2-(Arylmethyl)-3-substituted quinuclidines as selective α7 nicotinic receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2005.02.045

A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as α7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the α7 over other nAChRs (e.g., the α4β2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at α7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-8l), has potent agonistic activity for the α7 nAChR (EC₅₀ = 33 nM, I_max = 1.0), at concentrations below those that result in desensitization.

Full text of DOI:10.1016/j.bmcl.2005.02.045

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2073–2077
2-(Arylmethyl)-3-substituted quinuclidines as selective a7
nicotinic receptor ligands
Anatoly Mazurov,* Jozef Klucik, Lan Miao, Teresa Y. Phillips, Angela Seamans,
Jeffrey D. Schmitt, Terry A. Hauser, Raymond T. Johnson, Jr. and Craig Miller
Targacept, Inc., Medicinal Chemistry, 200 East First Street, Suite 300, Winston-Salem, NC 27101, USA
Received 5 January 2005; revised 11 February 2005; accepted 16 February 2005
Available online 19 March 2005
Abstract—A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as a7 neuronal nicotinic acetylcholine receptor
(nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the a7 over other nAChRs (e.g.,
the a4b2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at a7. One member of the series, (+)-
N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-8l), has potent agonistic activity for the a7 nAChR (EC50 = 33 nM,
Imax = 1.0), at concentrations below those that result in desensitization.
Ó 2005 Elsevier Ltd. All rights reserved.
The widely distributed and abundant, neuronal acetyl-
choline nicotinic receptors (nAChRs) are involved in a
number of processes, including cognition, neuroprotec-
tion, sensory gating, inflammation, and nociceptive
transmission. Thus, nAChRs are potential therapeutic
targets for a variety of conditions and disorders, such
as schizophrenia, chronic and neurophathic pain, neuro-
degenerative diseases, and cognitive deficits, many of
which represent major unmet medical needs.1 Nicotinic
receptors in the CNS exist as several subtypes, the most
common of which are the a4b2 and a7 subtypes. To cre-
ate an effective nAChR-based R&D strategy, it is impor-
tant to design ligands that selectively interact with
specific receptor subtypes, thus maximizing the thera-
peutic effect and minimizing potentially adverse side ef-
fects. Examples of such selective ligands include the
metanicotine and diazaspirocyclic classes identified by
Targacept.2 Recently, the full agonist AR-R 177793
(3S)-spiro[1-azabicyclo[2.2.2]octane-3,50-oxazolidin]-20-
one, Emax = 96%, EC50 = 21 lM)10 was shown to im-
prove learning and memory in rats by activation of the
a7 subtype.3 In this paper, we describe 2-(arylmethyl)-
3-substituted quinuclidines, a highly selective class of
agonists at the a7 subtype.15
The synthesis of 2-(arylmethyl)-3-substituted quinucli-
dines is shown in Scheme 1. The key intermediate 2-
(arylmethyl)quinuclidin-2-one was prepared by aldol
condensation of quinuclidin-3-one (1) with an aromatic
aldehyde, to afford the enone 2, followed by catalytic
hydrogenation. Further reduction of the ketone 3 with
aluminum isopropoxide resulted in predominantly one
diastereomer, cis alcohol 4, presumably by selective hy-
dride transfer to the least hindered face of the
carbonyl.12 The cis racemate was resolved by condensa-
tion with (S)-2-methoxy-2-phenylacetic acid to yield a
pair of diastereomeric esters, which was separated by
preparative HPLC and hydrolyzed into optically pure
alcohols. The carbonyl moiety of ketone 3 was
converted into amino group by reductive amination in
the presence of a catalytic amount of zinc chloride.13
Major cis amine 6 was separated fromminor trans-dia-
stereomer by HPLC. The racemic amine was then reso-
lved by fractional crystallization of its O,O0-bis-p-
toluoyltartrate salt. Addition of isocyanate to alcohol
4 or amine 6 produced carbamate 5 or urea 7, respec-
tively. Amine 6 was acylated to afford amide 817 and
treated with sulfonyl chloride to obtain sulfonamide 9.
Quinuclidine is a well established pharmacophoric ele-
ment, exemplified in both naturally occurring (e.g., qui-
nine) and synthetic (e.g., azasetrone, benzoclidine)
drugs. Its basic nitrogen, occupying a bridgehead posi-
tion within an azabicyclic system, allocates maximal
electrostatic interaction combined with minimal steric
Keywords: a7 Nicotinic receptor ligands; Quinuclidine.
*
Corresponding author. Tel.: +1 336 480 2179; fax: +1 336 480
2113; e-mail: anatoly.mazurov@targacept.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.02.045

2074
A. Mazurov et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2073–2077
H
N
OH
O
R2
O
O
d
c
O
b
a
O
N
N
N
N
R1
R1
N
R1
R1
3
4
5
2
1
e
R3
H
N
H
N
R4
NH
NH2
R1
g
f
O
O
N
N
N
R1
R1
8
7
6
h
O
H
N
S
R5
O
N
R1
9
Scheme 1. (a) R1CHO, KOH; (b) H2, Pd/C; (c) Al(O-i-Pr)3; (d) R2NCO; (e) HCO2NH4, ZnCl2, NaCNBH3; (f) R3NCO; (g) R4CO2H, Et3N,
(PhO)2P(O)Cl; (h) R5SO2Cl, Et3N.
Table 1. Effect of 2-(pyridine-3-yl)methyl substituent on affinity
demand. Among the quinuclidine derivatives designed
to interact with nAChRs are 2-(pyridylmethyl)quinucli-
dines4 and 3-substituted 1-azabicyclo[2.2.2]octanes.14
The former are moderately selective for a4b2 receptors
(but have activity at a7 and peripheral sites as well),
and the latter, especially 3-(N-arylcarbamoyl)quinucli-
dines,5 interact with a7 nicotinic,6 as well as muscarinic7
Compounds
a7 Affinity Ki (nM)
H
N
O
120
O
N
H
N
O
8
and 5-HT3 receptors. To further define pharmaco-
phoric elements of the a7 binding site, we initiated
40
53
O
N
Br
virtual and synthetic diversification around
a
H
N
combination of 2-position and 3-position substitutions
of the quinuclidine scaffold. The addition of substituents
in position 3 of 2-(pyridylmethyl)quinuclidine produced
compounds with decreased affinity for the a4b2 subtype
and, in some cases, increased affinity for the a7. This ef-
fort relatively quickly revealed the presence, in certain
derivatives, of three pharmacophoric elements: the catio-
nic site (the quinuclidine nitrogen), a hydrogen bond
acceptor at the 3-position, and another hydrogen bond
acceptor at the 2-position (the pyridine ring). Evidence
for this latter interaction can be seen by comparing
derivatives with and without the pyridylmethyl group
in position 2 (Table 1) and fromcomparison of the effect
of various 2-position substituents within a 3-substituent
series (e.g., the carbamates in Table 2). From Table 2, it
is clear that, in position 2 of the quinuclidine, hetero-
arylmethyl groups are favored, over benzyl, and that ste-
ric constraints restrict substitution on the heteroaryl
(pyridine) ring. The pharmacophoric element in position
3 was most amenable to diversification, resulting in the
generation of four classes of ligands: carbamates (Table
3), ureas (Table 4), amides (Table 5), and sulfonamides
(Table 6).16 cis-Configuration is favorable for binding
to the receptor, for example, trans-5a exhibits affinity
with Ki = 405 nM. Within the 3-position substituents,
comparison of aliphatic and aromatic (or heteroaro-
matic) groups (i.e., R2, R3, R4, R5) suggests that p-inter-
action may play a significant role in increasing affinity.
O
O
N
SPh
H
N
O
O
N
7
5
N
O
H
N
O
N
Br
N
O
H
N
O
N
9
SPh
N
Many of synthesized compounds exhibited high affinity
to the a7 nicotinic receptor subtype, as demonstrated by
their inhibition of radiolabeled 3H-methyllycaconitine
binding to rat brain hippocampus receptors,19 with

A. Mazurov et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2073–2077
Table 2. Optimization of 2-arylmethyl moiety
2075
H
N
O
R2
O
N
R1
Compounds
R1
R2
a7 affinity Ki (nM)
5a
5b
Pyridin-3-yl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
4-Bromophenyl
5
29
0.5
8
2-Methoxy-pyridin-5-yl
2-Phenoxy-pyridin-5-yl
3-Methoxy-pyridin-5-yl
5c
5d
>10,000
144
7016
5e
3-Isopropoxy-pyridine-5-yl
Pyridin-2-yl
Pyrimidin-5-yl
5f
5g
>10,000
40
5h
5i
Quinolin-3-yl
Phenyl
10,000
838
5j
5k
4-Methoxyphenyl
4-(Dimethyl-amino)phenyl
4-Fluorophenyl
4-(Methylsulfonyl)-phenyl
Imidazol-1-yl
>10,000
1193 74
263
5l
5m
6778
10
5n
5o
Thien-3-yl
Furan-2-yl
Benzo[b]furan-2-yl
534
234
5p
5q
8388
1748 597
2.3 0.2
(ꢀ)-Nicotine
Methyllycaconitine
Table 3. Carbamates
Table 4. Ureas
H
N
H
N
H
N
O
R2
R3
O
O
N
N
R1
R1
Compounds R1
R2
a7 Affinity Ki
(nM)
Compounds R1
R3
a7 Affinity
Ki (nM)
5a
5r
5s
5t
Pyridin-3-yl 4-Bromophenyl
Pyridin-3-yl 4-Fluorophenyl
Pyridin-3-yl 4-Methoxyphenyl
Pyridin-3-yl Phenyl
5
6
7a
7b
7c
7d
7e
7f
Pyridin-3-yl 4-Bromophenyl
Pyridin-3-yl 3-Bromophenyl
Pyridin-3-yl 2-Methoxyphenyl
Pyridin-3-yl 3-Methoxyphenyl
Pyridin-3-yl 4-Methoxyphenyl
Pyridin-3-yl 2,4-Dimethoxyphenyl
Pyridin-3-yl 4-(Methylthio)phenyl
Pyridin-3-yl 4-Fluorophenyl
Pyridin-3-yl 3-Fluorophenyl
Pyridin-3-yl 3,4-Dichlorophenyl
Pyridin-3-yl 3-(Trifluoromethyl)-
phenyl
9
52
5
30
43
7
5u
5v
5w
5x
Pyridin-3-yl 4-Phenoxyphenyl
Pyridin-3-yl 4-Biphenyl
Pyridin-3-yl Benzyl
50
500
670
37
31
7g
7h
7I
7j
6
74
Pyridin-3-yl 2-Phenylcyclopropyl 103
6
34
7k
91 13
equilibriumconstant ( Ki) values near or below 1 nM.18
High throughput screening indicates that none of the
compounds bound to a4b2 receptors20 with any signifi-
cant affinity (Ki values > 10 lM). Compounds show lit-
tle or no evidence of agonist activity at concentration
100 lM in functional assays of muscle-type receptors
(a1b1cd subtype in human TE671/RD clonal cells), or
ganglion-type receptors (a3b4 subtype in the Shooter
subclone of rat pheochromocytoma PC12cells and in
human SHSY-5Y clonal cells), generating only 1–12%
(human muscle), 1–19% (rat ganglion), and 1–15% (hu-
man ganglion) of nicotineÕs response at these subtypes.
These data indicate selectivity for CNS over PNS nAC-
hRs. Since arylcarbamoyl quinuclidines had been de-
scribed in the literature8 as exhibiting muscarinic
activity, representative compounds (5a,s,t, 8f,l)) were
evaluated for their ability to inhibit [3H]-quinuclidinyl
benzilate binding at muscarinic sites in the human clonal
7l
7m
Pyridin-3-yl 3-Cyanophenyl
Pyridin-3-yl 4-(Dimethylamino)-
phenyl
170
38
7n
7o
7p
7q
7r
Pyridin-3-yl 4-Phenoxyphenyl
Pyridin-3-yl 4-Biphenyl
Pyridin-3-yl Phenyl
16
424 105
16
Pyridin-3-yl 4-Bromobenzyl
Pyridin-3-yl 2-Phenylcyclopropyl
274 131
104
line TE671/RD.21 None of the compounds was able to
inhibit [3H]-quinuclidinyl benzilate binding, indicating
that these compounds do not bind to human M3
receptors.
The a7 nAChR subtype is particularly susceptible to
concentration dependent and rapid desensitization,

2076
A. Mazurov et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2073–2077
Table 5. Amides
adjustment of functional activity and desensitization to
optional levels.11
H
N
R4
In summary, highly potent and selective ligands for the
a7 subtype have been obtained by modification of 2-
(pyridylmethyl)quinuclidine. Three key pharmacophoric
elements have been identified: a basic nitrogen, a hydro-
gen-bond-accepting moiety and second polar region in-
volved in interaction with the receptor via H-bonding.
Electrophysiological data substantiate the therapeutic
potential of amide (+)-8l.
O
N
R1
Compounds R1
R4
a7 Affinity
Ki (nM)
8a
8b
8c
8d
8e
Pyridin-3-yl 4-Bromophenyl
Pyridin-3-yl 3-Bromophenyl
Pyridin-3-yl Phenyl
7
64
52
12
Pyridin-3-yl 4-Fluorophenyl
Pyridin-3-yl 4-(Dimethylamino)-
phenyl
134
Acknowledgements
8f
8g
8h
8i
Pyridin-3-yl 4-(Phenylthio)phenyl
Pyridin-3-yl 1-Methylpyrrol-2-yl
Pyridin-3-yl Thien-3-yl
9
155
790
0.4
Authors are indebted to Professor R. L. Papke (Univer-
sity of Florida) for in vitro functional characterization
of selected compounds.
Pyridin-3-yl 5-Bromothien-2-yl
Pyridin-3-yl 5-(Pyridin-2-yl)-
thien-2-yl
8j
0.7
References and notes
8k
8l
Pyridin-3-yl 5-Iodothien-2-yl
Pyridin-3-yl Benzo[b]furan-2-yl
Pyridin-3-yl Indol-3-yl
0.12 0.03
1
8
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8m
8n
8o
8p
8q
8r
Pyridin-3-yl 1-Methylindol-3-yl
Pyridin-3-yl 1-Hydroxynapht-2-yl
Pyridin-3-yl Styryl
521
1
0.6
5
Pyridin-3-yl a-Methylstyryl
Pyridin-3-yl b-Methylstyryl
87
Table 6. Sulfonamides
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O
S
H
N
R5
O
N
R1
Compounds
R1
R5
a7 Affinity
Ki (nM)
9a
9b
9c
9d
9e
Pyridin-3-yl
Pyridin-3-yl
Pyridin-3-yl
Pyridin-3-yl
Pyridin-3-yl
4-Bromophenyl
Phenyl
8088
418
4-Methoxyphenyl
4-Acetamidophenyl
Benzyl
8919
146
8839
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which creates a special challenge for the pharmacologi-
cal characterization of this receptor.9 Potency and
intrinsic activity values for carbamate (+)-5s
(EC50 = 300 nM; Imax = 0.19) and amide (+)-8l
(EC50 = 33 nM; Imax = 1.0) were determined by measur-
ing current activation in Xenopus oocytes expressing rat
nicotinic receptors. While carbamate (+)-5s is a partial
agonist, amide (+)-8l is a potent full agonist for the a7
receptor, which significantly exceeds the potency of the
known full agonist AR-R17779.10 Higher concentra-
tions of (+)-8l are required to produce residual inhibi-
tion (desensitization) than are required to activate the
receptor. Since the ratio of IC50 to EC50 is approxi-
mately 6, an optimal dose might be found to exhibit in
vivo efficacy of the a7 nicotinic full agonist. The nature
of substituents in positions 2 and 3 of the described
quinuclidine derivatives has an effect on the degree
of both activation and desensitization of the receptor.
Variation of diverse structural fragments allows the

A. Mazurov et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2073–2077
2077
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16. Affinity data are given for racemic compounds; some of
compounds were resolved, however, absolute configura-
tion has not been determined, for example, (+)-8l
(Ki = 0.3 nM) and (ꢀ)-8l (Ki = 41.8 nM).
17. 1H NMR (300 MHz, CD3OD): cis-8l, 1.98–2.42 (m, 5H),
3.40–3.87 (m, 6H), 4.32 (m, 1H), 4.55 (dd, 1H), 7.38 (m,
1H), 7.52 (m, 2H), 7.62 (m, 1H), 7.78 (d, 1H), 7.99 (m,
1H), 8.65 (d, 1H), 8.87 (d, 1H), 9.17 (s, 1H); trans-8l, 1.92–
2.48 (m, 5H), 3.20–3.58 (m, 6H), 3.81 (m, 1H), 4.54 (dd,
1H), 7.39 (m, 1H), 7.55 (m, 3H), 7.72 (m, 2H), 8.00 (d,
1H), 8.47 (d, 1H), 8.6 (s, 1H).
18. Ki Values were determined from one to three competitive
inhibition curves for each compound. Seven to eleven
concentrations of each compound were utilized to define
each inhibition curve with triplicate samples at each
concentration. Where multiple competitive inhibition
curves were available, SEM has been calculated and
provided.
19. Davies, A. R. L.; Hardick, D. J.; Blagbrough, I. S.; Potter,
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