7-Azabicyclo[2.2.1]heptane as a scaffold for the development of selective sigma-2 (σ2) receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2012.04.077

A series of N-substituted 7-azabicyclo[2.2.1]heptanes (12-17 and 22-25) and similarly substituted pyrrolidines (32-36 and 41-44) were synthesized as sterically-reduced, achiral analogs of adamantane- and trishomocubane-derived σ ligands. In vitro competition binding assays against σ receptors revealed that arylalkyl N-substituents conferred selectivity for the σ₂ subtype, while alicyclic or polycarbocyclic substituents imparted high affinity for both subtypes. The σ₂ binding and subtype selectivities of N-arylalkyl-7-azanorbornanes was generally greater than the analogously-substituted pyrrolidines, indicating that steric bulk and conformational restriction around the nitrogen atom are likely important for subtype discrimination.

Full text of DOI:10.1016/j.bmcl.2012.04.077

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4059–4063
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
7-Azabicyclo[2.2.1]heptane as a scaffold for the development of selective
sigma-2 (r2) receptor ligands
Samuel D. Banister a,b, Louis M. Rendina a, Michael Kassiou a,b,c,
⇑
a School of Chemistry, The University of Sydney, NSW 2006, Australia
b Brain and Mind Research Institute, Sydney, NSW 2050, Australia
c Discipline of Medical Radiation Sciences, The University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of N-substituted 7-azabicyclo[2.2.1]heptanes (12–17 and 22–25) and similarly substituted pyr-
rolidines (32–36 and 41–44) were synthesized as sterically-reduced, achiral analogs of adamantane- and
Received 14 March 2012
Revised 11 April 2012
Accepted 16 April 2012
Available online 30 April 2012
trishomocubane-derived
r ligands. In vitro competition binding assays against r receptors revealed that
arylalkyl N-substituents conferred selectivity for the r2 subtype, while alicyclic or polycarbocyclic sub-
stituents imparted high affinity for both subtypes. The r2 binding and subtype selectivities of N-arylal-
kyl-7-azanorbornanes was generally greater than the analogously-substituted pyrrolidines, indicating
that steric bulk and conformational restriction around the nitrogen atom are likely important for subtype
discrimination.
Keywords:
Azanorbornanes
Pyrrolidines
Sigma receptors
CNS
Ó 2012 Elsevier Ltd. All rights reserved.
Structure–activity relationships
More than 35 years after their discovery, sigma (
main widely studied due to their involvement in virtually all major
central nervous system (CNS) diseases.1 Two
receptor subtypes
2, differing in size, ligand selectivity,
r
) receptors re-
The implication of both r receptors subtypes in the pathophy-
siologies of multiple affective disorders, including anxiety, depres-
sion, and schizophrenia, as well as dysfunctions of memory
(Alzheimer’s disease) and movement (Parkinson’s disease), has
r
have been defined, r1 and
r
and anatomical distribution.2,3 The r1 receptor has been cloned
from numerous tissues and species, and its predicted 223 amino
acid sequence shares no homology with any other mammalian pro-
prompted the development of increasingly selective r ligands for
the potential treatment of CNS disorders.1,13 Indeed, many clinical
antidepressants and antipsychotics have demonstrated activity at
tein.4 Primarily,
r
1 receptors reside at the mitochondria-associated
r
receptors at therapeutically-relevant concentrations.14–17 Co-
enoplasmic reticulum membrane (MAM), where their ability to act
as chaperones for type 3 inositol-1,4,5-triphosphate (IP3) receptors
assists the maintenance of Ca2+ homeostasis under conditions of
cellular stress.5,6 However, r1 receptors may undergo unidirec-
tional translocation to the plasmalemma where they modulate
the activity of K+ and Ca2+ channels, as well as other components
of membrane-bound signal transduction.7–9
caine and methamphetamine also interact with
physiologically-relevant concentrations, and there is extensive evi-
dence that receptors are involved in both the toxic and reward-
ing effects of these widely abused stimulants, making receptors a
promising target for the treatment of substance abuse.18–21
Despite the therapeutic utility of receptors, the design of
drugs acting selectively at binding sites remains challenging.
No tertiary structural information is available for either subtype,
ligands is ex-
r receptors at
r
r
r
r
In contrast, the pharmacology of
r
2 receptors remains less well-
r
defined. The r2 receptor has not been cloned, but photoaffinity
studies have suggested it is smaller than the r1 receptor, approx-
imately 21.5 kDa.10 Fluorescent probes have indicated that the
and the structural heterogeneity of known r
treme.22,23 A pharmacophore for the r1 receptor has been pro-
posed and its simplicity allows it to encompass the majority of
r1 ligands, albeit at the expense of predictive utility.22 However,
subcellular localization of r2 receptors resembles that of
r1, with
high concentrations found in mitochondria, endoplasmic reticu-
lum, and plasma membrane.11 It was very recently proposed that
the hitherto unknown identity of the r2 binding site may be pro-
gesterone receptor membrane component 1 (PGRMC1), or a pro-
tein complex thereof.12
no such consensus model exists for
2 ligands are far outnumbered by those with selectivity for
a result, the use of relatively subtype non-selective ligands in
animal models of disease has often obscured the independent roles
of receptor subtypes in such models.
In an effort to delineate the roles of
stance abuse in vivo,24 we sought to develop chemotypes with im-
proved selectivity for each receptor subtype. Our efforts have
r
2 binding, and truly selective
r
r
1. As
r
r
r
1 and r2 receptors in sub-
⇑
Corresponding author.
E-mail address: michael.kassiou@sydney.edu.au (M. Kassiou).
r
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.077

4060
S. D. Banister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4059–4063
focused on the development of increasingly subtype-selective
r
and subsequent methanol quench to provide cubylcarbinol 31.
Parikh–Doering oxidation37 of 31 gave cubanecarboxaldehyde in
comparable yield to the previously reported Swern oxidation.38,39
A series of N-substituted pyrrolidines analogous to azanorborn-
anes 12–16 and 22–25 was also synthesized, as shown in Scheme
receptor ligands based on heterocyclic25–27 and heteropolycyclic
scaffolds,24,28–30 resulting in the generation of several classes of
highly selective r1 ligands with negligible off-target activity.
It was recently reported that deoxygenation of N-arylalkyl-2-
azaadamantan-1-ols (1) to the corresponding N-substituted 2-aza-
adamantanes (2) resulted in improved r1 binding and subtype
selectivity Figure 1. It was anticipated that an analogous transfor-
3, to investigate the
r receptor binding of the simplest possible
heterocyclic subunit of frameworks such as 3 and 4. Thus, pyrrol-
idines 32–36 were prepared by reductive alkylation with the
appropriate benzaldehyde using sodium triacetoxyborohydride.
Coupling suitably substituted arylalkanoic acids with pyrrolidine
using carbonyl diimidazole gave amides 37–40, which were re-
duced by lithium aluminum hydride to give 41, 42, and 44, or bor-
ane in the case of 43.
mation might enhance the well-established in vitro and in vivo
r
receptor-mediated pharmacology of trishomocubanes of type
3.24,31 However, the synthesis of similarly deoxygenated analogs
(4) proved extremely difficult. To further explore the steric contri-
bution of such polycarbocyclic amines to
r receptor binding and
subtype selectivity, a series of ligands was envisaged incorporating
7-azabicyclo[2.2.1]heptane (5), the simplest aza-bridged bicyclic
subunit of compound 4 (Fig. 1).
The synthesized azanorbornanes and pyrrolidines were rou-
tinely converted to their hydrogen oxalate salts, and subjected to
in vitro competition binding assays. Rat brain homogenates were
used as the source of r1 receptors, while PC12 cells were used as
the r2 receptor source. The radioligands [3H](+)-pentazocine and
The synthesis of this series of N-substituted 7-azanorbornanes
is shown in Scheme 1. The amine of trans-4-aminocyclohexanol
(6, Scheme 1) was protected as its benzyl carbamate (7) and the
remaining alcohol converted to the toluenesulfonate (8). Carba-
mate cleavage using hydrogen bromide in glacial acetic acid gave
hydrobromide salt 9. Dissolution of 8 in aqueous ethanol contain-
ing sodium hydroxide furnished transannularly-cyclized 5 as its
free base. The volatility of solid free base 5 necessitated immediate
conversion to the hygroscopic hydrochloride salt, which was puri-
fied by recrystallization. Thus, 5ÁHCl was obtained in 69% yield over
four steps without chromatographic purification, providing several
grams of this common precursor.
The synthesis of N-benzylic 7-azabicyclo[2.2.1]heptanes was
achieved by liberating the hydrochloride salt of 5 with triethyl-
amine in situ, and treating the solution with the appropriate aroyl
chloride. In this way the theoretically-interesting non-planar benz-
amide 10,32,33 and 3-fluorobenzamide 11, were synthesized in
excellent yield. Reduction of the amide group, using lithium alumi-
num hydride in each case, gave the amines 12 and 13 in 88% and
89% yield, respectively. Although this route provided the desired
amines in 79–82% yield over two steps from a common precursor,
a more direct approach was reductive alkylation of 5, using the
appropriately substituted aldehyde and sodium triacetoxyborohy-
dride, to give the desired amines 12–17 in 65–95% yield in a single
step. Azanorbornamides 18–21 were prepared by activating the
appropriate arylalkanoic acids with carbonyl diimidazole followed
by treatment with 5. Reduction of the amide group, to give the de-
sired amines 22–25, was achieved using lithium aluminum hy-
dride (22, 23, and 25), or borane (24).
[3H]DTG were used in the
r1 and r2 receptor assays, respectively.
The Ki values for 12–17, 22–25, 32–36, and 41–44 at r1 and r2
receptor subtypes are shown in Table 1. Selected compounds were
also screened for off-target activity against a panel of 42 common
CNS sites, and generally displayed negligible affinity for all sites
tested (see Table S1 for complete binding data).
N-Benzyl-7-azabicyclo[2.2.1]heptane (12) possessed moderate
affinity for the r2 receptor (Ki = 399 nM), and was essentially de-
void of affinity for the r1 receptor (Ki >10000 nM). Introduction
of a fluorine atom at the 3-position slightly improved r2 affinity
(13, Ki = 251 nM), but had no effect on r1 binding. A 3,4-dime-
thoxy-substitution pattern (14) conferred high affinity for r2
(Ki = 43.1 nM) without altering r1 affinity, resulting in more than
230-fold selectivity for the r2 subtype.
Incorporation of a heteroaromatic ring was detrimental to
binding, with 15 demonstrating only micromolar affinity for both
subtypes. Saturation of the aromatic ring, as in cyclohexyl deriv-
ative 16, resulted in unexpectedly high affinity for both receptor
r
r
r
subtypes (r1 Ki = 22 nM, r2 Ki = 18 nM), and substitution with a
cubane moiety (17) bestowed further improvement to r1 binding
(r1 Ki = 7 nM, r2 Ki = 18 nM).
Extending the distance between the bicyclic amine group and
the aromatic ring introduced significant affinity for r1 receptors.
The simple phenethyl derivative (22) had submicromolar affinity
for the r2 receptor (Ki = 131 nM) but also interacted with the r1
receptor (Ki = 276 nM), and binding at both
was improved by 3-fluorophenethyl substituent (23; r1
Ki = 103 nM, r2 Ki = 29.5 nM). Further homologation of 23 to give
3-(3-fluorophenyl)propyl analog 25 produced a high affinity 2 li-
gand with moderate subtype selectivity (r2 Ki = 11.9 nM, r2
r receptor subtypes
a
The synthesis of the azanorbornane analog containing a cub-
ylmethyl moiety (17) required the preparation of cubanecarboxal-
dehyde (26, Scheme 2). Cyclopentanone was converted to dimethyl
cubane-1,4-dicarboxylate (27) in 19% yield over six steps using the
previously reported procedure of Bliese and Tsanaktsidis.34 Diester
27 was monohydrolysed to acid-ester 28, which was subjected to a
Moriarty reaction, with subsequent saponoification of the remain-
ing ester furnishing 4-iodocubanecarboxylic acid (29).35,36 Reduc-
tion of iodo-acid 29 with borane dimethylsulfide complex gave
iodo-alcohol 30, which underwent lithium–halogen exchange
r
/
r
1 = 10). A pyridine ring within this homologous series imparted
low affinity for both
r
subtypes, with 24 demonstrating submi-
cromolar affinity for
r
2 receptors, but only micromolar 1 affinity.
r
When compared to the corresponding 7-azabicyclo[2.2.1]hep-
tanes, the substituted pyrrolidines (32–36, 41–44) generally
showed a reduction in both r1 and r2 binding. N-Benzylpyrrol-
idine (32) displayed barely submicromolar affinity for
r2 receptors
(Ki = 852 nM), a greater than two-fold reduction in binding com-
pared to the corresponding 7-azanorbornane, and was similarly
devoid of r1 affinity (Ki >10 lM). Substituting the benzyl group
with 3-fluorobenzyl (33) or 3,4-dimethoxybenzyl (34) moiety
had little effect on r2 affinity (Ki values of 1611 and 661 nM,
respectively), although both compounds interacted more poorly
with r2 than their 7-azabicyclo[2.2.1]heptane counterparts.
The cyclohexyl subunit, which had conferred high r1 and r2
affinity in the 7-azanorbornane series, produced low r2 affinity
within the pyrrolidine series, although moderate r1 affinity was
retained (36; r1 Ki = 51 nM, r2 Ki = 410 nM).
X
R
X
R
H
N
N
N
1: X = OH
3: X = OH
5
2
4
: X = H
: X = H
R = Ar(CH2)n
Figure 1. Azapolycarbocyclic receptor ligand scaffolds.
r

S. D. Banister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4059–4063
4061
OH
OH
OTs
a
b
NH2·HCl
NHCbz
NHCbz
6
7
8
c
OTs
e
O
d
N
R
NH·HCl
NH2·HBr
10: R = Ph
11
: R = 3-FPh
5·HCl
9
g
f
h
O
i or j
R
R
N
R
N
N
n
n
12: R = Ph
18: n = 1, R = Ph
22: n = 1, R = Ph
13: R = 3-FPh
19: n = 1, R = 3-FPh
20: n = 1, R = 2-pyridyl
21: n = 2, R = 3-FPh
23: n = 1, R = 3-FPh
24: n = 1, R = 2-pyridyl
25: n = 2, R = 3-FPh
14: R = 3,4-(OMe)2Ph
15
16
17
: R = 3-pyridyl
: R = cyclohexyl
: R = cubyl
Scheme 1. Reagents and conditions: (a) BnOC(O)Cl, Na2CO3, THF–H2O, 0 °C to rt, 2 h, 97%; (b) TsCl, C5H5N, 0 °C to rt, 24 h, 94%; (c) 33% HBr in AcOH, rt, 1 h, 97%; (d) NaOH,
EtOH–H2O, rt, 24 h, 78%; (e) RC(O)Cl, Et3N, CH2Cl2, 0 °C, 4.5 h, 90–92%; (f) LiAlH4, THF, reflux, 20 h, 88–89%; (g) RCHO, NaBH(OAc)3, ClCH2CH2Cl, rt, 14–22 h, 65–95%; (h)
R(CH2)nCOOH, CDI, Et3N, THF, rt, 12–20 h, 83–93%; (i) LiAlH4, THF, reflux, 20 h, 87–91% (22, 23, 25); (j) BH3ÁSMe2, THF, reflux, 23 h, 57% (24).
O
O
O
a
b, c
MeO
MeO
HO
OMe
OH
I
O
O
27
28
31
29
30
d
O
f
e
H
HO
HO
I
26
Scheme 2. Reagents and conditions: (a) NaOH in MeOH, THF, rt, 14 h, 92%; (b) PhI(OAc)2, I2, PhMe, 80 °C, 8 h; (c) aq NaOH, MeOH, THF, rt, 14 h, 74% over two steps; (d)
BH3ÁSMe2, THF, 0 °C to rt, 4.5 h, 93%; (e) n-BuLi, THF, À78 °C, 1 h, then MeOH, rt, 1 h, then 25% w/v NaOMe in MeOH, reflux, 1 h, 76%; (f) DMSO, SO3ÁC5H5N, Et3N, CH2Cl2, 0 °C to
rt, 18 h, 77%.
O
R
R
a
b
c or d
N
R
NH
N
N
n
n
32
33
34
35
36
37
38
39
41
42
43
: R = Ph
: n = 1, R = Ph
: n = 1, R = Ph
: R = 3-FPh
: n = 1, R = 3-FPh
: n = 1, R = 3-FPh
: n = 1, R = 2-pyridyl
: R = 3,4-(OMe)2Ph
: R = 3-pyridyl
: n = 1, R = 2-pyridyl
40: n = 2, R = 3-FPh
44: n = 2, R = 3-FPh
: R = cyclohexyl
Scheme 3. Reagents and conditions: (a) RCHO, NaBH(OAc)3, ClCH2CH2Cl, rt, 14–22 h, 90–96%; (b) R(CH2)nCOOH, CDI, THF, rt, 12–20 h, 86–92%; (c) LiAlH4, THF, reflux, 20 h,
86–97% (41, 42, 44); (d) BH3ÁSMe2, THF, reflux, 17 h, 66% (43).

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S. D. Banister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4059–4063
Table 1
r
subtypes, warranting the further investigation of cubane for the
Binding affinities and r2 subtype selectivities of N-substituted 7-azabicy-
clo[2.2.1]heptanes and pyrrolidines for
design of potent, but subtype non-selective,
r receptor ligands.
r receptors
The 7-azabicyclo[2.2.1]heptane scaffold represents a promising
candidate for the development of selective 2 ligands, particularly
when substituted with electron-rich benzylic systems, as in 14. In
order to further improve 2 receptor affinity and selectivity, future
work will focus on the exploration of alkoxy substitution patterns
(as well as alternative electron-donating substituents) around the
Compound
Ki (nM SEM)a
r2 Selectivity
r
r1
r2
r
12
13
14
15
16
17
22
23
24
25
32
33
34
35
36
41
42
43
44
NA
NA
NA
NA
22
7.0 0.3
276 47
103
399 21
251 38
43.1 7.2
6352 342
>25
>39
>232
>1.6
1.2
0.39
2.1
3.5
benzyl ring of 14. The development of potent and highly
r2-selec-
1
18
18
1
1
tive 7-azanorbornanes will enable the delineated investigation of
the role of the r2 receptor in CNS disorders such as anxiety,
depression, and substance abuse.
131
5
8
29.5 5.1
517 103
11.9 2.3
852 35
1611 47
661 27
NA
410 30
658 25
246 32
3516 165
3826 364
7.4
10
120
NA
NA
NA
NA
51
NA
NA
NA
NA
9
Acknowledgments
>11
>6.2
>15
—
0.12
>15
>40
>2.8
>260
Ki determinations for targets included in Table 1 and in the SI
were generously provided by the National Institute of Mental
Health’s Psychoactive Drug Screening Program, Contract
#NO1MH32004 (NIMH PDSP). The NIMH PDSP is directed by Bryan
L. Roth MD, PhD at the University of North Carolina at Chapel Hill
and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. For
experimental details please refer to the PDSP web site http://
pdsp.med.unc.edu/.
5
39
1
a
Ki values represent the mean SEM of four experiments. NA = less than 50%
inhibition of specific binding at 10 M.
l
Supplementary data
Phenethylpyrrolidine (41) showed a five-fold reduction in r2
affinity (Ki = 658 nM) when compared to corresponding 7-azabicy-
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.
2012.04.077.
clo[2.2.1]heptane, however, the reduction in
more pronounced (Ki >10 M). The same trend was observed for
3-fluorophenethyl-substituted pyrrolidine (42), which showed
approximately eight times lower affinity for 2 (Ki = 246 nM) than
the analogous 7-azanorbornane, but negligible affinity for r1 (Ki
>10 M). Compound 44, N-(3-(3-fluorophenyl)propyl)pyrrolidine,
showed a marked improvement in r2 binding (Ki = 39 nM), but
was still devoid of r1 affinity (Ki >10 M), resulting in an anoma-
lously selective r2 ligand (r1 2 = 256) for the series.
Replacement of the phenyl ring of 32 with a 3-pyridine ring (35)
abolished affinity for either receptor subtype (Ki > 10 M in each
case), and homologation to 2-pyridylethyl-substituted pyrrolidine
(43) did little to improve binding. Although the pyridine-con-
taining 15 and 24 were the least active azanorbornanes, the
binding of pyridine-derived pyrrolidines 35 and 43 was even
r1 affinity was much
l
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l
/r
r
l
r
r
poorer, consistent with the observed trend for reduced
when moving the pyrrolidine unit.
r affinities
Several structure–affinity relationships can be identified from
the binding data presented in Table 1. In the context of previ-
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steric reduction of the polycyclic framework was detrimental to
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r
from the 7-azanorbornane analogs, to give the corresponding pyr-
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cyclo[2.2.1]heptane series, benzylic substituents conferred the
greatest r2 selectivities, while increasing the distance between
the aryl group and the nitrogen atom increased affinity for both
r1 and r2 (particularly the former), resulting in r2 ligands with
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electronic factors are more important for
r1 than r2 binding. This
is further supported by the anomalous r1 affinity of the cyclo-
hexyl-bearing 36 within the pyrrolidine series. However, the possi-
bility of multiple binding orientations for non-aromatic
cannot be excluded and may contribute to the observed binding
profiles. Aliphatic compound 17, the first receptor ligand com-
prising a cubane subunit, showed remarkably high affinity for both
r ligands
r

S. D. Banister et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4059–4063
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