonize U69,593-stimulated
[35S]GTPγS binding, indicating that they are low efficacy
agonists.
using membranes from LHD1 cells expressing human D1
receptors and CHOp cells expressing human D2 and D3
receptors.23 None of the compounds showed any specific
binding to the D1 receptor, and much reduced binding to D2
and D3 receptors was displayed by the derivatives 3−6 in
comparison to the parent molecule 1 (Table 2). These data
indicate that the nature of the substituent at the nitrogen in
diphenethylamines is an important determinant for affinity to
the dopamine receptors and to the KOP receptor. In particular,
the presence of the N-CBM group appears to be favorable for
KOP receptor binding and leads to reduced interaction with
dopamine receptors.
Diphenethylamines 1, 3, 4, and 6 were evaluated for
functional activity at D2 and D3 receptors by determination
of stimulation of mitogenesis in CHOp cells expressing human
D2 and D3 receptors.23 Compound 1 was a full agonist at the
D2 receptor and a partial agonist at the D3 receptor (Table 2).
Substitution of the n-propyl group in 1 with cycloalkylalkyl
groups in 3 and 4 or a longer n-alkyl group in 6 was also found
to largely influence the activity at dopamine receptors. The N-
CPM substituted analogue 3 was a partial to full agonist at D2
and D3 receptors, having lower potency than 1, while the N-
CBM derivative 4 was a weak antagonist. Compound 6 also
displayed a low potency D2 antagonism.
Compound 4 was evaluated in vivo for analgesic activity
(Figure 2). Antinociceptive potency was assessed after sc
administration in mice in the acetic acid induced writhing
test.24 Dose-dependent inhibition of writhing was produced by
derivative 4 with an antinociceptive ED50 of 1.91 mg/kg, which
was comparable to the analgesic potency of the KOP agonist
U50,488 (ED50 = 1.54 mg/kg). Antinociceptive effects of
compound 4 were blocked by the selective KOP receptor
antagonist nor-BNI (Figure 2).
Lead compound 1 was initially described as a potent
dopamine agonist showing high selectivity for the D2
receptor.19 We also found that 1 displays binding affinity
comparable to that of dopamine to the D3 receptor (Table 2).
The corresponding n-pentyl analogue 2 was reported to be
devoid of dopaminergic activity,20 which was confirmed in our
study. The diphenethylamine analogues 3−6 were evaluated for
binding to dopamine receptors in radioligand binding assays
C
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Journal of Medicinal Chemistry
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126.77, 119.21, 115.67, 113.74, 56.42, 52.96, 29.96, 29.04, 26.76,
18.17; MS (EI) m/z 309 [M+]. Anal. (C21H27NO·HCl) C, H, N, Cl.
3-[2-[(Cyclopropylmethyl)(phenethyl)amino]ethyl]phenol
Hydrochloride (3·HCl). A part of the obtained oil of 3 (1.03 g, 91%)
was dissolved in Et2O and treated with HCl/Et2O. The precipitate was
isolated and recrystallized from acetone/Et2O to yield 3·HCl. Mp
134−136 °C; IR (KBr) 3434 (OH); 1H NMR (DMSO-d6) δ 10.81 (br
+
s, NH), 9.47 (s, OH), 7.39−7.08 (m, 6 arom H), 6.73−6.65 (m, 3
arom H), 3.18−2.96 (m, 10 aliphat H), 1.20 (m, 1 aliphat H), 0.71−
0.42 (m, 4 aliphat H); 13C NMR (DMSO-d6) δ 157.59, 138.45,
137.12, 129.55, 128.78, 128.61, 126.78, 119.22, 115.69, 113.75, 56.18,
52.59, 29.06, 5.37, 4.16; MS (EI) m/z 295 [M+]. Anal.
(C20H25NO·HCl·0.3Et2O) C, H, N.
Figure 2. Antinociceptive effects of derivative 4 and U50,488 after sc
administration to mice in the acetic acid induced writhing test: (A)
dose−response effect; (B) antagonism of compound 4 (2.5 mg/kg, sc)
by nor-BNI (20 mg/kg, sc). Values are the mean SEM (n = 5−6
mice per group): (∗∗∗) p < 0.001 vs control group; (###) p < 0.001
vs 4-treated animals (Student’s t-test).
3-[2-[Butyl(phenethyl)amino]ethyl]phenol (5). After column
chromatography 50% of 5 was obtained as colorless crystals. Mp 79−
1
82 °C; IR (KBr) 3434 (OH); H NMR (CDCl3) δ 7.32−7.11 (m, 6
arom H), 6.74−6.65 (m, 3 arom H), 2.82−2.79 (m, 8 aliphat H), 2.60
(m, NCH2), 1.54−1.25 (m, 4 aliphat H), 0.91 (t, J = 7.0 Hz, CH2−
CH3); 13C NMR (DMSO-d6) δ 157.73, 142.12, 140.49, 129.90,
128.94, 128.64, 126.27, 120.66, 115.95, 113.82, 55.92, 55.85, 53.70,
33.43, 32.93, 29.49, 21.00, 14.25; MS (CI) m/z 298 [M+ + 1]. Anal.
(C20H27NO) C, H, N.
CONCLUSIONS
■
We report on the design, synthesis, and biological evaluation of
diphenethylamines bearing different substituents at the nitro-
gen as new KOP receptor ligands. An N-CPM or N-CBM
substitution is more favorable for interaction with KOP
receptors than n-alkyl groups by causing a significant increase
in KOP receptor affinity and selectivity. In addition, an N-CBM
group leads to reduced interaction with dopamine receptors.
The N-CBM substituted derivative 4 was identified as a novel
highly selective KOP receptor agonist with potent antinoci-
ceptive action. Moreover, the N-CPM substituted analogue 3, a
selective KOR partial agonist, might have the potential for the
treatment of addiction and stress-related disorders.
3-[2-[Hexyl(phenethyl)amino]ethyl]phenol (6). After column
chromatography 66% of 6 was obtained as colorless crystals. Mp 70−
1
72 °C; IR (KBr) 3432 (OH); H NMR (CDCl3) δ 7.29−7.10 (m, 6
arom H), 6.74−6.65 (m, 3 arom H), 2.60 (m, NCH2), 1.50 (m, 2
aliphat H), 1.27 (m, 6 aliphat H), 0.88 (t, J = 6.4 Hz, CH2−CH3); 13
C
NMR (DMSO-d6) δ 156.48, 142.39, 140.68, 129.88, 128.64, 126.25,
120.84, 115.92, 113.68, 55.99, 54.07, 33.53, 33.13, 32.00, 27.52, 26.51,
22.87, 14.26; MS (CI) m/z 326 [M+ + 1]. Anal. (C22H31NO) C, H, N.
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional information on syntheses and methods and
elemental analysis results. This material is available free of
charge via the Internet at http://pubs.acs.org.
EXPERIMENTAL SECTION
■
General Methods. Melting points were determined on a Kofler
melting point microscope and are uncorrected. 1H NMR spectra were
recorded on a Varian Gemini 200 (200 MHz) spectrometer and 13C
NMR spectra on a Bruker Avance DPX-300 (75.47 MHz). IR spectra
were taken on a Mattson Galaxy FTIR series 3000 (in cm−1). Mass
spectra were recorded on a Varian MAT 44 S apparatus. Elemental
analyses were performed at the Microanalytic Laboratory of the
University of Vienna, Austria. For column chromatography (MPLC),
silica gel 60 (0.040−0.063 mm, Fluka, Switzerland) was used.
Compounds 1−4 were used as hydrochloride salts, and 5 and 6
were used as bases. Purities of tested compounds were determined by
elemental analysis and were ≥95%.
AUTHOR INFORMATION
Corresponding Author
*Phone: +43 512 50758248. Fax: +43 512 50758299. E-mail:
helmut.schmidhammer@uibk.ac.at.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Holger Kopacka for recording the 13C NMR
spectra.
General Procedure for the Synthesis of Phenols 3−6 (4 as
Example). A mixture of 10 (300 mg, 0.93 mmol), sodium
ethanethiolate (623 mg, 7.42 mmol), and anhydrous DMF (7 mL)
was stirred under N2 at 130 °C for 20 h. After cooling, the mixture was
poured on saturated NH4Cl solution. The resulting mixture was
slightly acidified with 2 N HCl and then alkalinized with diluted
NH4OH solution and extracted with CH2Cl2 (3 × 15 mL). The
organic phase was washed with H2O (5 × 15 mL), brine (15 mL),
dried over Na2SO4, and evaporated. The resulting oil was purified by
column chromatography (silica gel, CH2Cl2/MeOH/NH4OH,
97.5:1.5:1) to give 247 mg (86%) of 4 as a transparent oil. 1H
NMR (CDCl3) δ 7.28−7.10 (m, 6 arom H); 6.70−6.23 (m, 3 arom
H); 2.96−2.48 (m, 10 H); 2.10−1.57 (m, 7 H).
ABBREVIATIONS USED
■
CBM, cyclobutylmethyl; CHO, Chinese hamster ovary; CPM,
cyclopropylmethyl; D1, D2, D3, dopamine receptor subtypes;
DOP, δ opioid; EDCI, 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide methiodide; HOAt, 1-hydroxy-7-azabenzotria-
zole; KOP, κ opioid; MOP, μ opioid; U50,488, 2-(3,4-
dichlorophenyl)-N-methyl-N-[(1R,2R)-2-pyrrolidin-1-
ylcyclohexyl]acetamide; U69,593, N-methyl-2-phenyl-N-
[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]-
acetamide
3-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]phenol Hy-
drochloride (4·HCl). A part of the obtained oil of 4 was dissolved in
Et2O and treated with HCl/Et2O. The precipitate was isolated and
recrystallized from acetone/Et21O to afford 4·HCl. Mp 153−155 °C;
IR (KBr) 3134 (OH, +NH); H NMR (DMSO-d6) δ 10.73 (br s,
+NH), 9.45 (s, OH), 7.39−7.08 (m, 6 arom H), 6.72−6.64 (m, 3 arom
REFERENCES
■
(1) Carlezon, W. A., Jr.; Beguin, C.; Knoll, A. T.; Cohen, B. M.
Kappa-Opioid Ligands in the Study and Treatment of Mood
Disorders. Pharmacol. Ther. 2009, 123, 334−343.
(2) Lemos, C. J.; Chavkin, C. Kappa Opioid Receptor Function. In
The Opiate Receptors, 2nd ed.; Pasternak, G. W., Ed.; Humana Press:
New York, 2011; pp 265−305.
H), 3.10−2.78 (m, 10 aliphat H), 2.11−1.82 (m, 7 aliphat H); 13C
NMR (DMSO-d6) δ 157.66, 138.32, 136.99, 129.53, 128.76, 128.58,
D
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Journal of Medicinal Chemistry
Brief Article
(3) Kivell, B.; Prisinzano, T. E. Kappa Opioids and the Modulation of
Pain. Psychopharmacology (Berlin) 2010, 210, 109−119.
White, A.; Kennedy, J. M.; Craymer, K.; Farrington, L.; Auh, J. S.
Standard Binding and Functional Assays Related to Medications
Development Division Testing for Potential Cocaine and Opiate
Narcotic Treatment Medications. NIDA Res. Monogr. 1998, 178, 440−
466.
(4) Nagase, H.; Fujii., H. Opioids in Preclinical and Clinical Trials.
Top. Curr. Chem. 2011, 299, 29−62.
(5) Walker, J. S. Anti-Inflammatory Effects of Opioids. Adv. Exp. Med.
Biol. 2003, 521, 148−160.
(6) Bileviciute-Ljungar, I.; Saxne, T.; Spetea, M. Anti-Inflammatory
Effects of Contralateral Administration of the Kappa-Opioid Agonist
U-50,499H in Rats with Unilaterally Induced Adjuvant Arthritis.
Rheumatology (Oxford, U. K.) 2006, 45, 295−302.
(7) Birch, P. J.; Rogers, H.; Hayes, A. G.; Hayward, N. J.; Tyers, M.
B.; Scopes, D. I. C.; Naylor, A.; Judd, D. B. Neuroprotective Actions of
GR89696, a Highly Potent and Selective Kappa-Opioid Receptor
Agonist. Br. J. Pharmacol. 1991, 103, 1819−1823.
(24) Al-Khrasani, M.; Spetea, M.; Friedmann, T.; Riba, P.; Kiraly, K.;
Schmidhammer, H.; Furst, S. DAMGO and 6β-Glycine Substituted
̈
14-O-Methyloxymorphone but Not Morphine Show Peripheral,
Preemptive Antinociception after Systemic Administration in a
Mouse Visceral Pain Model and High Intrinsic Efficacy in the Isolated
Rat Vas Deferens. Brain Res. Bull. 2007, 74, 369−375.
(8) Aldrich, J. V.; McLaughlin, J. P. Peptide Kappa Opioid Receptor
Ligands: Potential for Drug Development. AAPS J. 2009, 11, 312−322.
(9) Yamaotsu, N.; Hirono, S. 3D-Pharmacophore Identification for
Kappa-Opioid Agonists Using Ligand-based Drug-Design Techniques.
Top. Curr. Chem. 2011, 299, 277−307.
(10) Cunningham, C. W.; Rothman, R. B.; Prisinzano, T. E.
Neuropharmacology of the Naturally Occurring Kappa-Opioid
Hallucinogen Salvinorin A. Pharmacol Rev. 2011, 63, 316−347.
(11) Metcalf, M.; Coop, A. Kappa Opioid Antagonists: Past
Successes and Future Prospects. AAPS J. 2005, 7, E704−E722.
(12) Knoll, A. T.; Carlezon, W. A. Dynorphin, Stress, and
Depression. Brain Res. 2010, 1314, 56−73.
(13) Portoghese, A. S.; Lipkowski, A. W.; Takemori, A. E.
Bimorphinans as Highly Selective, Potent κ Opioid Receptor
Antagonists. J. Med. Chem. 1987, 30, 238−239.
(14) Jones, R. M.; Hjorth, S. A.; Schwartz, T. W.; Portoghese, P. S.
Mutational Evidence for a Common Kappa Antagonist Binding Pocket
in the Wild Type Kappa and Mutant Mu [K303E] Opioid Receptors.
J. Med. Chem. 1998, 41, 4911−4914.
(15) Thomas, J. B.; Atkinson, R. N.; Rothman, R. B.; Fix, S. E.;
Mascarella, S. W; Vinson, N. A.; Xu, H.; Dersch, C. M.; Lu, Y.;
Cantrel, B. E.; Zimmerman, D. M.; Carroll, F. I. Identification of the
First trans-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)piperidine Deriva-
tive To Possess Highly Potent and Selective Opioid Kappa Receptor
Antagonist Activity. J. Med. Chem. 2001, 44, 2687−2690.
(16) Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G. W.;
Vardy, E.; Liu, W.; Thompson, A. A.; Huang, X. P.; Carroll, F. I.;
Mascarella, S. W.; Westkaemper, R. B.; Mosier, P. D.; Roth, B. L.;
Cherezov, V.; Stevens, R. C. Structure of the Human κ-Opioid
Receptor in Complex with JDTic. Nature 2012, 485, 327−332.
́
(17) Beguin, C.; Cohen, B. M. Medicinal Chemistry of Kappa Opioid
Receptor Antagonists. In Opiate Receptors and Antagonists; Dean, R. L.,
Bilsky, E. J., Negus, S. S., Eds.; Humana Press: New York, 2009; pp
99−118.
́
(18) Munro, T. A.; Berry, L. M.; Van’t Veer, A.; Beguin, C.; Carroll,
F. I.; Zhao, Z.; Carlezon, W. A., Jr.; Cohen, B. M. Long-Acting κ
Opioid Antagonists nor-BNI, GNTI and JDTic: Pharmacokinetics in
Mice and Lipophilicity. BMC Pharmacol. 2012, 12, 5−23.
(19) Nedelec, L.; Dumont, C.; Oberlander, C.; Frechet, D.; Laurent,
́
́
̀ ́
e et Etude de lActivite Dopaminergique de
J.; Boissier., J. R. Synthes
Derives de la Di(phenethyl)amine. Eur. J. Med. Chem. 1978, 13, 553−
563.
́
́
́
́
(20) Fortin, M.; Degryse, M.; Petit, F.; Hunt, P. F. The Dopamin D2
Agonist RU 241213 and RU 24926 Are Also Kappa-Opioid Receptor
Antagonists. Neuropharmacology 1991, 30, 409−412.
(21) Cosquer, P.; Delevallee, F.; Droux, S.; Fortin, M.; Petit, F.
Amine Compounds. U.S. Patent 5,141,962, 1992.
(22) Schullner, F.; Meditz, R.; Krassnig, R.; Morandell, G.; Kalinin, V.
̈
N.; Sandler, E.; Spetea, M.; White, A.; Schmidhammer, H.; Berzetei-
Gurske, I. P. Synthesis and Biological Evaluation of 14-Alkoxymor-
phinans. 19. Effect of 14-O-Benzylation on the Opioid Receptor
Affinity and Antagonist Potency of Naltrexone. Helv. Chim. Acta 2003,
86, 2335−2341.
(23) Toll, L.; Berzetei-Gurske, I. P.; Polgar, W. E.; Brandt, S. R.;
Adapa, I. D.; Rodriguez, L.; Schwartz, R. W.; Haggart, D.; O’Brien, A.;
E
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