N-Arylalkyl-2-azaadamantanes as cage-expanded polycarbocyclic sigma (σ) receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2011.07.028

A series of racemic N-arylalkyl-2-azaadamantan-1-ols (9-15) and the corresponding deoxygenated, achiral N-arylalkyl-2-azaadamantanes (23-29) were synthesized and screened in competition binding assays against a panel of CNS targets. Adamantyl hemiaminals 9-15 displayed generally low affinity for both σ₁ (K_i values = 294-1950 nM) and σ₂ receptors (K_i values = 201-1020 nM), and negligible affinity for 42 other CNS proteins. Deoxygenation of 9-15 to give the corresponding achiral azaadamantanes 23-29 greatly improved affinity for σ₁ (K _i values = 8.3-239 nM) and σ₂ receptors (K _i values = 34-312 nM).

Full text of DOI:10.1016/j.bmcl.2011.07.028

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5289–5292
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
N-Arylalkyl-2-azaadamantanes as cage-expanded polycarbocyclic
sigma (r) receptor ligands
Samuel D. Banister a, David T. Yoo a, Sook Wern Chua b, Jinquan Cui c, Robert H. Mach c, Michael Kassiou a,b,d,
⇑
a School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia
b Brain and Mind Research Institute, Sydney NSW 2050, Australia
c Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
d Discipline of Medical Radiation Sciences, The University of Sydney, 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 racemic N-arylalkyl-2-azaadamantan-1-ols (9–15) and the corresponding deoxygenated, achi-
ral N-arylalkyl-2-azaadamantanes (23–29) were synthesized and screened in competition binding assays
against a panel of CNS targets. Adamantyl hemiaminals 9–15 displayed generally low affinity for both r1
(Ki values = 294–1950 nM) and r2 receptors (Ki values = 201–1020 nM), and negligible affinity for 42
other CNS proteins. Deoxygenation of 9–15 to give the corresponding achiral azaadamantanes 23–29
greatly improved affinity for r1 (Ki values = 8.3–239 nM) and r2 receptors (Ki values = 34–312 nM).
Ó 2011 Elsevier Ltd. All rights reserved.
Received 14 June 2011
Revised 4 July 2011
Accepted 6 July 2011
Available online 14 July 2011
Keywords:
Adamantanes
Polycarbocyclic
Sigma receptors
CNS
Structure–activity relationships
The
widely distributed in the central nervous system (CNS) and periph-
eral organs, and two subtypes have been defined: 1 and 2 recep-
tors, differing in size, anatomical distribution, and ligand
selectivity.1–3 While the human r1 receptor has been cloned from
various tissues, and shows no sequence homology with any known
r
receptors are a unique class of mammalian proteins
biomarkers of tumorcell proliferation, potentially allowingselective
2 ligands to act as diagnostic probes.17,18
An interest in receptors persists more than 35 years after their
discovery due to their implication in virtually all major CNS dis-
eases.19,20 Some of the earliest
receptor ligands identified were
r
r
r
r
r
clinical antipsychotics, such as haloperidol, which binds to
r1 and
mammalian protein, the
r
2 receptor has not been cloned from any
r2 receptors with nanomolar affinity.21 In addition to structurally
species.4,5
diverse antipsychotics, several antidepressants from disparatephar-
r
1 receptors primarily reside at the interface between the endo-
macological classes were also found to interact with r1
/
r
2 receptors
plasmic reticulum (ER) and the mitochondrion, where they mobi-
lize ER Ca2+ stores by acting as a molecular chaperones for type 3
inositol (1,4,5)-triphosphate receptors.6 However, r1 receptors
can also translocate to the plasma membrane where they modulate
Ca2+ flux via K+ channels and voltage-dependent Ca2+ channels.7,8
The role of r1 receptors in the maintenance of Ca2+ homeostasis
may partially account for their diverse pharmacology. Indeed, r1
receptors may regulate adrenergic, cholinergic, dopaminergic,
glutamatergic, and serotonergic neurotransmissions.9–15
with high affinity.22,23 The implication of
r receptors in anxiety dis-
orders,24 depression,25 Alzheimer’s disease,26 and drug addiction27
is well accepted, however, elucidation of the precise mechanistic
role of
r receptors in many of these diseases has been hampered
by the historical lack of truly selective ligands.
A myriad of structurally dissimilar ligands are known to interact
with r1 and r2 receptors. The finding that adamantine (1, Fig. 1),
used in the treatment of Parkinson’s disease, interacts with
r
receptors at therapeutically-relevant concentrations prompted
the investigation of alternate polycarbocyclic ‘cage’ amines with
potential activity at
receptors.28,29 N-Arylalkyl-4-azahexacy-
Relatively less is known about the structureand function(s) of the
r
2 receptor. The
Ca2+ concentrations, however, the precise mechanisms involved are
yet to be elucidated.16 The over-expression of
2 receptors in several
r
2 receptor is also believed to regulate intracellular
r
clo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ols (2), derived from the tris-
homocubane scaffold, can be modified to provide compounds with
selectivity for either r1 or r2 receptors.30–32 Moreover, congeners
of 2 were able to modulate amphetamine-stimulated dopamine re-
lease in vitro, and have shown promising alteration of cocaine-med-
iated effects in behavioral assays.33,34
r
cancer cell lines suggests that they may represent potential
⇑
Corresponding author.
E-mail address: michael.kassiou@syndney.edu.au (M. Kassiou).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.07.028

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S. D. Banister et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5289–5292
Table 1
Binding affinities, and subtype selectivities, of compounds 9–15 and 23–29 for
r1 and
r2
OH
R
NH2
Compound
R
n
X
Kia (nM SEM)
Selectivity
N
n
r1
r2
r1
r2
1
2
9
10
11
12
13
14
15
23
24
25
26
27
28
29
H
3-F
4-F
3-OMe
4-OMe
3-F
4-F
H
3-F
4-F
3-OMe
4-OMe
3-F
0
0
0
0
0
1
1
0
0
0
0
0
1
1
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
1450 170
862 150
650 55
1950 91
1240 100
234 20
1020 91
705 66
826 19
353 29
426 28
250 28
201 19
95 11
1.4
1.2
Figure 1. Polycarbocyclic ‘cage’ amines with
r
receptor activity.
1.3
1.1
5.5
2.9
246 55
1.2
OH
R
29
22
5
2
3.3
6.0
7.5
R
132
90
64
54
40
34
5
6
2
7
2
3
N
N
n
n
12.0 0.4
239
9
3.7
3
4
12.4 0.8
8.3 0.6
12.8 0.8
4.4
4.8
2.7
H
H
Figure 2. Proposed N-arylalkyl-2-azaadamantan-1-ols and the corresponding
N-arylalkyl-2-azaadamantanes.
4-F
a
Ki values represent the mean SEM of four experiments.
To further explore the structure–affinity relationships of poly-
carbocyclic amines acting at receptors, we sought to synthesize
azaadamantanes, providing information about the importance of
the hydroxy group to this class of receptor ligands. The
r
r
and screen a series of N-arylalkyl-2-azaadamantan-1-ols (3, Fig. 2)
as cage-expanded analogs of trishomocubane hemiaminals like 2.
Furthermore, these adamantyl hemiaminals could be deoxygen-
ated to give the corresponding N-substituted 2-azaadamantanes
(4), thereby providing information about the steric and electronic
tolerance of the postulated hydrophobic region surrounding the
adamantyl hemiaminals 9–15 were converted to the corresponding
alkyl chlorides (16–22) by refluxing in thionyl chloride. Alkyl
chlorides 16–22 underwent reductive dehalogenation with lithium
aluminum hydride to give the symmetrical N-arylalkyl-2-
azaadamantanes 23–29.
The synthesized azaadamantanols 9–15 and azaadamantanes
23–29 were routinely converted to their hydrochloride salts, and
subjected to in vitro binding assays. The Ki values for 9–15 and
basic nitrogen atom at the
r
receptor binding site.35
Commercially available 2-adamantanone (5, Scheme 1) was
subjected to a Baeyer–Villiger oxidation to generate lactone 6.
Chromatographic purification of 6 afforded an analytical sample,
but the crude material was sufficiently pure for use in further reac-
tions. Complete reduction of 6 with lithium aluminum hydride
gave diol 7, requiring no further purification. Treatment of 7 with
excess pyridinium dichromate (PDC) furnished diketone 8 as the
result of an unusual oxidation.36 Stirring a solution of 8, acetic acid,
and the appropriate arylalkylamine with sodium triacetoxy
borohydride at ambient temperature afforded the desired N-
arylalkyl-2-azaadamantan-1-ols 9–15.
23–29 at
r1 and r2 receptor subtypes are shown in Table 1. Guinea
pig brain membrane homogenates were used as the source of r1
receptors, while rat liver membrane homogenates were used as
the r2 receptor source. The radioligands [3H](+)-pentazocine and
[3H]DTG were used in the
r
1 and
The r2 receptor binding assay was conducted in the presence of
M (+)-pentazocine to mask ligand binding to r1 receptors. To
confirm the selectivity of these chemotypes for receptors, repre-
r2 receptor assays, respectively.
1
l
r
sentative compounds (9, 10, 23, and 24) were screened against a
panel of 42 other CNS proteins, and showed negligible affinity at
all sites tested (see Table S1 for full binding profiles).
Like 4 and it congeners, 9–15 were synthesized as racemates.
However, deoxygenation of 9–15 gives the corresponding achiral,
a
b
c
O
OH
O
O
OH
O
d
O
5
6
7
8
OH
Cl
R
f
e
R
R
N
N
n
N
n
n
23: n = 0, R = H
16: n = 0, R = H
9: n = 0, R = H
24
25
17
18
10
11
: n = 0, R = 3-F
: n = 0, R = 4-F
: n = 0, R = 3-F
: n = 0, R = 4-F
: n = 0, R = 3-F
: n = 0, R = 4-F
26: n = 0, R = 3-OMe
19: n = 0, R = 3-OMe
12: n = 0, R = 3-OMe
27
28
20
21
13
14
: n = 0, R = 4-OMe
: n = 1, R = 3-F
: n = 0, R = 4-OMe
: n = 1, R = 3-F
: n = 0, R = 4-OMe
: n = 1, R = 3-F
29: n = 1, R = 4-F
22: n = 1, R = 4-F
15: n = 1, R = 4-F
Scheme 1. Reagents and conditions: (a) m-CPBA, CH2Cl2, rt, 18 h, 97%; (b) LiAlH4, Et2O, reflux, 19 h, 99%; (c) PDC, CH2Cl2, rt, 66 h, 40%; (d) Ar(CH2)nNH2, AcOH, NaBH(OAc)3,
ClCH2CH2Cl, rt, 18 h, 94–100%; (e) SOCl2, reflux, 1 h, 91–99%; (f) LiAlH4, 1,4-dioxane, reflux, 18 h, 62–92%.

S. D. Banister et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5289–5292
5291
F
F
F
a
OH
Cl
N
N
N
30
31
32
Scheme 2. Reagents and conditions: (a) SOCl2, reflux, 8 h.
The simple benzylic adamantyl hemiaminal (9) showed only
micromolar affinity for r1 (Ki = 1.45 M) and r2 receptors
(Ki = 1.02 M). The introduction of a fluorine atom to the phenyl
ring of 9 produced a small increase in receptor affinity, regard-
less of substitution position; 3-fluorobenzyl derivative 10 (r1
Ki = 862 nM, r2 Ki = 705 nM) showed a similar binding profile to
that of the 4-fluoruobenzyl congener 11 (r1 Ki = 650 nM, r2
Ki = 826 nM). Although 9–11 displayed negligible subtype selectiv-
ity, a methoxy substituent was able to introduce a small degree of
r2 selectivity. The 3-methoxybenzyl analog 12 showed a slight
returned only starting material, and alkyl chloride 31 could not be
obtained.
l
l
Due to the relatively increased rigidity of the trishomocubane
scaffold compared to that of adamantane, the hemiaminal carbon
of trishomocubane 30 is likely unable to adopt a sufficiently planar
configuration in order to stabilize the carbocation-like transition
state required for chlorination to occur. Investigation of alternative
direct and indirect deoxygenation approaches to achiral azatris-
homocubanes like 32 are currently underway.
Taken together, the results of the binding assays suggest that
deoxygenation of N-arylalkyl-2-azaadamantanols to the corre-
sponding achiral, N-arylalkyl-2-azaadamantanes, increases r1
r
preference for r2 receptors (r2 Ki = 353 nM, r1
rable in magnitude to the 4-methoxy isomer 13 (r2 Ki = 426 nM,
2 = 2.9).
Extending the distance between the polycyclic cage and the aryl
group produced the greatest increase in receptor binding. The 3-
fluorophenethyl adamantyl hemiaminal 14 showed increased
affinity for both receptor subtypes r1 Ki = 234 nM, r2
/r2 = 5.5), compa-
r1
/r
affinity by up to two orders of magnitude, and improves r2 binding
by as much as a single order of magnitude. Excluding compound
26, all N-substituted 2-azaadamantanes showed a preference, al-
beit slight, for r1 receptors (r1 selectivity = 2.7–7.5). Most deoxy-
genated compounds showed low nanomolar affinity for r1
receptors, and excellent selectivity over 42 other CNS targets.
r
r
(
Ki = 250 nM) when compared to 10, but subtype selectivity was
similarly negligible. Much like the corresponding benzylic analogs,
the binding profile of the 4-fluoruophenethyl derivative 15 (r1
Although structural refinement is required to improve
r subtype
selectivity, the N-arylalkyl-2-azaadamantane chemotype repre-
sents a novel lead for the development of potent, selective r1
receptor ligands.
Ki = 246 nM,
r2 Ki = 201 nM) largely resembled that of 14, demon-
strating that positional isomerism is similarly unimportant for
these ethylene-spaced congeners. Overall, 9–15, showed only
micromolar or submicromolar affinity for r1 receptors (Ki values
234–1950 nM), and similar r2 binding (Ki values 234–1020 nM).
Deoxygenation of hemiaminals 9–15 to the corresponding aza-
adamantanes 23–29 generally produced a dramatic increase in r1
binding, but a less pronounced increase in r2 affinity. When com-
pared to hemiaminal 9, the simple N-benzyl-2-azaadamantane
Acknowledgements
Ki determinations for targets included 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 M.D., Ph.D. at the Uni-
versity 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/.
(23) demonstrated
a 50-fold improvement in r1 affinity
(Ki = 29 nM), and a greater than 10-fold increase in r2 affinity
(Ki = 95 nM). The 3-fluorobenzyl-substituted azaadamantane 24
showed a similar level of improvement over hemiaminal 10, fur-
nishing a moderately
1 = 6), and the same trend was observed for 4-fluorobenzyl con-
gener 25 (r1 Ki = 12 nM, r2 1 = 7.5) when compared to 11.
The 3-methoxybenzyl-substituted 26 represented the sole in-
stance in which deoxygenation imparted similar increases in both
r1 (Ki = 239 nM) and r2 affinity (Ki = 64 nM) when compared to
r1-selective ligand (r1 Ki = 22 nM, r2/
Supplementary data
r
/r
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.07.028.
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