Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2: Propellane derivatives with an amide side chain

Article abstract of DOI:10.1016/j.bmcl.2012.02.082

We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the other hand, although the affinities of the 7-amides decreased compared to the 6-amides, some 7α-amides showed the highest selectivities for the κ receptor among the tested compounds. The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives.

Full text of DOI:10.1016/j.bmcl.2012.02.082

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2775–2779
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of new opioid derivatives with a propellane skeleton and their
pharmacology. Part 2: Propellane derivatives with an amide side chain
Hiroshi Nagase a, , Junko Akiyama a, Ryo Nakajima a, Shigeto Hirayama a, Toru Nemoto a, Hiroaki Gouda b,
⇑
Shuichi Hirono b, Hideaki Fujii a
a Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
b Physical Chemistry for Drug Design, 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 designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the
Received 28 January 2012
Revised 22 February 2012
Accepted 24 February 2012
Available online 2 March 2012
active conformation of the
receptor, and one of the 6b-amides showed higher
although the affinities of the 7-amides decreased compared to the 6-amides, some 7
the highest selectivities for the receptor among the tested compounds. The affinities of 7b-isomers
j
selective agonist nalfurafine. The 6-amides showed high affinities for the
selectivity than nalfurafine. On the other hand,
-amides showed
j
j
a
j
were extremely low, which was postulated to result from the shielding effect of the 7b-amide side chain
against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-
amide side chain in propellane derivatives.
Keywords:
Opioid
Propellane derivative
Shielding effect
Lone electron pair
Ó 2012 Elsevier Ltd. All rights reserved.
Three types of opioid receptors (
l
, d,
j
) are now well established
the j2 subtype for which benzomorphans like (À)-pentazocine
not only by pharmacological studies, but also by molecular biolog-
and bremazocine20,22 are proposed to show high affinity.
ical studies.1 Narcotic addiction is believed to be derived from the
l
receptor type, and therefore the d and
targets for analgesics without addiction. To obtain ideal analgesics
without addiction and other side effects derived from the recep-
j types are promising drug
l
OH
tor, we have synthesized various kinds of naltrexone derivatives
Me
N
N
O
and have reported selective ligands for the j2–8 or d9–13 receptors.
Recently, one of our designed
j selective agonists, nalfurafine
O
O
hydrochloride (TRK-820, Fig. 1),2,3,6,8 was launched in Japan as an
antipruritic for patients undergoing dialysis.6,8 Although many ary-
lacetamide derivatives such as U-50,488H14,15 and U-69,593
· HCl
OH
nalfurafine hydrochloride (TRK-820)
(Fig. 1)16 have been synthesized and developed as
j agonists, all
Cl
of these derivatives were eliminated from clinical trials not only
as analgesics but also as antipruritics because of their serious side
effects like psychotomimetic and aversive reactions.17,18 On the
other hand, nalfurafine has neither aversive nor addictive effects.19
We have been interested in the pharmacological differences be-
tween nalfurafine and arylacetamide derivatives with or without
aversion side effects. We postulated that the differences in pharma-
cological effects between these two classes of compounds may de-
O
O
O
N
Cl
N
Me
Me
N
N
U-50,488H
N
U-69,593
Me
H
OH
N
Me
Me
Me
rive from the differences in their affinities for
j receptor subtypes
(j1 and j3)
20–22 (arylacetamide derivatives: j121,22 and nalfurafine:
j323–27). We were also interested in the pharmacological effects of
OH
OH
bremazocine
pentazocine
⇑
Corresponding author.
E-mail address: nagaseh@pharm.kitasato-u.ac.jp (H. Nagase).
Figure 1. Structures of nalfurafine hydrochloride, U-50,488H, U-69,593, pentazo-
cine, and bremazocine.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.02.082

2776
H. Nagase et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2775–2779
C-ring
17
N
be introduced in the 6- or 7-position of 1, the amide group would
7
C-ring
7
6
OH
17
N
be expected to orient at a position that was closer to the upper side
as compared to that of nalfurafine. Therefore, we attempted to
synthesize propellane derivatives with an amide side chain in the
O
6
O
O
6- or 7-position. Herein, we report the synthesis of more
j selec-
tive propellane derivatives with an amide side chain and their
pharmacologies.
OH
3
naltrexone
HO
3
1
As the 17-cyclopropylmethyl (CPM) group was known to pro-
j
selectivity,30 we synthesized only the derivatives with a
Figure 2. Structures of propellane 129 and naltrexone.
mote
17-CPM substituent. The synthesis of 6-amide derivatives com-
menced with propellane 2 (Scheme 1). Propellane 2 was converted
to methylamines 5 and 6 by reductive amination followed by deb-
enzylation. Obtained methylamines 5 and 6 were treated with acyl
chlorides to provide 7 and 8 and then the O-methyl group in 7 and
8 was removed by boron tribromide treatment.
The 7-amides 18 and 19 were synthesized from propellane 2
(Scheme 2). Condensation of 2 with dimethyl carbonate gave
ketoesters 11 and 12. The keto group in 11 and 12 was removed
by reduction, and then subsequent dehydration and hydrogenation
gave 7-esters 14 and 15 as a diastereomixture. 7-Esters 14 and 15
were alternatively prepared from 13 by reduction using magne-
sium.33 The epimerization of the major 7b-isomer 15 gave the min-
O
H
O
O
N
Me
N
C-ring
O
OH
Figure 3. Proposed active conformation of nalfurafine binding to the
j receptor.
or 7
by ester-amide exchange reaction of 14 and 15 followed by
demethylation. ,b-Unsaturated amides 21 were provided from
the intermediate 13 by the same method shown in Scheme 2
(Scheme 3).
The binding affinities of the prepared propellane derivatives for
the opioid receptors were evaluated with a competitive binding as-
say (Table 1). The assays were performed by a previously reported
procedure.13
All the 6-amide derivatives 9 and 10 showed higher affinities
for all three receptor types than did propellane 1 which lacked
a-isomer 14 in 24% yield. 7-Amides 18 and 19 were prepared
In the course of our synthetic and pharmacological studies with
naltrexone derivatives, we discovered the synthesis of propellane
derivatives.28 In contrast to nalfurafine, the propellane derivative
1 (Fig. 2) lacks an amide side chain, thought to be a crucial struc-
a
tural determinant for binding to the
Surprisingly, 1 showed
agonist activity,30 indicating that the
propellane skeleton would have a potential to bind to the recep-
tor. We also proposed that in its binding to the receptor, nalfura-
j receptor (j address).
j
j
j
fine would acquire an active conformation in which the C-ring
assumes the boat form to orient the 6-side chain toward the upper
side of the C-ring (Fig. 3).4,5,31,32 The 6-keto group in the C-ring of
propellane 1 could therefore exist in a relatively higher position
than that observed for naltrexone (Fig. 2). If an amide group could
the amide side chain. The
was improved as compared to those of nalfurafine and propellane
1. Interestingly, 6b-isomers 10 were more selective over the
receptor than the corresponding 6 -isomers 9. This result with
j selectivity over the l receptor of 10b
j
l
a
the 6b-isomers may be caused by the orientation of the side chain
toward the upper side of the C-ring, as opposed to the orientation
of the side chain in the 6a-isomers. Meanwhile, the affinities of 7-
R1
amide derivatives 18, 19, and 21 were lower than those of the 6-
amide derivatives 9 and 10. Especially, the affinities of 7b-isomers
19 were low and 19b showed almost no interaction with the d and
N
O
6
N
N
Me
i), ii)
j
receptors. On the other hand, 7
amides 21 exhibited somewhat higher affinities for the three
receptor types as compared to the b-isomers 19. The ,b-unsatu-
-isomers 18
selectivities of 18a
a-isomers 18 and a,b-unsaturated
a
MeO
MeO
rated amides 21 showed
except for 18c exhibited
and 18b were higher than those of nalfurafine and 6b-amide 10b.
These outcomes may result from the different orientation of the
amide side chain (Fig. 4). The amide side chain of 18 may be able
l
j
selectivity, whereas the
selectivity. The
a
3 (6α, R1 = Bn)
2
j
4 (6β, R1 = Bn)
iii)
5 (6α, R1 = H)
6 (6β, R1 = H)
to locate in a direction that enhances binding to the
j receptor,
Me
N
R3
whereas that of 21 cannot. The extreme decrease in the affinities
of the 7b-isomer 19 is difficult to explain by an unfavorable orien-
tation of the amide side chain, that is, the side chain is incapable of
N
iv)
O
functioning as the
j address. So, we postulated that the flexible 7b-
side chain could locate over the 17-nitrogen to interfere with the
ionic interaction between the 17-nitrogen and the opioid receptor.
The ionic interaction of the 17-nitrogen, along with a p–p interac-
tion with the phenol ring and formation of a hydrogen bond with
the phenolic hydroxy group are three important processes that
have been identified in opioid ligand–receptor binding.35–37
To confirm our hypothesis, we carried out conformational anal-
yses of three 7-amides 18b, 19b, and 21b using Conformational
Analyzer with Molecular Dynamics And Sampling (CAMDAS) 2.1
program38 (Fig. 5). The benzene ring of the 7b-amide side chain
R2O
7a, 7b (6α, R2 = Me)
Ph
a: R3
b: R3
=
=
8a, 8b (6β, R2 = Me)
O
v)
9a, 9b (6α, R2 = H)
10a, 10b (6β, R2 = H)
Scheme 1. Reagents and conditions: (i) BnMeNH, PhCO2H, p-TsOHÁH2O, PhH reflux;
(ii) NaBH3CN, MeOH, 0 °C, 3: 40%, 4: 25%; (iii) H2, Pd/C, MeOH, rt; (iv) R3COCl, Et3N,
CH2Cl2, 0 °C to rt, 7a: 88% from 3, 7b: 76% from 3, 8a: 77% from 4, 8b: 80% from 4;
(v) BBr3, CH2Cl2, À78 °C to rt, 9a: 70%, 9b: 35%, 10a: 43%, 10b: 56%.

H. Nagase et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2775–2779
2777
O
O
O
7
7
OMe
OMe
OMe
O
i)
iv) or v)
N
ii), iii)
N
N
2
MeO
MeO
MeO
13
11 (7α)
14 (7α)
15 (7β)
vi)
12 (7β)
O
O
7
7
Ph
Ph
n
N
H
N
H
n
vii)
viii)
N
N
MeO
HO
16a-c (7α)
17a-c (7β)
18a-c (7α)
19a-c (7β)
Scheme 2. Reagents and conditions: (i) NaH, CO(OMe)2, 50 °C; (ii) NaBH4, MeOH, 0 °C; (iii) POCl3, pyridine, 60 °C, 61% from 2; (iv) H2, Pd/C, MeOH, rt, 14: 5%, 15: 77%; (v) Mg,
MeOH, rt, 14: 30%, 15: 53%; (vi) LDA, THF, À78 °C, then BHT, 14: 24%, 15: 65% (recovery); (vii) Ph(CH2)nNH2, n-BuLi, THF, À78 °C, 16a (n = 0): 90%, 16b (n = 1): 85%, 16c (n = 2):
99%, 17a (n = 0): 72%, 17b (n = 1): 83%, 17c (n = 2): 65%; (viii) BBr3, CH2Cl2, À78 °C to rt, 18a: 80%, 18b: 88%, 18c: 75%, 19a: 64%, 19b: 83%, 19c: 92%. BHT: 2,6-di-tert-butyl-4-
methylphenol(butylated hydroxytoluene).
Table 1
O
Binding affinities of propellane derivatives 1, 9, 10, 18, 19, 21, and nalfurafine for
opioid receptorsa,b
Ph
N
H
n
Compound
Ki (nM)
Selectivity
d/j
i)
N
13
lc
dd
je
l
/
j
Nalfurafine
1f
9a
0.431
58.2
1.23
2.20
31.9
12.2
79.7
106
51.3
448
44.3
35.0
65.2
121
0.178
17.4
7.10
0.83
16.4
3.43
13.4
19.2
169
108
>1000
641
46.7
72.7
253
2.42
3.34
0.17
2.65
1.95
3.56
5.95
5.52
0.32
0.75
288
25.7
6.24
42.2
3.98
35.3
21.0
RO
9b
20a-c (R = Me)
ii)
10a
10b
18a
18b
18c
19a
19b
19c
21a
21b
21c
21a-c (R = H)
282
Scheme 3. Reagents and conditions: (i) Ph(CH2)nNH2, n-BuLi, THF, À78 °C, 20a
(n = 0): 87%, 20b (n = 1): 80%, 20c (n = 2): 85%; (ii) BBr3, CH2Cl2, À78 °C to rt, 21a:
32%, 21b: quant, 21c: 84%.
g
>1000
>1000
207
>1000
>1000
192
—
—
g
54.1
80.8
112
1.92
h
h
—
—
—
g
453
0.71
0.27
0.47
0.14
in 19b located over the 17-nitrogen to almost completely shield
the lone electron pair of the 17-nitrogen (Fig. 5C). On the other
12.4
33.9
35.9
4.11
4.10
1.63
298
412
hand, the side chain in 7
electron pair of 17-nitrogen (Fig. 5A). The shielding effect of the
side chain in the ,b-unsaturated amide 21b would be insufficient
a-amide 18b would not shield the lone
a
Binding assays were carried out in duplicate (j: cerebellum of guinea pig, l and
a
d: whole brain without cerebellum of mouse).
b
See Ref. 34.
(Fig. 5B). However, the longer the length of the side chain, the low-
er the affinity (phenyl 21a > benzyl 21b > phenethyl 21c). The re-
sults of conformational analyses supported our hypothesis and
indicated that the ionic interaction between the 17-nitrogen and
the opioid receptor would be especially important among the three
known opioid ligand–receptor interactions.35–37 The identification
of the stereospecific shielding effects against the lone electron pair
of the 17-nitrogen would be the foremost significant outcome of
c
[3H] DAMGO was used.
d
[3H] DPDPE was used.
e
[3H] U-69,593 was used.
f
Ref. 30.
g
Selectivity was not calculated because the Ki value for the d receptor was over
1000 nM.
h
Selectivity was not calculated because the Ki value for the
j receptor was over
1000 nM.
the flexible propellane derivatives. Furthermore, the higher
j
showed higher selectivities for the
j receptor than nalfurafine
selectivity of 7 -amides 18a and 18b compared to that of nalfura-
a
and 6b-amide 10b. Among the 7-amides, the affinities of 7b-iso-
mers 19 were extremely low. We postulated that the low affinities
of the 7b-isomers 19 would result from the shielding of the lone
electron pair of the 17-nitrogen conferred by the 7b-amide side
chain. The conformational analysis by CAMDAS also supported this
postulation. This is the first conformational information about the
7-amide side chain in propellane derivatives. These finding affor-
ded important information that may be applied to the design of
new types of opioid ligands.
fine supports the active conformation of nalfurafine for
binding (Fig. 3).
In conclusion, we have synthesized propellane derivatives with
6- or 7-amide side chains based on the concept of an active confor-
mation of nalfurafine. The 6-amide derivatives 9 and 10 showed
j receptor
high affinities for the
selectivity over the
hand, although the affinities of 7-amides 18, 19, and 21 decreased
compared to 6-amides 9 and 10, the 7 -amides 18a and 18b
j
receptor, and 6b-isomer 10b showed higher
j
l
receptor than nalfurafine. On the other
a

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H. Nagase et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2775–2779
Figure 4. Comparison of 3D-alignments of (A) 7a-amide 18b and (B) 7b-amide 19b.
Figure 5. Results of conformational analyses of (A) 7
a
-amide 18b, (B)
a,b-unsaturated amide 21b, and (C) 7b-amide 19b. Structures within 10 kcal/mol of the most stable
conformer were collected.
12. Nagase, H.; Nemoto, T.; Matsubara, A.; Saito, M.; Yamamoto, N.; Osa, Y.;
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Acknowledgments
We acknowledge the financial supports from Shorai Foundation
for Science and Uehara Memorial Foundation. We also acknowl-
edge the Institute of Instrumental Analysis of Kitasato University,
School of Pharmacy for its facilities.
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nomenclature is shown below. However, in this letter we used a tentative

H. Nagase et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2775–2779
2779
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2
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1
3
11
N
O
9
9a
10
Some groups have reported that the
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4
13
12
4a
4b
5
8a
8
HO
6
7
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