Synthesis of pyrrolomorphinan derivatives as κ opioid agonists

Article abstract of DOI:10.1016/j.bmcl.2010.07.035

We synthesized pyrrolomorphinan derivatives 6, 7, and 9 to examine whether the pyrrole ring would be an accessory site in the κ opioid receptor selective antagonist, nor-binaltorphimine. Derivative 6 had an α,β-unsaturated ketone substituent that strongly bound to the κ receptor. The compound with the highest κ receptor selectivity, 6e, produced a dose-dependent antinociceptive effect in the mouse acetic acid writhing test. However, derivatives 7 and 9, which did not have α,β-unsaturated ketone substituents, showed less κ receptor selectivity than compound 6. Based on structure-activity relationships, we proposed that these compounds adopted active structures for κ selective agonist activity. The pyrrole ring would not function as an accessory site, but the ability of the side chain on the pyrrole ring to localize above the C-ring appeared to confer κ selective agonist activity. These results will promote the design of novel κ agonists.

Full text of DOI:10.1016/j.bmcl.2010.07.035

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5035–5038
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of pyrrolomorphinan derivatives as
j opioid agonists
Hideaki Fujii a, Yoshihiro Ida a, Shinichi Hanamura a, Yumiko Osa a, Toru Nemoto a, Mayumi Nakajima b,
Ko Hasebe b, Kaoru Nakao b, Hidenori Mochizuki b, Hiroshi Nagase a,
*
a School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
b Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1, Tebiro, Kamakura 248-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We synthesized pyrrolomorphinan derivatives 6, 7, and 9 to examine whether the pyrrole ring would be
Received 19 June 2010
Revised 8 July 2010
Accepted 9 July 2010
Available online 13 July 2010
an accessory site in the
a
j
opioid receptor selective antagonist, nor-binaltorphimine. Derivative 6 had an
,b-unsaturated ketone substituent that strongly bound to the receptor. The compound with the high-
receptor selectivity, 6e, produced a dose-dependent antinociceptive effect in the mouse acetic acid
,b-unsaturated ketone substituents,
receptor selectivity than compound 6. Based on structure–activity relationships, we pro-
posed that these compounds adopted active structures for selective agonist activity. The pyrrole ring
would not function as an accessory site, but the ability of the side chain on the pyrrole ring to localize
j
est
j
writhing test. However, derivatives 7 and 9, which did not have
showed less
a
j
Keywords:
Opioid
Pyrrolomorphinan
Accessory site
Address site
j
above the C-ring appeared to confer
of novel agonists.
j
selective agonist activity. These results will promote the design
j
Ó 2010 Elsevier Ltd. All rights reserved.
Morphine is used for the management of severe pain, like that
experienced in cancer or postoperatively. However, morphine also
has adverse effects, including dependence, constipation, and respi-
ratory depression. Intense efforts have been focused on obtaining
an ideal analgesic without the morphine-like side-effects; however,
this goal remains elusive. In 1984, a landmark investigation1 with
OH
OH
N
N
N
H
O
O
OH HO
the irreversible
phine-like side-effects would be derived from the
from the d and receptors. This has driven medicinal chemists to fo-
cus on the properties of d or agonists. Recently, a novel, j selective
l
antagonist, b-funaltrexamine, showed that mor-
nor-BNI
l
receptor, not
OH
j
N
j
X
agonist, TRK-820 (nalfurafine hydrochloride),2,3 which produced
neither preferential nor aversive effects, was developed and
launched in Japan as an antipruritic for hemodialysis patients. Nalf-
O
OH
OH
N
O
N
urafine hydrochloride was rationally designed from the
j selective
antagonist, nor-binaltorphimine (nor-BNI),4,5 based on the ‘mes-
sage-address’ concept6–8 and the ‘accessory site’ hypothesis.9,10 In
the drug design, a potential accessory site was removed, because it
couldhaveinterfered withthe inducedfit necessary foreliciting ago-
nist activity; conversely, a potential address site was retained, be-
cause it was important for opioid receptor type selectivity (Fig. 1).
This led to the successful synthesis of nalfurafine. However, it re-
mains unclear whether the pyrrole moiety could be an accessory site
in nor-BNI. Clarification of the accessory site would provide useful
O
Me
O
OH
Nalfurafine
Figure 1. Drug design of
antagonist, nor-BNI. A potential accessory site and a potential address site are
indicated in red and blue, respectively.
j selective agonist, nalfurafine from the j selective
information in the design of novel
j selective agonists or antago-
nists. Therefore, in this study, we synthesized the pyrrolomorphinan
derivative, 111–14 to examine whether the pyrrole ring could be an
accessory site (Fig. 2). Herein, we report synthesis of the pyr-
rolomorphinan derivative 1 and its pharmacology.
Abbreviations: nor-BNI, nor-binaltorphimine; CSA, camphorsulfonic acid;
KHMDS, potassium hexamethyldisilazide; SAR, structure–activity relationship.
* Corresponding author. Tel.: +81 3 5791 6372; fax: +81 3 3442 5707.
E-mail address: nagaseh@pharm.kitasato-u.ac.jp (H. Nagase).
Pyrrolomorphinan derivatives were synthesized from the nal-
trexone methyl ether (2)15–17 (Scheme 1), to make variations of 6,
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.035

5036
H. Fujii et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5035–5038
OH
OH
N
OH
N
N
a)
N
R
N
CHO
N
R
O
O
O
Me
Me
Me
OH
OMe
OR'
1
4
8a-b (R'=Me)
b)
Figure 2. Synthesized pyrrolomorphinan derivative 1. A potential address site is
9a-b (R'=H)
indicated in blue.
Scheme 2. Reagents and conditions: (a) RCH2SO2(1-phenyl-1H-tetrazol-5-yl),
KHMDS, THF, ꢀ78 °C to rt, 86–91%; (b) BBr3, CH2Cl2, rt, 61%.
OH
OH
N
N
a), b) or c)
BNI. Derivative 6e, which was the most selective for the
j receptor,
O
N
R
was evaluated for agonist activity in the mouse acetic acid writhing
assay. We found that, when compound 6e was administered sub-
cutaneously, it induced a dose-dependent antinociceptive effect
(Fig. 3) with an ED50 value of 5.87 mg/kg. This indicated that 6e
O
O
Me
OMe
OMe
2
3 (R=H)
d)
N
was a
in the pyrrolomorphinan derivatives could not be an accessory site.
All the ,b-unsaturated ketone derivatives 6a–e had a longer ad-
j receptor agonist. This result suggested that the pyrrole ring
4 (R=CHO)
a
OH
N
dress site than nalfurafine; in contrast, the olefin derivative 9a pos-
sessed an address site the same length as that in nalfurafine.
Moreover, a heteroaromatic ring, like pyrrole, had been previously
applied as a bioisostere with amide functionality.23 Therefore, we
e)
R
O
O
Me
OR'
expected that the olefin derivatives 9a, b would bind to the
receptor with higher selectivity and affinity than the ,b-unsatu-
rated ketone derivatives 6a–e. However, contrary to our expecta-
tion, compound 9a was not selective for the receptor, and its
j
5a-e (R'=Me)
a
f)
6a-e (R'=H)
j
binding affinity was eightfold weaker than that of compound 6c.
The only structural difference between compounds 6 and 9 was
the presence or absence of the ketone moiety. The selectivity for
OH
N
g)
R
N
6a
the
j
receptor over the
l
receptor of the saturated ketone deriva-
,b-unsatu-
O
Me
O
(R=phenethyl)
tive 7 was also lower than that of the corresponding
a
rated ketone derivative 6a. These results could not be explained
by the message-address concept, where the length of the address
site plays an important role in receptor type selectivity. We re-
cently reported a putative active conformation of nalfurafine;24–
OH
7
Scheme 1. Reagents and conditions: (a) 2,2-diethoxyethanamine, CSA, DMF,
benzene, reflux, 27%; (b) NaH, MeI, DMF, rt, 81%; (c) N-methyl-2,2-dimethoxye-
thanamine, CSA, DMF, benzene, reflux, 65%; (d) POCl3, DMF, 0 °C, 85%; (e)
RC(@O)CH2P(@O)(OMe)2, NaH, THF, 50 °C, 28–95%; (f) BBr3, CH2Cl2, rt, 31–85%;
(g) H2, 10% Pd/C, MeOH, rt, 83%.
26
we proposed that nalfurafine would adopt this conformation
to bind to the
tion, the C-ring in nalfurafine was in the boat conformation and the
amide side chain ( address) was localized above the C-ring. This
j receptor (Fig. 4). In the proposed active conforma-
j
hypothesis was supported both by the structure–activity relation-
ship (SAR) in nalfurafine derivatives24,25 and by conformational
analyses26 with the CAMDAS software program.27 Based on the
plausible active conformation of nalfurafine and the observed
SAR in pyrrolomorphinan derivatives 6, 7, and 9 (Table 1), we
which has an
a,b-unsaturated ketone substituent. Treatment of 2
with 2,2-diethoxyethanamine in the presence of camphorsulfonic
acid (CSA)13 and subsequent N-methylation gave pyrrolomorphinan
3, but the yield of this two-step procedure was low (22%). The use of
N-methyl-2,2-dimethoxyethanamine instead of 2,2-diethoxyethan-
amine gave compound 3 directly from 2 and improved the yield
(65%). A Vilsmeier–Haack formylation18 of compound 3 gave the
50-formyl derivative 4 in 85% yield, along with a 40-formyl derivative
(14%). A Horner–Wadsworth–Emmons reaction was performed on
compound 4 with acylmethylphosphonate19 to afford compounds
5a–e; these were then converted to compounds 6a–e by O-demeth-
ylationwith BBr3. A catalytichydrogenation of the enone 6a afforded
compound 7, with a saturated ketone side chain (Scheme 1). To syn-
developed the working hypothesis that the
derivatives 6a–e might adopt the active structures of 11a–e to
achieve selective agonist activity (Fig. 5). We conjectured that
the ,b-unsaturated ketone 6 could adopt the structure of the
a,b-unsaturated ketone
j
a
iminium species 10 due to the electron withdrawing ketone func-
tionality. In contrast, compounds 7 and 9 would not be able to
adopt such iminium species, because the saturated ketone deriva-
tive 7 lacks the conjugation between the pyrrole ring and ketone
moiety, and the olefin derivative 9 lacks the electron withdrawing
ketone functionality. The iminium species 10a–e could be con-
verted to the plausible active structures of 11a–e owing to the
equilibriums between 10a–e and 11a–e. To confirm this working
hypothesis, we attempted to trap the proposed active structures
11a–e by acetylation; we used the formyl derivative 4 as a model
compound. After intense investigation to optimize the acetylation
conditions, 4 was treated with a solvent amount of Ac2O in the
presence of CSA (2 equiv) at 50 °C (disappearance of the starting
material 4 was observed by TLC analysis). A subsequent aqueous
workup gave crude compounds including compounds 13 and 14
thesize other pyrrolomorphinan derivatives, we performed
a
Kocienski-modified Julia olefination20,21 of the formyl derivative 4
and a subsequent O-demethylation. This afforded derivatives 9a, b
with an olefin moiety (Scheme 2).
The binding affinities of the synthesized compounds 6, 7, and 9
were evaluated with a competitive binding assay22 (Table 1). All
the
the
a
j
,b-unsaturated ketone derivatives 6a–e strongly bound to
receptor. Among these derivatives, compound 6c showed
the strongest binding affinity, with a twofold weaker affinity than
that of nalfurafine and a twofold stronger affinity than that of nor-

H. Fujii et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5035–5038
5037
Table 1
Binding affinities of pyrrolomorphinan derivatives 6, 7, and 9 for opioid receptorsa
OH
OH
OH
N
N
N
R
N
N
N
R
O
O
O
Me
Me
Me
O
O
OH
OH
OH
Ph
6a-e
7
9a-b
Ph
a: R =
a: R =
b: R =
Ph
b: R =
c: R =
Ph
O
d: R =
e: R =
Me
Compound
Ki (
j
) (nM)b
Ki (l
) (nM)c
Ki (d) (nM)d
Selectivity
l/
j
d/j
Nalfurafine
nor-BNI
6a
6b
6c
6d
6e
7
9a
0.225
0.861
0.935
1.13
0.467
1.15
1.24
0.342
3.79
0.582
28.2
6.89
6.58
3.76
6.20
96.5
29.3
1.73
2.08
3.74
1.47
3.55
1.59
NDe
6.58
2.6
33
7.4
5.8
8.1
5.4
429
34
1.9
1.8
8.0
1.3
2.9
4.6
15.0
12
0.548
1.76
5.85
1.6
0.5
0.8
—
0.9
9b
7.38
a
b
c
Binding assay was carried out in duplicate using homogenate of guinea pig brain (
[3H] U-69593 was used.
j: cerebellum, l and d: forebrain).
[3H] DAMGO was used.
d
e
[3H] NTI was used.
ND: The Ki value was not determined because the IC50 value was over 1000 nM.
1H NMR spectra, six singlets at 2.00, 3.80, 4.07, 5.52, 6.53, and
9.47 ppm and a doublet at 4.55 ppm were observed, consistent
with the structure of compound 13. Moreover, four characteristic
signals were detected, including three singlets at 5.51, 5.99, and
7.69 ppm and a doublet at 4.52 ppm. The three singlets and a dou-
blet would represent the 5-proton, vinylic protons of a 3-pyrroline
ring, an enol acetate moiety, and a 9-methine proton, respectively.
The doublet at 4.52 ppm suggested the production of compound
14, and not compound 12, because acylation of a 14-hydroxy group
generally induces a downfield shift of the 9-methine proton signal
from approximately 3.2 ppm to approximately 4.5 ppm. The mass
spectrometry spectra indicated a peak at m/z = 505, which would
stem from compound 15 derived from 14 by fragmentation; this
also supported the structure of 14. However, an attempt to isolate
compound 14 failed, due to its instability.28–40 These outcomes
Figure 3. Antinociceptive effect of compound 6e in the mouse acetic acid writhing
test. p <0.025 versus vehicle-treated group.
*
suggested that a,b-unsaturated ketone derivatives 6a–e could pro-
duce the iminium species 10, which could then be converted to the
active structures 11a–e. Taken together, our results suggested that
the pyrrole ring in the pyrrolomorphinan derivatives 6, 7, and 9
O
H
N
O
would not function as an accessory site, however the
that is, the side chain on the pyrrole ring localized above the C-ring
may play a key role in conferring selective agonist activity.
j address,
Me
H
O
N
C-ring
j
O
In conclusion, we synthesized pyrrolomorphinan derivatives 6,
7, and 9 to confirm whether the pyrrole ring might be an accessory
OH
site in the
b-unsaturated ketone derivatives 6a–e strongly bound to the
receptor. Moreover, the most selective for the receptor, com-
j selective antagonist, nor-BNI. We found that a,
j
Figure 4. Proposed active conformation of nalfurafine.
j
pound 6e, produced a dose-dependent antinociceptive effect in
mice. Based on the SAR analysis of the synthesized compounds, a
(Fig. 6). IR spectra of the crude products showed a sharp band at
1761 cmꢀ1, which suggested the presence of enol acetate. In the
hypothetical active structure was proposed for conferring
j

5038
H. Fujii et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5035–5038
R
Me
N
OH
OH
N
OH
O
N
N
R
R
OH
N
N
O
O
O
Me
Me
O
OH
OH
OH
6a-e
10a-e
11a-e
Figure 5. Hypothetical active structure 11 and plausible mechanism from 6 to 11.
10. Fujii, H.; Narita, M.; Mizoguchi, H.; Hirokawa, J.; Kawai, K.; Tanaka, T.; Tseng, L.
F.; Nagase, H. Bioorg. Med. Chem. Lett. 2004, 14, 4241.
11. Although some pyrrolomorphinan derivatives have already been synthesized,
their detailed pharmacological profiles have not yet been reported. See the
Refs. 12–14.
12. Kotick, M. P.; Leland, D. L.; Polazzi, J. O. J. Med. Chem. 1981, 24, 1445.
13. Portoghese, P. S.; Nagase, H.; Lipkowski, A. W.; Larson, D. L.; Takemori, A. E. J.
Med. Chem. 1998, 31, 836.
14. Schwarz, P.; Schmidhammer, H. Heterocycles 1994, 39, 35.
15. Uwai, K.; Uchiyama, H.; Sakurada, S.; Kabuto, C.; Takeshita, M. Bioorg. Med.
Chem. 2004, 12, 417.
OAc
Me
N
OAc
9
O
N
N
N
N
14
N
CHO
O
O
Me
OMe
OMe
12
13
OAc
OAc
9
16. Nemoto, T.; Fujii, H.; Sato, N.; Nagase, H. Tetrahedron Lett. 2007, 48, 7413.
17. Nagase, H.; Watanabe, A.; Harada, M.; Nakajima, M.; Hasebe, K.; Mochizuki, H.;
Yoza, K.; Fujii, H. Org. Lett. 2009, 11, 539.
14
HO
OAc
OAc
N
N
O
O
Me
Me
18. Jones, G.; Stanforth, S. P. Org. React. 1997, 49, 1.
19. Wakita, H.; Matsumoto, K.; Yoshiwara, H.; Hosono, Y.; Hayashi, R.; Nishiyama,
H.; Nagase, H. Tetrahedron 1999, 55, 2449.
OMe
OMe
20. Blakemore, P. R.; Cole, W. J.; Kocienski, P.; Morley, A. Synlett 1998, 26.
21. Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
22. Fujii, H.; Ogawa, R.; Ohata, K.; Nemoto, T.; Nakajima, M.; Hasebe, K.;
Mochizuki, H.; Nagase, H. Bioorg. Med. Chem. 2009, 17, 5983.
23. Ciapetti, P.; Giethlen, B. In The Practice of Medicinal Chemistry; Wermth, C. G.,
Ed., 3rd ed.; Elsevier: Amsterdam, 2008; pp 290–342.
24. Nemoto, T.; Fujii, H.; Narita, M.; Miyoshi, K.; Nakamura, A.; Suzuki, T.; Nagase,
H. Bioorg. Med. Chem. Lett. 2008, 18, 6398.
25. Nagase, H.; Watanabe, A.; Nemoto, T.; Yamaotsu, N.; Hayashida, K.; Nakajima,
M.; Hasebe, K.; Nakao, K.; Mochizuki, H.; Hirono, S.; Fujii, H. Bioorg. Med. Chem.
Lett. 2010, 20, 121.
26. Yamaotsu, N.; Fujii, H.; Nagase, H.; Hirono, S. Bioorg. Med. Chem. 2010, 18, 4446.
27. Tsujishita, H.; Hirono, S. J. Comput. Aided Mol. Des. 1997, 11, 305.
28. Although compounds with an aminomethanol moiety are generally labile,
some natural compounds are known to possess this moiety; for example,
fawcettimine, yuzurimine, and vincamine, and some medicines like anoretic
mazindol. See the Refs. 29 and 30.
14
15
Figure 6. Structures of compounds 12–15.
selective agonist activity. The pyrrole ring in the compounds could
not function as an accessory site, however, the ability of the side
chain on the pyrrole ring to localize above the C-ring may have
played a key role in conferring
study provided useful information for the further design of novel
agonists.
j selective agonist activity. This
j
Acknowledgments
´
29. Hudlicky, T.; Reed, J. W. In The Way of Synthesis, Evolution of Design and Methods
We acknowledge financial support from the Shorai Foundation
for Science and the Uehara Memorial Foundation. We also
acknowledge the Institute of Instrumental Analysis of Kitasato Uni-
versity, School of Pharmacy, for its facilities.
for Natural Products; Wiley-VCH: Weinheim, 2007. pp. 574, 604, and 760.
30. Bacon, E. R.; Chatterjee, S.; Williams, M. In Comprehensive Medicinal Chemistry
II; Williams, M. Vol. Ed.; Taylor, J. B.; Triggle, D. J. Eds-in chief; Elsevier:
Amsterdam, 2007; p 154.
31. Some recent examples of natural compounds that have an aminomethanol
moiety include the followings. See the Refs. 32–38 for the isolation, and the
Refs. 39 and 40 for the total synthesis.
32. Chen, F.-Z.; Chen, D.-L.; Chen, Q.-H.; Wang, F.-P. J. Nat. Prod. 2009, 72, 18.
33. Kubota, T.; Suzuki, T.; Ishiuchi, K.; Kuhara, T.; Kobayashi, J. Chem. Pharm. Bull.
2009, 57, 504.
34. Zhang, Y.; Di, Y.-T.; Mu, S.-Z.; Li, C.-S.; Zhang, Q.; Tan, C.-J.; Zhang, Z.; Fang, X.;
Hao, X.-J. J. Nat. Prod. 2009, 72, 1325.
35. Zhang, Z.-J.; Rao, G.-W.; Hou, X.-R.; Li, C.-P.; Shan, W.-G. Helv. Chim. Acta 2009,
92, 1562.
36. Zaima, K.; Hirata, T.; Hosoya, T.; Hirasawa, Y.; Koyama, K.; Rahman, A.;
Kusumawati, I.; Zaini, N. C.; Shiro, M.; Morita, H. J. Nat. Prod. 2009, 72, 1686.
37. Zhang, C.-R.; Liu, H.-B.; Dong, S.-H.; Zhu, J.-Y.; Wu, Y.; Yue, J.-M. Org. Lett. 2009,
11, 4692.
38. Hirasawa, Y.; Miyama, S.; Hosoya, T.; Kiyama, K.; Rahman, A.; Kusumawati, I.;
Zaini, N. C.; Morita, H. Org. Lett. 2009, 11, 5718.
39. Zaed, A. M.; Swift, M. D.; Sutherland, A. Org. Biomol. Chem. 2009, 7, 2678.
40. Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 11, 5554.
References and notes
1. DeLander, G. E.; Portoghese, P. S.; Takemori, A. E. J. Pharmacol. Exp. Ther. 1984,
231, 91.
2. Nagase, H.; Hayakawa, J.; Kawamura, K.; Kawai, K.; Takezawa, Y.; Matsuura, H.;
Tajima, C.; Endo, T. Chem. Pharm. Bull. 1998, 46, 366.
3. Kawai, K.; Hayakawa, J.; Miyamoto, T.; Imamura, Y.; Yamane, S.; Wakita, H.;
Fujii, H.; Kawamura, K.; Matsuura, H.; Izumimoto, N.; Kobayashi, R.; Endo, T.;
Nagase, H. Bioorg. Med. Chem. 2008, 16, 9188.
4. Portoghese, P. S.; Lipkowski, A. W.; Takemori, A. E. J. Med. Chem. 1987, 30, 238.
5. Portoghese, P. S.; Sultana, M.; Nagase, H.; Takemori, A. E. J. Med. Chem. 1988, 31,
281.
6. Portoghese, P. S.; Sultana, M.; Takemori, A. E. J. Med. Chem. 1990, 33, 1714.
7. Portoghese, P. S. Trends Pharmacol. Sci. 1989, 10, 230.
8. Portoghese, P. S. J. Med. Chem. 1991, 34, 1757.
9. Nogrady, T. In Medicinal Chemistry A Biochemical Approach; Oxford University
Press: New York, 1985; pp 68–69.