(+)-3-[2-(Benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]-octane as potent agonists for the α7 nicotinic acetylcholine receptor

Article abstract of DOI:10.1016/j.bmcl.2004.04.091

A series of 3-substituted 1-azabicyclo[2.2.2]octanes was discovered as the α7 nicotinic acetylcholine (α7) receptor agonists. It was found that (+)-3-[2-(benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]octane (+)-15b has potent agonistic activity for the α7 receptor.

Full text of DOI:10.1016/j.bmcl.2004.04.091

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3781–3784
(+)-3-[2-(Benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]-
octane as potent agonists for the a7 nicotinic acetylcholine receptor
Ryo Tatsumi,* Kohji Seio, Masakazu Fujio, Jiro Katayama, Takashi Horikawa,
Kenji Hashimotoà and Hiroshi Tanaka
Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, 1000 Kamoshida-cho,
Aoba-ku, Yokohama, Kanagawa 227-0023, Japan
Received 28 March 2004; revised 27 April 2004; accepted 28 April 2004
Available online 25 May 2004
Abstract—A series of 3-substituted 1-azabicyclo[2.2.2]octanes was discovered as the a7 nicotinic acetylcholine (a7) receptor agonists.
It was found that (+)-3-[2-(benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]octane (+)-15b has potent agonistic activity for the
a7 receptor.
Ó 2004 Elsevier Ltd. All rights reserved.
Neuronal nicotinic acetylcholine receptors (nAChRs)
are pentameric ligand-gated cation channels, composed
of various combinations of a and b subunits (a2-10, b2-
4). Recent advances in molecular biology suggest that
neuronal nicotinic receptors play important roles in
cognition, schizophrenia, sensory gating, and anxiety.1–5
Although the subtypes which mediate nicotine’s CNS
actions are largely unknown, the distribution and
abundance of the a7 and the a4b2 subtypes in the CNS
suggest these subtypes may be involved in at least some
of these functions.6 Therefore, a7 nicotinic acetylcholine
receptor agonists are thought to be potential pharma-
cological targets.
OMe
OMe
N
O
H
N
O
O
NH
O
N
R
N
N
GTS-21 (1)
2
3
Figure 1. a7 nicotinic acetylcholine receptor agonists.
receptor than for the a7 receptor, and it acts as an
antagonist toward the a4b2 receptor.8 On the other
hand, by screening our library compounds, 1-azabicy-
clo[2.2.2]octane derivative 4 was identified to have
moderate affinity for the a7 receptor. Furthermore,
carbamate derivatives 29 and 310 were also reported as
a7 receptor agonists. We hypothesized that the 1-aza-
bicyclo[2.2.2]octane derivatives, bearing an aromatic
part and a spacer group at the 3-position, may be in-
volved in a7 receptor agonistic activity (Fig. 2).
In recent investigations of the a7 receptor, a number of
compounds were reported as a7 receptor agonists
(Fig. 1). One example is GTS-21 (1), which acts as a
partial agonist at the a7 receptor.7 It has been reported
to be ‘functionally’ selective a7 receptor agonists; how-
ever GTS-21 possesses a higher affinity for the a4b2
Keyword: a7 Nicotinic acetylcholine receptor.
* Corresponding author. Tel.: +81-459634414; fax: +81-459634211;
e-mail: Tatsumi.Ryo@mg.m-pharma.co.jp
In this paper, we describe a synthetic approach and the
SAR of 3-substituted 1-azabicyclo[2.2.2]octane deriva-
tives. We found that (+)-3-[2-(benzo[b]thiophen-2-yl)-2-
oxoethyl]-1-azabicyclo[2.2.2]octane (+)-15b is a potent
agonist for the a7 receptor.
Present address: Frontier Collaborative Research Institute, Tokyo
Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8503, Japan.
à
Present address: Department of Psychiatry, Graduate School of
Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba 260-
8670, Japan.
The synthesis of 3-substituted 1-azabicyclo[2.2.2]octane
derivatives is shown in Scheme 1.11 Ester derivative 4
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.091

3782
R. Tatsumi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3781–3784
f), g)
a)
COOEt
(CH2)n
COOH
aromatic
part
O
spacer
N
12
N
13a (n=0)
O
b)- e)
N
N
13b (n=1), 72%
4
13c (n=2), 8% for 4steps
Figure 2. Synthetic strategy for the a7 nicotinic acetylcholine receptor
agonist.
O
O
S
CH3
h)
(CH2)n
(CH2)n
N
OCH3
N
N
was synthesized by the coupling of 3-hydroxy-1-aza-
bicyclo[2.2.2]octane 5 and benzoyl chloride in the pres-
ence of pyridine. Ether derivatives 8–11 were prepared
by the reaction of 3-hydroxy-1-azabicyclo[2.2.2]octane-
borane complex 6 with arylmethyl chloride using
sodium hydride, and subsequent treatment with 3N-
hydrochloric acid. The enantiomers of 11 were obtained
in the same manner as chiral 5.12
15a (n=0), 42%
15b (n=1), 43%
15c (n=2), 98%
14a (n=0), 97% for 2steps
14b (n=1), 88% for 2steps
14c (n=2), 89% for 2steps
S
i), j)
(CH2)n+1
N
16a (n=0), 81% for 2steps
16b (n=1), 22% for 2steps
16c (n=2), 13% for 2steps
The synthesis of benzo[b]thiophene derivatives is shown
in Scheme 2. Carboxylic acid derivatives 13a,b were
prepared by a previously reported method.13;14 Com-
pound 13c was synthesized from ester 12 in 4 steps.
Compounds 13a–c were treated with SOCl2 to give the
corresponding acid chlorides. Subsequent treatment
with N,O-dimethylhydroxylamine afforded Weinreb
amides 14a–c.
Scheme 2. (a) cHCl, reflux; (b) LiAlH4; (c) SOCl2; (d) NaCN/DMSO;
(e) cHCl, reflux; (f) SOCl2; (g) HNCH3(OCH3)–HCl, Et3N; (h) 2-
Lithiobenzo[b]thiophene, )78 °C; (i) NaBH4; (j) TMSCl, NaI/CH3CN.
Table 1. Binding affinities of 1-azabicyclo[2.2.2]octane derivatives for
the a7 nicotinic acetylcholine receptor
aromatic
Ketone derivatives 15a–c were synthesized from 14a–c
using 2-lithiobenzo[b]thiophene. 15a–c were reduced
with NaBH4 to afford alcohol derivatives, followed by
treatment with NaI/TMSCl to give compounds 16a–c.15
spacer
part
N
Compound No. Spacer
Aromatic part
a7 affinity
(IC50; lmol/L)
Resolution of 15b was accomplished via the
D- or L-
malate salt.16 Enantiomers of 16b were obtained by the
reduction of the enantiomers of 15b.
4
–OCO–
–OCH2–
–OCH2–
–OCH2–
Ph
Ph
2.6
3.7
8
9
10
2-Naphthyl
1-Naphthyl
0.15
0.73
Table 1 summarizes the binding affinity of 3-substituted
1-azabicyclo[2.2.2]octanes for a-Bungarotoxin binding
inhibition.17 The ester derivative 4 had moderate affin-
ity. The ether derivative 8 had almost the same potency
for the a7 receptor as ester derivative 4. The introduc-
tion of an a or b-naphthyl moiety as the aromatic part
dramatically enhanced the a7 receptor binding affinity (9
and 10). Moreover, the replacement of the naphthyl part
with the benzo[b]thiophen-2-yl part, also known as a
bioisostere of naphthyl part, increased the affinity for
the a7 receptor. (S)-11 showed a potent affinity almost
20-fold more than (R)-11.
S
S
S
11
–OCH2–
–OCH2–
–OCH2–
0.059
(R)-11
0.515
(S)-11
0.026
0.76
GTS-21 (1)
The benzo[b]thiophene derivative (S)-11 showed potent
affinity for the a7 receptor; however, this compound
showed poor bioavailability (data not shown). We esti-
mated that this defect might be contributed to the
arylmethyl ether part of compound 11. Thus next, the
conversion of the oxygen atom to a carbon atom was
examined. To investigate the optimum length between
the 1-azabicyclo[2.2.2]octane part and the aromatic part,
the spacer length was changed from one carbon to three
carbons, and the results are shown in Table 2. In this
series, ethylene derivative 16b was observed to have the
most potent affinity. Corresponding ketone analogue
15b reduced the affinity for the a7 receptor. Elongation
(15c, 16c) or reduction (15a, 16a) of the spacer length
resulted in the reduction in affinity for the a7 receptor.
Alkylene analogues 16a–c had a higher affinity than
their corresponding ketone analogues 15a–c.
OH
O
a)
O
44%
N
N
4
5
b)
85%
O
Ar
OH
O
Ar
c)
d)
N
BH3
7
N
BH3
6
N
16-53%
31-69%
8-11
Scheme 1. (a) Benzoyl chloride, pyridine; (b) BH3–THF; (c) NaH,
arylmethyl chloride, DMF; (d) 3N-HCl, acetone.

R. Tatsumi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3781–3784
3783
Table 2. Binding affinities of benzo[b]thiophen-2-yl derivatives
100
90
80
70
60
50
40
30
20
10
0
(+)-15b
(-)-15b
(+)-16b
(-)-16b
GTS-21
S
n
X
N
Compound No.
n
X
a7 affinity
(IC50; lmol/L)
15a
16a
15b
16b
15c
16c
0
0
1
1
2
2
O
0.95
0.11
0.15
0.023
1.7
H2
O
H2
O
1
10
100
1000
Concentrations
(
µ
mol/L)
H2
0.37
Figure 3. Agonistic activity of benzo[b]thiophene-2-yl derivatives for
the a7 nicotinic receptor by electrophysiological measurements of the
a7 nicotinic receptor-mediated inward current in PC12 cells.
Next, we evaluated the pharmacokinetics on the com-
pounds 15b, 16a, and 16b, which have potent or modest
affinity for the a7 receptor. Methylene analogue 16a was
not detected in the rat plasma (30 mg/kg, p.o.); however,
two carbon analogues 15b (Cmax; 270 ng/mL, 30 mg/kg,
p.o.) and 16b (Cmax; 450 ng/mL, 30 mg/kg, p.o.) showed
modest PK profile.
(benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo-[2.2.2]-
octane (+)-15b has potent agonistic activity for the a7
receptor. (+)-15b would be a useful tool to investigate
the pharmacophore of the a7 nicotinic acetylcholine
receptor.
The enantiomers of selected compounds (15b and 16b)
were synthesized and evaluated for the a7 binding
affinities (Table 3). A comparison of the enantiomers
of 15b confirmed that (+)-15b was slightly preferred
over ())-15b. On the other hand, ethylene analogue
())-16b was conversely 3-fold more potent than (+)-
16b.
Acknowledgements
The authors would like to thank Dr. M. Arita and Dr.
K. Adachi for their helpful discussions and comments
during the preparation of the manuscript.
Finally, agonistic activities of these four compounds
(each enantiomer of 15b and 16b) were evaluated by
electrophysiological measurement of the a7 receptor
mediated response using PC12 cells. The assay was as-
sessed by the measurement of relative inward current
towards 10 mmol/L choline in PC12 cells.18 Figure 3
shows the agonistic activities of each enantiomer and
GTS-21 (1). The results indicate that neither ())-15b nor
())-16b show agonistic activity. (+)-16b showed slight
agonistic activity at 100 lmol/L, however this was
abolished at 1000 lmol/L. (+)-15b showed dose-depen-
dent agonistic activity, which was more potent than
GTS-21 (1) at lower concentrations. Consequently, (+)-
15b was the most potent agonist in this evaluation.
References and notes
1. Zarei, M.; Radcliffe, K. A.; Chem, D.; Patrick, J. W.;
Dani, J. A. Neuroscience 1999, 88, 755–764.
2. Franzier, C. J.; Buhler, A. V.; Weiner, J. L.; Dunwiddie, T.
V. J. Neurosci. 1998, 18, 8228–8235.
3. Radcliffe, K. A.; Dani, J. A. J. Neurosci. 1998, 18, 7075–
7083.
4. Stevens, K. E.; Kem, W. R.; Mahnir, V. M.; Freedman, R.
Psychopharmacology 1998, 136, 320–327.
5. Adler, L. E.; Olincy, A.; Waldo, M.; Harris, J. G.; Griffith,
J.; Stevens, K.; Flach, K.; Nagamoto, H.; Bickford, P.;
Leonard, S.; Freedman, R. Schizophrenia Bull. 1998, 24,
189–202.
6. Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem.
1997, 40, 4169–4194.
In summary, we have identified the potent a7 receptor
agonists. We showed that in this series, (+)-3-[2-
7. Nanri, M.; Miyake, H.; Murakami, Y.; Matsumoto, K.;
Watanabe, H. Jpn. J. Pharmacol. 1998, 78, 463–469.
8. Meyer, E. M.; Kuryatov, A.; Gerzanich, V.; Lindstrom, J.;
Papke, R. L. J. Pharmacol. Exp. Ther. 1998, 287, 918–
925.
Table 3. Binding affinities of chiral benzo[b]thiophene-2-yl derivatives
S
9. Macor, J. E.; Wu, E. WO 97/30998.
*
10. Mullen, G.; Napier, J.; Balestra, M.; DeCory, T.; Hale,
G.; Macor, J.; Mack, R.; Loch, J., III; Wu, E.; Kover, A.;
Verhoest, P.; Sampognaro, A.; Phillips, E.; Zhu, Y.;
Murray, R.; Griffith, R.; Blosser, J.; Gurley, D.; Mac-
hulskis, A.; Zongrone, J.; Rosen, A.; Gordon, J. J. Med.
Chem. 2000, 43, 4045–4050.
X
N
Compound No.
X
a7 affinity
(IC50; lmol/L)
(+)-15b
())-15b
(+)-16b
())-16b
O
0.13
0.17
0.065
0.22
1
11. All novel compounds gave satisfactory H NMR and MS
O
data in full agreement with their proposed structures.
12. Langlois, M.; Meyer, C.; Soulier, J. L. Synth. Commun.
1992, 22, 1895–1911.
H2
H2

3784
R. Tatsumi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3781–3784
13. Kato, M.; Ito, K.; Nishino, S.; Yamakuni, H.; Takasugi,
H. Chem. Pharm. Bull. 1995, 43, 1351–1357.
14. Orlek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S. G.;
Hadley, M. S., et al. J. Med. Chem. 1991, 34, 2726–2735.
15. Storner, E. J.; Cothron, D. A.; Balmer, M. K.; Roden, B.
A. Tetrahedron 1995, 51, 11043–11062.
essential medium (DMEM) for 1–2 days. The membrane
currents were measured by nystatin-perforated patch
recording19 in an external solution of the following
composition (mM): NaCl, 150; KCl, 5; MgCl2, 1; CaCl2,
2;
D-glucose, 10; HEPES, 10. The pH of the external
solution was adjusted with Tris-base to 7.4. Application of
choline (10 mM), a full agonist at the a7 nicotinic receptor,
induced a rapidly desensitizing inward current in 19% of
the PC12 cells tested (N ¼ 105). The choline-induced
rapidly desensitizing current was blocked by a 1 nM of
methyllycaconitine, an antagonist at the a7 nicotinic
receptor, suggesting that the choline-induced inward
current is mediated by the a7 nicotinic receptor.
16. Absolute configurations of enantiomeric 15b and 16b were
not determined.
17. All data in the tables are the mean of two experiments.
18. Intrinsic activities of test compounds for the a7 nicotinic
receptor were investigated by electrophysiological mea-
surement of a7 nicotinic receptor-mediated inward current
in PC12 cells. PC12 cells were plated in collagen-coated
culture dishes in Dulbecco’s modified Eagle’s minimal
19. Akaike, N.; Harada, N. Jpn. J. Physiol. 1994, 44, 433–473.