The effect of 17-N substituents on the activity of the opioid κ receptor in nalfurafine derivatives

Article abstract of DOI:10.1016/j.bmcl.2012.10.100

We have previously reported the essential structure of the opioid κ receptor agonist nalfurafine hydrochloride (TRK-820) for binding to the κ receptor. In the course of this study, we focused on the effect of the substituent at 17-N in nalfurafine on the binding affinity for the κ receptor. The exchange of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups, which are strong electron withdrawing substituents, almost completely diminished the binding affinities for the μ and δ opioid receptors, but the binding affinity for the κ receptor was still maintained. As a result, nalfurafine derivatives with 17-fluoro-substituted alkyl groups showed higher selectivities for the κ receptor than did nalfurafine itself. With regard to the κ agonistic activities, the conversion of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups led to the gradual decrease of the agonistic activities in the order corresponding to their binding affinities for the κ receptor. In contrast, the derivative with the bulky 17-isobutyl group showed lower affinity and agonistic activity for the κ receptor than the derivatives with the smaller functional groups. This research suggested that both the electronic property and the steric characteristics of the 17-N substituent would have a great influence on the binding property for the κ receptor.

Full text of DOI:10.1016/j.bmcl.2012.10.100

Bioorganic & Medicinal Chemistry Letters 23 (2013) 268–272
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The effect of 17-N substituents on the activity of the opioid
in nalfurafine derivatives
j receptor
Toru Nemoto, Naoshi Yamamoto, Naohisa Wada, Yukimasa Harada, Miyuki Tomatsu, Marina Ishihara,
⇑
Shigeto Hirayama, Takashi Iwai, Hideaki Fujii, Hiroshi Nagase
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have previously reported the essential structure of the opioid
j receptor agonist nalfurafine hydro-
Received 29 September 2012
Revised 19 October 2012
Accepted 23 October 2012
Available online 30 October 2012
chloride (TRK-820) for binding to the
j
receptor. In the course of this study, we focused on the effect
of the substituent at 17-N in nalfurafine on the binding affinity for the
17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups, which are
strong electron withdrawing substituents, almost completely diminished the binding affinities for the
j
receptor. The exchange of the
l
and d opioid receptors, but the binding affinity for the
urafine derivatives with 17-fluoro-substituted alkyl groups showed higher selectivities for the
than did nalfurafine itself. With regard to the agonistic activities, the conversion of the 17-N substituent
in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups led to the gradual decrease of
the agonistic activities in the order corresponding to their binding affinities for the receptor. In contrast,
the derivative with the bulky 17-isobutyl group showed lower affinity and agonistic activity for the
j
receptor was still maintained. As a result, nalf-
Keywords:
Opioid
Morphinan
17-Substituent
j
receptor
j
j
j
receptor than the derivatives with the smaller functional groups. This research suggested that both the
electronic property and the steric characteristics of the 17-N substituent would have a great influence
on the binding property for the
j receptor.
Ó 2012 Elsevier Ltd. All rights reserved.
Three types of opioid receptors (
l
, d,
j
) are now well established
Our compound, which was launched in Japan as an antipruritic
not only by pharmacological studies, but also through molecular
agent for kidney dialysis patients in 2009,7–9 is the first opioid drug
that caused neither addiction nor aversion. Our interest in the dif-
ferences in the pharmacological effects between nalfurafine and
arylacetamide derivatives led us to examine the structure–activity
relationship of nalfurafine derivatives. Recently, we have reported
biological studies.1 For the past three decades, considerable effort
has been expended on obtaining an opioid
eliminate undesirable morphine-like side effects like addiction. In
j selective agonist to
1982, U-50,488H was discovered to be a highly selective
j agonist
by researchers at Upjohn (now merged with Pfizer).2–4 Since then,
numerous research groups have modified its structure and suc-
the essential structure of nalfurafine for binding to the j recep-
tor.10–12 In the course of this study, we paid attention to the effect
of the 17-substituent in nalfurafine on the binding affinity and the
ceeded in preparing more selective and potent
j agonists. These
compounds had potent antinociceptive effects in animal models
and also succeeded in eliminating the morphine-like side effects.
However, all these compounds have structures similar to that of
U-50,488H, with arylacetamide skeleton (Fig. 1), and showed se-
vere aversion like psychotomimetic effects. We recently reported
agonistic activity to the j receptor.
The 4,5-epoxymorphinan structure (message site) in nalfurafine
(Fig. 2) is believed to influence the intrinsic activity of the ligand
for the opioid receptor and the substituents (address site) would
help the drug distinguish among the opioid receptor types.13 The
message structure contributed to three points of association be-
tween the drug molecule and the receptor site, which included
an ionic interaction (formed by the 17-nitrogen (17-N) atom), a
a novel
has
j
agonist, TRK-820 (nalfurafine hydrochloride),5–9 which
structure quite different from U-50,488H. Unlike
a
U-50,488H, TRK-820 bears a tyrosine-glycine dipeptide unit which
is a structural motif commonly found in endogenous opioid pep-
tides (Fig. 1).
p–p interaction (formed by the benzene ring), and formation of a
hydrogen bond (contributed by the 3-hydroxy group) in Fig-
ure 2.14,15 On the other hand, we concluded in a previous report
that the phenol ring in nalfurafine increased its binding affinity
to the
j
receptor, but was not indispensable for binding.10–12 We
Abbreviation: CPM, cyclopropylmethyl; CHO, Chinese hamster ovary.
Corresponding author. Tel.: +81 3 5791 6372; fax: +81 3 3442 5707.
E-mail address: nagaseh@pharm.kitasato-u.ac.jp (H. Nagase).
next attempted to investigate the importance of the ionic interac-
tion, which was believed to be the strongest of the three actions,
⇑
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.100

T. Nemoto et al. / Bioorg. Med. Chem. Lett. 23 (2013) 268–272
269
Cl
Cl
OH
OH
17
N
O
N
O
O
RN
O
N
N
CH3
·HCl
O
Me
O
CH3
O
N
OH
R = CH2CH2F: 1 R = methyl; 4
OH
TRK-820
U-50,488H
tyrosine-glysine
moiety
5
R = ethyl;
2
R = CH2CHF2:
R = propyl; 6
R = CH2CF3: 3
R = isobutyl; 7
Figure 1. The structures of U-50,488H and TRK-820.
Figure 4. The structures of compounds 1–7.
by the reductive amination with N-methylbenzylamine and subse-
quent hydrogenolysis in the presence of 10%Pd-C to give 6b-amine
13a–c.11 Compounds 13a–c were converted to amides 14a–c by
amidation with 3-(furan-3-yl)acryloyl chloride.6 The resulting
compounds 14a–c were demethylated with BBr3 to afford objec-
tive compounds 1–3 (Scheme 1).21
To synthesize the compounds with ethyl or propyl group on the
17-nitrogen atom, compound 8 was N-ethylated with ethyl iodide,
or was N-propylated by amidation with propionyl chloride, fol-
lowed by reduction with LiAlH4. Compounds 15a and 15b were
converted to the objective compounds 5 and 6 in a similar manner
as shown in Scheme 1 (Scheme 2). Compound 2022 was converted
to compound 21, bearing a 17-isobutyl group, by hydrogenation in
the presence of PtO2 catalyst.23,24 Compound 21 was converted to
the objective compound 7 by the reported method (Scheme 3).6
Compound 4 with a 17-methyl group was synthesized by the re-
ported method.6 To evaluate the pharmacological profiles of the
thus synthesized compounds for the opioid receptors, the resulting
compounds 1–7 were converted into the respective hydrochlorides
(SYK-52, 53, 60, 305, 235, 304, 463: Table 1).
message address
site
site
OH
14
5
O
N
N
CH3
O
O
an ionic interaction
a π−π interaction
4
3
OH
a hydrogen bond
nalfurafine
Figure 2. The message site and address site of nalfurafine.
for binding to the
j receptor. Generally speaking, in morphinan
derivatives the 17-N substituent plays an important role in distin-
guishing between the agonist and antagonist. With regard to
peptide
acetylated dynorphin A derivatives like JVA-901 and arodyn are
antagonists (Fig. 3).16,17 These compounds maintained sufficient
binding affinities for the receptor despite the decrease of the ba-
j ligands, dynorphin A is a potent j agonist while N-
j
j
We evaluated the binding affinities of the synthesized com-
sicity of nitrogen. The basicity of nitrogen may affect the agonist
pounds toward opioid
pose of comparison, the results of the standard
l
, d, and
j
receptors (Table 1). For the pur-
agonist U-69,593
property of dynorphin A. On the basis of the hypothesis that the
j
loss of the basicity of the terminal nitrogen in peptide
j ligands
and
j agonist TRK-820 were also shown. The assays were per-
may convert the property of the ligand from agonist to antagonist,
formed for each receptor type by previously reported procedures.21
Schiller co-worker prepared dynantin (Fig. 3), a selective
j antag-
onist derived from dynorphin A.18 However, this structure–activity
relationship concerning the nature of the substituent on the nitro-
The evaluated compounds except SYK-53 (2) and SYK-60 (3)
showed high affinities and selectivities for the
820 showed the highest affinity, whereas all compounds except
SYK-305 (4) with a 17-methyl group showed higher selectivities
for the receptor than did TRK-820. With the exception of SYK-
j receptor. TRK-
j
gen has not yet been applied to non-peptide
j agonists. Therefore,
we examined the effect of the 17-N substituent, especially 17-N
electron-withdrawing substituents, in nalfurafine on the agonistic
j
463 (7) and SYK-52 (1), the general trend was the stronger the
activities for the
j receptor. We designed the N-fluoroalkylated
electron-donating properties of the 17-N substituents, the higher
delivatives 1–3 (Fig. 4). We also designed nalfurafine derivatives
4–7 with 17-alkyl substituents, some of which were similar in size
to fluoro-substituted alkyl groups of derivatives 1–3. Herein, we
report the synthesis of these compounds and their pharmacologi-
cal effects.
The 17-NH-morphinan 8 was synthesized from noroxycodone
by the reported method.19 The compound 8 was converted to com-
pounds 10a–c with a 17-fluoro-substituted alkyl group by amida-
tion20 and subsequent reduction with BH3ꢀTHF (Scheme 1). The
hydrolysis of compounds 10a–c provided ketones 11a–c, followed
the
j affinities. The binding affinities for the l and d receptor of
the derivatives with 17-fluoro-substituted alkyl substituents
[SYK-52 (1), SYK-53 (2), and SYK-60 (3)], declined markedly, while
their binding affinities for the
maintained.
j receptor were reasonably
We also evaluated the functional activities of the synthesized
compounds toward the opioid S binding
j
receptor in the [35S]GTP
c
assay (Table 2). The assays were performed by procedures similar
to those previously reported.25 The standard ligand U-69,593 was
dynorphin A (1-11) NH2: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-NH2
JVA-901: Ac-Tyr-Lys-Trp-Trp-Leu-Arg-Arg- -Ala-Arg-Pro-Lys-NH2
arodyn: Ac-Phe-Phe-Phe-Arg-Leu-Arg-Arg-
D
D
-Ala-Arg-Pro-Lys-NH2
a
dynantin: [(2S)-Mdp1]Dynorphin A (1-11) NH2
Figure 3. The structures of dynorphin A (1-11) NH2 and N-acetylated dynorphin A derivatives (JVA-901 and arodyn), and dynantin.
aMdp: 2-methyl-3-(20,60-dimethyl-4-hydroxyphenyl)propanoic acid.

270
T. Nemoto et al. / Bioorg. Med. Chem. Lett. 23 (2013) 268–272
O
OH
OH
OH
R
N
HN
(c)
(a) or (b)
RN
a
: R = CH2F
b: R = CHF2
O
O
O
O
O
O
O
O
O
c
: R = CF3
OMe
9a-c
OMe
OMe
8
10a-c
OH
OH
OH
(d) or (e)
(f), (g)
RN
(h)
RN
RN
6
NHMe
NMe
O
O
O
O
OMe
OMe
13a-c
OMe
12a-c
11a-c
OH
OH
O
O
N
RN
RN
O
(j)
(i)
N
O
Me
O
Me
O
OMe
14a-c
OH
R = CH2CH2F:
R = CH2CHF2: 2
1
3
R = CH2CF3:
Scheme 1. Reagents and conditions: (a) RCOOEt, Me3Al, CH2Cl2, 0 °C to rt; 70% (9a), 51% (9b); (b) (CF3CO)2O, Et3N, CH2Cl2, rt; (c) BH3ꢀTHF, THF, 0 °C to rt, 70% (10c: 2 steps
from 8); (d) 6 M HCl, 0 °C to 50 °C, 72% (11a: 2 steps from 9a),76% (11b: 2 steps from 9b); (e) 2 M HCl, THF, 50 °C, 96% (11c); (f) p-TsOHꢀH2O, N-methylbenzylamine, benzoic
acid, toluene, reflux; (g) NaCNBH3, EtOH, MS3A, 0 °C to rt, 59% (12c: 3 steps from 10c); (h) 10%Pd-C, H2, MeOH, rt, 98% (13a: 3 steps from 11a), 98% (13b: 3 steps from 11b),
61% (13c), (i) 3-(furan-3-yl)acryloyl chloride, Et3N, CH2Cl2, 0 °C to rt, 69% (14a), 79% (14b), 87% (14c); (j) BBr3, CH2Cl2, 0 °C to rt, 90% (1), 23% (2), 82% (3).
OH
OH
OH
OH
HN
(a)
RN
(f), (g)
RN
RN
(d)
O
O
O
O
NMe
Me
O
O
O
O
O
or (b), (c)
O
O
O
O
or (e)
Me
Me
Me
8
15a, b
: R = ethyl
b: R = propyl
16a, b
17a, b
a
OH
OH
OH
O
N
RN
RN
O
RN
(h)
or (i)
O
NHMe
(j)
(l)
or (m)
O
N
O
O
Me
O
O
Me
O
or (k)
Me
Me
OH
18a, b
19a, b
5
R = ethyl:
R = propyl: 6
Scheme 2. Reagents and conditions: (a) EtI, K2CO3, DMF, rt, 100%; (b) EtCOCl, Et3N, CH2Cl2, 0 °C to rt, quant.; (c) LiAlH4, THF, 0 °C to 50 °C, 96%; (d) 2 M HCl, THF, reflux, 84%
(16a); (e) 2 M HCl, MeOH, 80 °C, 96% (16b); (f) p-TsOHꢀH2O, N-methylbenzylamine, benzoic acid, benzene, reflux; (g) NaCNBH3, EtOH, 0 °C to rt, 63% (17a; 2 steps from 16a),
42% (17b: 2 steps from 16b); (h) 10%Pd-C, H2, MeOH, rt, 76% (18a); (i) 5%Pd-C, H2, MeOH, rt, 50% (18b); (j) 3-(furan-3-yl)acryloyl chloride, CH2Cl2, 0 °C to rt, 83% (19a); (k) 3-
(furan-3-yl)acryloyl chloride, Et3N, CH2Cl2, 0 °C to rt, 44% (19b); (l) BBr3, CH2Cl2, ꢁ78 °C to rt, 83% (5); (m) BBr3, CH2Cl2, 0 °C to rt, 100% (6).
OH
were similar to those of SYK-235 (5) (with an ethyl group) and
SYK-304 (6) (with a propyl group).
Earlier, we reported that high affinities for the opioid receptors
would arise from 17-N substituents with strong electron-donating
properties.19,26 Indeed, our results in that investigation showed
that the greater the electron-donating property of the 17-N substi-
OH
R
N
O
(b)
(c)
N
O
NHMe
N
O
Me
O
OH
OH
20
R = CPM:
R = isobutyl: 21
7
(a)
tuent, the higher the affinity for the
also observed in the agonistic activity for the
SYK-52 (1) and SYK-463 (7) did not follow this predicted trend.
Interestingly, SYK-52 (1) with the electron-withdrawing 2-fluoro-
ethyl group showed higher affinity and agonistic activity for the
j
receptor. This tendency was
receptor. However,
Scheme 3. Reagents and conditions: (a) 1 M HCl, PtO2, rt, quant.; (b) 3-(furan-3-
yl)acryloyl chloride, Et3N, CH2Cl2, 0 °C to rt; (c) 2 M NaOH, MeOH, 86% (2 steps from
21).
j
j
receptor than did SYK-235 (5) with the electron-donating ethyl
included for comparison. All compounds showed almost full agonis-
group, which was of similar size to the 2-fluoroethyl group. Per-
haps the fluorine atom of the 2-fluoroethyl group in SYK-52 (1)
interacts with the
activity toward the
(with an isobutyl group) showed lower affinity and activity than
SYK-305 (4), SYK-235 (5), and SYK-304 (6) despite its strong
tic activities equipotent to the standard
j agonist U-69,593. Among
them, the conversion of 17-substituent in TRK-820 from CPM to
fluoro-substituted alkyl groups led to a decrease in the potency of
agonistic activities, consistent with our observations regarding the
j
receptor, affording high affinity and agonistic
receptor. On the other hand, SYK-463 (7)
j
binding affinity for the
j receptor. The affinity and the agonistic po-
tency for the receptor of SYK-52 (1) (with a 2-fluoroethyl group)
j

T. Nemoto et al. / Bioorg. Med. Chem. Lett. 23 (2013) 268–272
271
Table 1
electron density on the nitrogen. In addition, SYK-53 (2) with the
17-difluoroethyl substituent showed more selectivity than
U-69,593 and almost the same activity as that of U-69,593 for
The binding affinities and selectivities of U-69,593, TRK-820, and SYK-compounds for
opioid
l
, d, and
j
receptorsa
the
electron-donating group) showed low
tent agonistic activity. On the basis of these results, the selectiv-
ity and agonistic activity for the receptor was controlled by the
introduction of the 17-fluoro-substituted groups. These findings
j
receptor while TRK-820 with the 17-CPM group (a strong
Cl
Cl
l/j
selectivity and very po-
OH
R
O
N
O
N
O
j
N
j
CH3
N
O
Me
O
HCl
OH
are expected to be useful for designing novel
agonists.
j selective and potent
U-69,593
As mentioned above, the peptide
tent agonist while the N-acetylated dynorphin A derivatives are
antagonist (Fig. 3).16,17 In contrast, nalfurafine derivatives main-
tained agonistic activities toward the receptor despite the de-
crease in the basicity of the nitrogen. It is difficult to explain why
nalfurafine derivatives with the morphinan skeleton showed a dif-
j ligand dynorphin A is a po-
j
j
Compounds
R
Affinity (Ki, nM)
Selectivity
j
l
d
j
l/
j
d/j
U-69,593
TRK-820
548
391
1.37
400.0
2.42
3.77
17.6
58.4
78.4
16.6
—
285.4
288
48.6
818
537
871.6
—
CPM
Me
Et
Propyl
Isobutyl
–CH2CH2F
–CH2CHF2
–CH2CF3
0.431
2.767
10.99
19.17
46.22
8.394
>1000
>1000
51.3
0.178
0.7346
0.6252
0.3283
0.5895
0.507
2.192
4.584
ferent tendency from that of the peptide
j ligands. It may be that
SYK-305 (4)
SYK-235 (5)
SYK-304 (6)
SYK-463 (7)
SYK-52 (1)
SYK-53 (2)
SYK-60 (3)
35.67
511.6
176.2
513.8
>1000
>1000
>1000
peptides and nonpeptides bind to different binding sites of the
j
receptor,17 a possibility that requires further investigation.
Of the synthesized compounds, SYK-304 (6) with a 17-propyl
substituent showed the highest affinity, the most balanced and
highest selectivity, and an elevated agonistic activity for the
j
—
j
—
—
receptor. These favorable properties of SYK-304 (6) could be attrib-
uted to the electron-donating property and the appropriate size of
the 17-propyl group.
a
Evaluated by ability of each compound to displace [3H]DAMGO (
l
), [3H]DPDPE
(d), or [3H]U-69,593 (
cerebellum (l and d) or the guinea pig cerebellum (j). The data represent means of
j) binding from membranes of mouse whole brain without
three samples.
In conclusion, 17-N electron-donating substituents increased
the binding affinity and agonistic activities for the
j receptor. Elec-
tron-withdrawing substituents at 17-N (fluorinated substituents)
in nalfurafine derivatives significantly increased the receptor type
Table 2
j
-Agonist activities of U-69,593, TRK-820, and SYK-compoundsa
selectivity while they decreased the
(7), with a bulky isobutyl group, exhibited low affinity and
j
agonistic activities. SYK-463
ago-
j
Compounds
17-substituents
EC50 (nM)
Emax (%)
nistic activity. Therefore, not only the electronic properties but also
the steric characteristics of the 17-N substituent would have a
great influence on the binding ability and the agonistic activity
U-69,593
TRK-820
28.1
0.05
100.0
98.1
CPM
Me
Et
Propyl
Isobutyl
–CH2CH2F
–CH2CHF2
–CH2CF3
SYK-305 (4)
SYK-235 (5)
SYK-304 (6)
SYK-463 (7)
SYK-52 (1)
SYK-53 (2)
SYK-60 (3)
11.26
3.787
2.721
8.071
2.231
22.41
32.21
90.44
97.38
86.47
99.53
95.24
101.4
89
for the
showed high affinity and agonistic potency for the
These findings are expected to be useful for designing novel
j
receptor. As a result, SYK-304 (6) with a propyl group
j
receptor.
j
selective agonists. We are currently examining the effects of fluo-
rinated substituents in opioid d ligands.
a
Membranes were incubated with [35S] GTP
human recombinant cell membrane (CHO) was used in this assay. U-69,593 was
used as the standard agonist. The data represent means of four samples.
cS and GDP with the compound. The
Acknowledgments
j
j
We acknowledge the Institute of Instrumental Analysis of Kita-
sato University, School of Pharmacy for its facilities. This work was
supported by JSPS KAKENHI (23590133) [Grant-in-Aid for Scien-
tific Research (C)].
electron-donating property. The larger size of the isobutyl group
may be responsible for the lower affinities and activities for the
j
receptor. These results suggested that not only the basicity of
nitrogen but also the bulkiness of the 17-N substituent could con-
tribute to the binding affinity and agonist properties and that the
favorable balance between the two factors would lead to the im-
References and notes
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proved affinity and agonistic activity for the
j receptor. Therefore,
the noticeable decrease in the affinities and agonistic activities of
SYK-53 (2) and SYK-60 (3) with the fluoro-substituted alkyl group
may be derived from the bulkiness26 as well as the strong electron-
withdrawing property of this functional group.
Although the binding affinities of 17-fluoro-substituted alkyl
derivatives SYK-52 (1), SYK-53 (2), and SYK-60 (3) for the
tor decreased, they remained reasonable. In contrast, their affini-
ties for the and d receptors were extremely decreased. As a
result, TRK-820 derivatives with the 17-fluoro-substituted ethyl
groups showed markedly higher selectivities for the receptor
than did TRK-820 itself. To account for these observations, we pro-
posed that the address part (Fig. 2), which adequately interacts
with the receptor, can compensate for the binding to the recep-
j recep-
l
j
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