Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor

Article abstract of DOI:10.1016/j.bmcl.2017.07.011

The essential structure of the orexin 1 receptor (OX₁R) antagonist YNT-707 (2) was clarified, particularly the roles to OX₁R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX₁R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX₁R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX₁R ligands.

Full text of DOI:10.1016/j.bmcl.2017.07.011

Accepted Manuscript
Essential structure of orexin 1 receptor antagonist YNT-707: Part I Role of the
4
,5-epoxy ring for binding with orexin 1 receptor
Naoshi Yamamoto, Sayaka Ohrui, Takahiro Okada, Masahiro Yata, Tsuyoshi
Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe,
Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa,
Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase
PII:
S0960-894X(17)30707-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.07.011
BMCL 25124
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
23 May 2017
29 June 2017
3 July 2017
Please cite this article as: Yamamoto, N., Ohrui, S., Okada, T., Yata, M., Saitoh, T., Kutsumura, N., Nagumo, Y.,
Irukayama-Tomobe, Y., Ogawa, Y., Ishikawa, Y., Watanabe, Y., Hayakawa, D., Gouda, H., Yanagisawa, M.,
Nagase, H., Essential structure of orexin 1 receptor antagonist YNT-707: Part I Role of the 4,5-epoxy ring for binding
with orexin 1 receptor, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2
017.07.011
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Essential structure of orexin 1 receptor
antagonist YNT-707: Part I Role of the 4,5-
epoxy ring for binding with orexin 1 receptor
Leave this area blank for abstract info.
Naoshi Yamamoto, Sayaka Ohrui, Takahiro Okada, Masahiro Yata, Tsuyoshi Saitoh, Noriki Kutsumura,
Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi
Hayakawa, Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Essential structure of orexin 1 receptor antagonist YNT-707: Part I Role of the
4
,5-epoxy ring for binding with orexin 1 receptor
a,1
Naoshi Yamamoto , Sayaka Ohrui , Takahiro Okada , Masahiro Yata , Tsuyoshi
a,1
b
b
a
a
a
a
Saitoh , Noriki Kutsumura , Yasuyuki Nagumo , Yoko Irukayama-Tomobe ,
a
Yasuhiro Ogawa , Yukiko Ishikawa , Yurie Watanabe , Daichi Hayakawa , Hiroaki
a
c
c
c
Gouda , Masashi Yanagisawa , Hiroshi Nagase
a
a,b,*
a
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan
b
c
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
The essential structure of the orexin 1 receptor (OX
particularly the roles to OX R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-
hydroxy group, and the orientation of the 6-amide side chain.
1
The 3-OMe and 17-sulfonamide group were shown to be essential for the OX R antagonistic
1
R) antagonist YNT-707 (2) was clarified,
1
Revised
Accepted
Available online
activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide
group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction
of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward
the upper side of the C-ring.
Keywords:
orexin
Finally, we proposed the difference in the active conformation between OX
receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a
useful guide for medicinal chemists to design OX R ligands.
1
R and κ opioid
opioid
1
nalfurafine
YNT-707
4
,5-epoxy ring
morphinan
2
009 Elsevier Ltd. All rights reserved.
9
Orexin 1 and orexin 2 receptors (OX
protein coupled receptors and they mediate physiological
1
R and OX
2
R) are G-
and the κ opioid receptor (KOR) have been reported,
respectively.
1
,2
responses of orexin peptides (orexin-A and orexin-B). The
Based on the above reasoning, we postulated that some KOR
agonists might interact with OX R or the OX R-KOR dimer. We
1 1
orexin system is important for the regulation of the sleep/wake
3
cycle and arousal, and additionally, OX
1
R contributes to
4
were interested in the interaction between orexin and opioids, and
evaluated the many opioid ligands in our library. As a result, the
KOR agonist, nalfurafine (1) (Figure 1) showed antagonistic
1
regulating reward-related behaviors. The selective OX R
5
6
antagonists, SB-334867 and GSK-1059865, have been reported
to attenuate the psychological dependence induced by cocaine
and amphetamine in rats. Orexin might also be implicated in
opioid addiction; orexin knockout mice as well as rats treated
with the SB-334867 displayed reduced morphine-induced
activity for OX
the other opioid ligands did not. We attempted to optimize the
structure of nalfurafine (1) to improve the OX R antagonistic
activity, and finally obtained sulfonamide YNT-707 (2) (OX
= 8.14 nM, OX R: Not active) and water soluble compound
YNT-1310 (3) (OX R: K = 1.36 nM, OX R: Not active) (Figure
1 1 i 2
R (OX R: K = 250 nM, OX R: Not active), but
10
1
7
1
R:
psychological dependence.
Recently, the colocalization of orexin and dynorphin
K
i
2
1
i
2
(
endogenous κ opioid receptor agonist) in the same synaptic
10
8
1).
1
vesicle in orexin neurons, and the heterodimerization of OX R
∗
Corresponding author. Tel.: +81-29-853-6437; fax: +81-29-853-6437; e-mail: nagase.hiroshi.gt@u.tsukuba.ac.jp
Both authors have equally contributed.
1

helpful in clarifying the pharmacophores for OX
report the changes of the activity and selectivity toward OX
1
R. Herein, we
R by
1
the deletion of the 4,5-epoxy ring in YNT-707 (2) and we also
determined the stereochemistry of the 6-amide side chain which
allowed us to clarify the essential structure in (2).
Figure 1. The structures of nalfurafine (1), YNT-707 (2) and YNT-1310 (3).
In the course of the above optimization study, we found the
specific character of the morphinan skeleton to contribute to the
Figure 2. The structures of YNT-1760 (4) and YNT-1745 (5).
astounding selectivity for OX
derivatives showed extremely high selectivity toward OX
although many low selective derivatives for OX R (some
derivatives showed some selectivity for OX R) were observed in
the course of structure-activity relationship studies of the other
1
R. Almost all of the nalfurafine
1
R,
Table 1. K
compounds for OX
i
values and their selectivities of the obtained
1
a
1 2
R and OX R.
2
K
i
(nM)
Compounds
Selectivity
1
1–14
known antagonists without the morphinan skeleton.
been interested in what leads to the remarkable OX
we would say specificity for OX R) and examined the
We have
OX
1
R
2
OX R
1
R selectivity
–b
–b
YNT-1369 (8)
YNT-707 (2)
YNT-816 (13)
849 ± 177
8.14 ± 0.61
11.2 ± 1.91
31.6 ± 10.6
–
(
1
contribution of each functional group in the morphinan skeleton
to the activity and selectivity. In this paper, we focus on the
change of the 3-methoxy group, the removal of the 4,5-epoxy
ring, and the stereochemistry of the 6-amide side chain. The
essential structure of YNT-707 (2) is also expected to lead to the
–
294 ± 77.7
26.1
–
b
YNT-817 (14)
–
a
Ki values represent the mean ± SEM. These values were calculated using
IC50 values of nalfurafine derivatives and at least three independent calcium
assays performed in triplicate (Cheng−Prusoff equation).
1
clarification of the active conformation of OX R selective
ligands. The most potent antagonist, YNT-1310 (3) among our
1
0
b
obtained compounds, has unfavorable moieties (two basic
functional groups) to examine for determining the essential
structure. We therefore selected YNT-707 (2) with a simpler 17-
substitutent and 6-amide side chain, as a parent compound. We
have already reported a case of success, the essential structure of
Ki value was not calculated. IC50 value was over 10,000 nM (cut off value) or
was not obtained from the concentration−response curve.
1
5–18
nalfurafine (1) to bind with KOR,
which would become
Scheme 1. Synthesis of YNT-1369 (8), YNT-816 (13) and YNT-817 (14). (a) PhSO
MeNH ·HCl, NaBH(OAc) , Et N, 1,2-dichloroethane, rt, 78%; (d) (E)-3-(furan-3-yl)acryloyl chloride, Et
10 °C, 91%; (f) 1 M HCl aq., 60 °C, 92%; (g) (Boc) O, EtN(i-Pr) , CH Cl , rt, 98%; (h) MeNH ·HCl, NaBH
-yl)acryloyl chloride, Et N, CH Cl , rt, 6α: 94%, 6β: quant.; (j) HCl–MeOH, rt; (k) PhSO Cl, Et N, CH Cl , rt, YNT-816 (13): 72% (2 steps), YNT-817 (14):
0% (2 steps).
2
Cl, Et
3
N, CH
2
Cl
2
, 0 °C to rt, 97%; (b) 2 M HCl, AcOH, 90 °C, 79%; (c)
N, CH Cl , 0 °C to rt, 87%; (e) 12 M KOH aq., DMSO,
CN, MeOH, rt, 11: 40%, 12: 43%; (i) (E)-3-(furan-
2
3
3
3
2
2
1
3
6
2
2
2
2
2
3
3
2
2
2
3
2
2

1
Figure 3. (a) OX R-bound conformation of YNT-1310 (3) obtained in our previous docking study; (b) Superimpositions of low-energy conformations of YNT-
1
310 (3) within 2.0 kcal/mol of the lowest energy conformation obtained by CAMDAS; (c) YNT-1369 (8), YNT-707 (2), YNT-816 (13) and YNT-817 (14)
within 2.0 kcal/mol of the lowest energy conformation obtained by CAMDAS.
In advance of the deletion of the 4,5-epoxy ring in
YNT-707 (2), we have to mention about the role of the 17-
substituent. As we already reported, the role of the electron
density of the 17-substituent was very important for the affinity
epoxy ring did not affect the selectivities of most of the 6β-amide
derivatives and showed no affinity for OX R. This discovery
could be an important clue for the design of selective ligands for
OX R with the morphinan skeleton.
2
2
1
0
1
to OX R. The conversion of the electron rich substituents, e.g.,
cyclopropylmethyl, to the electron deficient groups
carboxyamide and sulfonamide markedly improved the activity.
It is noteworthy that the sulfonamide group not only increased
the activity for OX
We also examined the role of the 3-OMe group for binding of
YNT-707 (2) to OX R. The conversion of the OMe to an OBn
1
R, but also decreased the affinity for KOR.
1
group resulted in almost no activity (YNT-1760 (4)), and
complete removal of the OMe led to extremely low activity
(
1 2
YNT-1745 (5), OX R: IC50 = 1910 nM, OX R: IC50 = >10000
nM). Based on these results, the 3-OMe and 17-sulfonamide
groups in the morphinan skeleton were retained in the following
conversion of the 4,5-epoxy ring.
Figure 4. (a) The dipole–dipole interaction between the 4,5-epoxy ring and
the 6α-amide side chain; (b) The proposed active conformation for binding
with the KOR.
The synthesis of YNT-1369 (8), the 6α-amide isomer of YNT-
1
0
7
07 (2), is described in Scheme 1. Sulfonamidation of 6 and
deacetalization of the obtained sulfonamide afforded ketone 7 in
good yield. The treatment of ketone 7 with MeNH ·HCl and
NaBH(OAc) followed by acylation gave 6α-isomer YNT-1369
8). The morphinan derivatives YNT-816 (13) and YNT-817 (14)
Next, we delved into the role of the 4,5-epoxy ring to
affect the activity of the 6α- and 6β-amide isomers. The
2
1
following discussion is based on the OX R-bound conformation
3
of the most potent compound YNT-1310 (3) obtained in the our
(
1
0
1
9
previous docking study. As shown in Figure 3 (a), the docking
study suggested that the 17-sulfonamide and the 6β-amide groups
of YNT-1310 (3) needed to orient toward the upper side of the D-
ring and the lower side of the C-ring, respectively, to interact
were prepared from compound 9 in 7 steps. The removal of the
Troc and the acetyl groups, deacetalization and protection of the
resulting amine with a Boc group gave ketone 10 in good yield.
Reductive amination of ketone 10 with MeNH
2
·HCl and
1
with OX R. Figure 3 (b) shows the lower-energy conformers of
YNT-1310 (3) obtained by conformational analysis using the
NaBH CN afforded 6α-methylamine 11 and 6β-methylamine 12
3
2
0
in 40% and 43% yield, respectively. YNT-816 (13) was
synthesized from 6α-isomer 11 via 6-amidation, deprotection of
the Boc group, and sulfonamidation. YNT-817 (14) was
synthesized from the 6β-isomer 12 by a method similar to YNT-
Conformational Analyzer with the Molecular Dynamics And
2
1
Sampling (CAMDAS) 2.1 program. We could see that similar
conformers to the OX R-bound conformation were observed
among lower-energy conformers of YNT-1310 (3), suggesting
that YNT-1310 (3) could bind to OX R without significant
1
8
16 (13).
1
We evaluated the activities of YNT-707 (2) derivatives
with the 4,5-epoxy ring for OX R. Although YNT-707 (2) with
the 6β-amide side chain showed potent antagonistic activity for
OX R, the activity of the 6α-isomer YNT-1369 (8) was
energy cost related to conformational change. This favorable
conformation would partly contribute to the potent activity of
YNT-1310 (3). Figure 3 (c) also shows results of conformational
analyses of YNT-1369 (8), YNT-707 (2), YNT-816 (13) and
YNT-817 (14). When we compared the lower-energy conformers
between YNT-707 (2) and YNT-1369 (8), we found that the 6β-
amide group in YNT-707 (2) would be mainly located toward the
lower side of the C-ring, while the 6α-amide group in YNT-1369
1
1
extremely decreased (Table 1). Then, we evaluated the activities
of the derivatives without a 4,5-epoxy ring. Interestingly, the 6α-
isomer without 4,5-epoxy ring, YNT-816 (13) was more potent
than the corresponding 6β-isomer YNT-817 (14). Unexpectedly,
we found that some 6α-isomers without the 4,5-epoxy ring
(
8) would be mainly located toward the upper side of the C-ring,
2
showed the affinities for OX R although the existence of a 4,5-

which might be partly attributed to the dipole-dipole interaction
between the 4,5-epoxy ring and the 6α-amide side chain (Figure
Carr, S. A.; Annan, R. S.; McNulty, D. E.; Liu, W. S.; Terrett, J.
A.; Elshourbagy, N. A.; Bergsma, D. J.; Yanagisawa, M. Cell
1
998;92:573−585.
4
(a)). This result suggested that YNT-707 (2) would bind to
OX R with little energy cost as YNT-1310 (3), but YNT-1369 (8)
would require a significant energy cost upon binding to OX R.
This consideration would explain the lower affinity of YNT-1310
3) for OX R. On the other hand, the 6α-isomer YNT-816 (13)
2
.
de Lecea, L.; Kilduff, T. S.; Peyron, C.; Gao, X.; Foye, P. E.;
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(
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3
4
5
.
.
.
without a 4,5-epoxy ring showed improved activity, which was
higher than that of the corresponding 6β-isomer YNT-817 (14)
because no dipole-dipole interaction could lead the 6α-amide side
chain to the lower side of the C-ring, as shown in lower-energy
conformers of YNT-816 (13) (Figure 3 (c)).
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Hutcheson, D. M.; Quarta, D.; Halbout, B.; Rigal, A.; Valerio, E.;
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The hydrogen bond between the 14-hydroxy and the
7
.
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lone pair of 17-nitrogen could lead the 17-sulfonamide group
toward the lower side of the D-ring. Actually, all of the most
stable conformations of YNT-1369 (8), YNT-707 (2), YNT-816
8. Chou, T. C.; Lee, C. E.; Elmquist, J. K.; Hara, J.; Willie, J.
T.;Beuckmann, C. T.; Chemelli, R. M.; Sakurai, T.; Yanagisawa,
M.;Saper, C. B.; Scammel, T. E. J. Neurosci. 2001;21:RC168.
(
13) and YNT-817 (14) adopted the orientation with the 17-
sulfonamide group to the lower side of the D-ring. However, as
shown in Figure 3 (a), the 17-sulfonamide group must orient
toward the upper side of the D-ring in order to interact with
9
.
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Y.; Gouda, Y.; Yanagisawa, M. J. Med. Chem. 2017;60:1018–
1
1
OX R. In the lower-energy conformers of YNT-816 (13) and
YNT-817 (14), the 17-sulfonamide group is oriented toward the
upper side of the D-ring in YNT-816 (13), but not for YNT-817
1
040.
1. Boss, C.; Brisbare-Roch, C.; Jenck, F. J. Med. Chem.
009;52:891−903.
(
14). This observation might help to explain the higher activity of
YNT-816 (13) as compared to YNT-817 (14). Furthermore, the
4-hydroxy group could interact with the 6β-amide group and
1
2
1
1
2. Lebold, T. P.; Bonaventure, P.; Shireman, B. T. Bioorg. Med.
Chem. Lett. 2013;23:4761−4769.
13. Boss, C.; Roch, C. Bioorg. Med. Chem. Lett. 2015;25:2875
−2887.
raise it to the upper side of C-ring (Figure 4 (b)), which resulted
in lower activity of YNT-817. On the other hand, the
conformation in Figure 4 (b) was reported as an active
1
4. Roecker, A. J.; Cox, C. D.; Coleman, P. J. J. Med. Chem.
2016;59:504–530.
1
5–18
conformation for binding with the κ opioid receptor.
1
5. Nagase, H.; Fujii, H. Curr. Pharmaceutical Des. 2013;19:7400–
414.
16. Nagase, H.; Imaide, S.; Yamada, T.; Hirayama, S.; Nemoto, T.;
Based on our results, we now have an improved
understanding of the differences of the active conformations of
nalfurafine derivatives, especially, the orientation of the 6-amide
7
Yamaotsu, N.; Hirono, S.; Fujii, H. Chem. Pharm. Bull.
2
012;60:945–948.
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Bioorg. Med Chem. Lett. 2012;22:5071–5074.
group for differentiation between OX
discovery will provide important information for designing OX
ligands with morphinan structures.
In conclusion, we modified YNT-707 (2) to clarify the
1
R and KOR. This
1
1
1
R
8. Fujii, H.; Imaide, S.; Hirayama, S.; Nemoto, T.; Nagase, H.
Bioorg. Med. Chem. lett. 2012;22:7711–7714.
essential structure of parent compound (2), especially, the 3-
methoxy group, 4,5-epoxy ring, 14-hydroxy group, and the
orientation of the 6-amide group. Our results show that the 3-
methoxy and 17-sulfonamide groups are essential for the activity,
and the 4,5-epoxy ring could play an important role to orient the
19. Nagase, H.; Nemoto, T.; Matsubara, A.; Saito, M.; Yamamoto, N.;
Osa, Y.; Hirayama, S.; Nakajima, M.; Mochizuki, H.; Fujii, H.
Bioorg. Med. Chem. Lett. 2010;20:6302–6305.
2
0. The stereochemistries of 11 and 12 at the 6-position were
determined as follows. The Boc groups in compound 11 and 12
were deprotected with HCl–MeOH to afford 11’ and 12’,
respectively. The NOESY correlation between H4 and H6 in 12’
was observed, while 11’ showed no correlation between them.
OH
6
1
-amide group into an active conformation to bind with OX R.
The 14-hydroxy group could lower the activity of the 6β-amide
isomers by the interaction of 14-hydroxy group with 6β-amide
group. Finally, the differences of the active conformation
HN
6
NHMe
1
between OX R and KOR were proposed, which are expected to
4
HH
NOESY
be a useful guide for medicinal chemists to design orexin ligands.
OMe
1
2'
1. Tsujishita, H.; Hirono, S. J. Comput. Aided Mol. Des.
997;11:305–315.
Acknowledgments
2
1
This work was supported by JSPS KAKENHI (Grant-in-Aid for
Young Scientists (B)) Grant 15K16557 (T.S.), (Grant-in-Aid for
Scientific Research (B)) Grant 16H05098 (H.N.), MEXT Grant-
in-Aid for Scientific Research on Innovative Areas, Grant
JP15H05942 “Living in Space”, and TORAY Industries, Inc. IIIS
is also supported by the World Premier International Research
Center (WPI) Initiative, Japan. We thank Professor Shuichi
Hirono (Kitasato University) for generously allowing us to use
CAMDAS program.
References and notes
1
.
Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R.
M.; Tanaka, H.; Williams, S. C.; Richardson, J. A.; Kozlowski, G.
P.; Wilson, S.; Arch, J. R.; Buckingham, R. E.; Haynes, A. C.;