Molecular hybridization of 4-azahexacyclo[5.4.1.02,6.0 3,10.05,9.08,11]dodecane-3-ol with sigma (σ) receptor ligands modulates off-target activity and subtype selectivity

Article abstract of DOI:10.1016/j.bmcl.2011.04.098

A series of N-substituted 4-azahexacyclo[5.4.1.0^2,6.0 ^3,10.0^5,9.0^8,11]dodecan-3-ols incorporating the respective arylalkyl subunits from several known sigma (σ) receptor ligands were synthesized and evaluated for their affinity against σ receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4-6) showed good selectivity for σ₁ and σ₂ receptors over multiple dopamine receptors. The molecular hybrid obtained from haloperidol and 4-azahexacyclo[5.4.1.0^2,6.0^3,10.0 ^5,9.0^8,11]dodecan-3-ol (4, σ₁ K _i = 27 nM, σ₂ K_i = 55 nM) showed reduced affinity for D₁-D₅ dopamine receptors when compared to haloperidol itself. The compound with the greatest σ₁ affinity in the series, benzamide 4 (σ₁ K_i = 7.6 nM, σ₂ K_i = 225 nM) showed a complete reversal of the subtype selectivity displayed by the highly σ₂ selective parent benzamide, RHM-2 (3, σ₁ K_i = 10412 nM, σ₂ K_i = 13.3 nM).

Full text of DOI:10.1016/j.bmcl.2011.04.098

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3622–3626
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Molecular hybridization of 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11
]
dodecane-3-ol with sigma (
r) receptor ligands modulates
off-target activity and subtype selectivity
Samuel D. Banister a, Iman A. Moussa a, William T. Jorgensen a, Sook Wern Chua b, Michael Kassiou a,b,c,
⇑
a School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
b Brain and Mind Research Institute, Sydney, NSW 2050, Australia
c 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
A series of N-substituted 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ols incorporating the respec-
tive arylalkyl subunits from several known sigma ( ) receptor ligands were synthesized and evaluated
for their affinity against receptors and dopamine receptors. The hybrid trishomocubane-derived
Article history:
Received 30 March 2011
Revised 19 April 2011
Accepted 21 April 2011
Available online 28 April 2011
r
r
ligands (4–6) showed good selectivity for r1 and r2 receptors over multiple dopamine receptors. The
molecular hybrid obtained from haloperidol and 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ol
(4,
to haloperidol itself. The compound with the greatest r1 affinity in the series, benzamide 4 (r1
Ki = 7.6 nM, 2 Ki = 225 nM) showed a complete reversal of the subtype selectivity displayed by the highly
r2 selective parent benzamide, RHM-2 (3, r1 Ki = 10412 nM, r2 Ki = 13.3 nM).
Ó 2011 Elsevier Ltd. All rights reserved.
r1 Ki = 27 nM, r2 Ki = 55 nM) showed reduced affinity for D1–D5 dopamine receptors when compared
Keywords:
Trishomocubanes
Sigma receptors
CNS
r
Structure–activity relationships
Since their discovery 35 years ago, sigma (
r
) receptors continue
vasive assessment of tumor proliferation using positron emission
tomography (PET),17,18 and several potential PET agents have been
described.19 Moreover, r2 receptors have shown promise as a tar-
get for the treatment of drug-resistant cancers.20,21
to be widely studied.1,2 Two
r
receptor subtypes have been well de-
fined pharmacologically, r1 and 2, differing in size, distribution,
and drug selectivity.3 The
1 receptor has been cloned from numer-
r
r
ous mammalian tissue sources, including human brain, and shares
no homology with any known mammalian protein.4 r1 receptors
are primarily located at the interface between endoplasmic reticu-
lum (ER) and mitochondria, the mitochondria-associated ER mem-
brane (MAM), where they control cellular Ca2+ levels by acting as
molecular chaperones for type 3 inositol 1,4,5-triphosphate IP3
receptors.5 However, r1 receptors can also translocate to the
plasma membrane where they modulate K+ and Clꢀ channels.6,7
Despite the current shortcomings in our understanding of
receptors, much is known about their links to disease.22,23 Indeed,
receptors have been implicated in the pathophysiology of a di-
r
r
verse spectrum of central nervous system (CNS) diseases, including
anxiety disorders,24 depression,25,26 psychotic disorders,27 Alzhei-
mer’s disease,28 and drug addiction.29 Many clinically-utilized anti-
depressant and antipsychotic drugs,30–32 as well as drugs of
abuse,33 have been shown to act at r1
cally relevant concentrations. Although r
/
r2 receptors at physiologi-
Additionally,
r
1 receptors have been shown to regulate the neuro-
receptors represent
transmission mediated by acetylcholine,8 dopamine,9 glutamate,10
5-hydroxytryptamine (5-HT),11 and norepinephrine,12 accounting
for their diverse pharmacology.
promising targets for the development of novel treatments for sev-
eral CNS diseases, the elucidation of the function and structure of r1
and
selective ligands.
Many early receptor ligands, such as the clinical antipsychotic
haloperidol (1, Fig. 1), showed little selectivity. Haloperidol is a
r2 receptors has been hampered by the historical lack of truly
The r2 receptor is yet to be cloned, and much less is known
about its molecular structure and biochemical function. It was re-
cently proposed that the r2 receptor may belong to the histone
r
r
protein family.13 Like
r
1 receptors, the primary role of
r2 receptors
classic ‘dirty drug’, possessing high affinity for r1 (reported Ki val-
ues range from 0.90 to 10 nM)34–36 and r2 (reported Ki values
range from 7.93 to 78 nM) receptors34–36 in addition to many other
is thought to involve Ca2+ modulation, although the precise signal
transduction pathways remain unclear.14 The over-expression of
r
2 receptors in several tumor cell lines,15,16 has led to the proposal
CNS sites, particularly dopamine, 5-HT, a adrenergic, and hista-
of
r2 receptors as therapeutically useful biomarkers for the nonin-
mine receptors.37–40 Several selective r1 receptor ligands have
now been reported, including NE-100 (2).41 NE-100 shows high
affinity for the
r1 receptor subtype, comparable to that of haloper-
⇑
Corresponding author.
E-mail address: m.kassiou@usyd.edu.au (M. Kassiou).
idol, but approximately 205-fold selectivity over the r2 receptor
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.098

S. D. Banister et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3622–3626
3623
F
OH
F
OH
N
N
O
Cl
O
1: haloperidol
4
5
O
O
O
O
OH
N
N
2: NE-100
H
N
OH
H
O
O
N
N
N
O
O
O
O
3: RHM-2
6
Figure 1. Known
r
ligands and their corresponding ‘hybrid’ 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ol analogs.
(
r
1 Ki = 1.03 nM,
r
2 Ki = 212 nM).42 Unlike haloperidol, NE-100 is a
The synthetic route to N-substituted 4-azahexacy-
clo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ols (10, Scheme 1)45 in-
volves the condensation of Cookson’s diketone monoethylene
acetal (7) with the desired primary amine under pressure, and sub-
sequent reduction of formed imine 8 using sodium borohydride,
gives endo-amine 9. Hydrolysis of ketal 9 by aqueous hydrochloric
acid in acetone, followed by a basic work-up, gives transannularly-
cyclized hemiaminals of type 10 in reasonable yield over three
steps. This general route was amenable to the production of 4–6,
but required the synthesis of the necessary primary amine
reactants.
The synthesis of haloperidol analog 4 is shown in Scheme 2. 4-
Chloro-40-fluorobutyrophenone (11) was treated with ethylene
glycol in the presence of catalytic p-toluenesulfonic acid under
Dean–Stark conditions to give acetal 12. Nucleophilic substitution
of the chloro group to give azide 13 was achieved under relatively
mild conditions by using a stoichiometric amount of potassium io-
dide. Staudinger reduction of the azide afforded primary amine 14.
Subjecting 14 to the conditions outlined in Scheme 1 gave 4 in 42%
yield over three steps.
selective
r
ligand, displaying negligible affinity at other CNS
sites.41 Fewer selective r2 receptor ligands are known, however
Mach and co-workers have reported the r2 selectivity of several
benzamides, such as RHM-2 (3).43,44 RHM-2 shows high affinity
and selectivity for the r2 receptor subtype (Ki = 13.3 nM, r1
2 = 783), with only micromolar affinity for D2 and D3 dopamine
receptors.43,44
We recently reported structure-affinity relationships for a small
series of N-substituted
4-azahexacyclo[5.4.1.02,6.03,10
2 receptors, and selec-
/
r
.
05,9.08,11]dodecan-3-ols with affinity for r1
/r
tivity over other CNS receptors, transporters, and ion channels.45
These polycarbocyclic hemiaminals demonstrate promising phar-
macological activity, both in vitro46 and in vivo.47 To further ex-
plore the
hemiaminal scaffold, we sought to synthesize chimeric structures
incorporating the arylalkyl subunits from known ligands. Com-
pounds 1–3 were selected as candidate parent molecules based
on the diversity of their binding profiles, and are shown in Figure
1 alongside the proposed, molecular-hybrid N-substituted 4-aza-
hexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ols (4–6, respec-
r selectivity conferred by this polycarbocyclic
r
The synthesis of NE-100 analog 5 (Scheme 3) started with phen-
ethyl bromide alkylation of isovanillin (15) to afford aldehyde 16.
Subjecting 16 to a Henry reaction under classical conditions gave
tively). Haloperidol, with its dual r1
significant dopaminergic activity, was included to determine
whether incorporation of the 4-azahexacyclo[5.4.1.02,6.03,10
05,9.08,11]dodecan-3-ol moiety could improve selectivity for
receptors over dopamine receptors. Compounds 2 and 3 were cho-
/r2 binding profile and
.
r
nitrostyrene 17. Complete reduction of the a,b-unsaturated nitro
group of 17 was achieved using lithium aluminium hydride, to give
desired amine 18. Subjecting 18 to the conditions described in
Scheme 1 gave 5 in 50% yield over three steps. Alternatively, reduc-
tive alkylation of 18 with propanal using sodium triacetoxyborohy-
dride gave NE-100 in excellent isolated yield. This novel route to
NE-100 proceeds in 56% unoptimized yield over four steps and rep-
sen to determine the effect of 4-azahexacyclo[5.4.1.02,6
.
03,10.05,9.08,11]dodecan-3-ol incorporation on their selectivity for
r1 and r2 receptors, respectively. Additionally, 1–3 each contain
only a single basic nitrogen atom, limiting the possibility of multi-
ple binding modes for 4–6.
a
b
c
O
O
O
OH
R
O
O
R
O
N
O
N
HN
R
7
8
9
10
Scheme 1. Reagents and conditions: (a) R–NH2, EtOH, 100 °C, 18 h; (b) NaBH4, EtOH, rt, 8 h; (c) aq 4 M HCl, acetone, rt, 12 h, basic work-up.

3624
S. D. Banister et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3622–3626
O
O
O
O
O
F
F
F
Cl
a
Cl
b
N3
11
12
13
c
F
O
O
d, e, f
OH
F
NH2
N
O
4
14
Scheme 2. Reagents and conditions: (a) HOCH2CH2OH, p-TsOH (cat.), PhMe, reflux, Dean–Stark conditions, 16 h, 98%; (b) NaN3, KI, DMF, 60 °C, 26 h, 96%; (c) PPh3, Et2O, 0 °C
to rt, then H2O, 22 h, 95%; (d) 7, EtOH, 100 °C, 18 h; (e) NaBH4, rt, 8 h; (f) aq 4 M HCl, acetone, rt, 12 h, 42% over three steps.
resents a synthetically expedient improvement over the previously
reported sequence of eight steps.48
cells expressing the human forms of dopamine receptor subtypes.
The radioligands [3H](+)-pentazocine and [3H]DTG were used in
the r1 and r2 receptor assays, respectively, whilst [3H]
SCH233930 and [3H]N-methylspiperone were employed in the D1
and D5, and D2–D4 assays, respectively.
The hybrid analogs 4–6 were all moderately selective for the r1
receptor. In the case of haloperidol analog 4, the mixed r1/r2 bind-
ing profile of haloperidol itself was retained. The r1 and r2 Ki val-
ues for 4 (27 and 55 nM, respectively) reveal comparable r2
binding, but reduced r1 binding, when compared to its parent
structure 1. The off-target activity of 4 was diminished at all dopa-
mine receptor subtypes screened (D1–D5) relative to haloperidol.
At D1 and D4 receptors, 4 (D1 Ki = 209 nM, D4 Ki = 93 nM) demon-
strated less than a 10-times and 20-times reduction in binding
affinity, respectively, when compared to 1 (D1 Ki = 25 nM,40 D4
The synthesis of RHM-2 analog 6 is shown in Scheme 4. Com-
mercially available 2-methoxy-5-benzoic acid (19) was activated
with carbonyldiimidazole (CDI) and treated with an excess of
1,2-diaminoethane, easily removed during aqueous work-up, to
give amide 20. Subjecting 20 to the conditions described in Scheme
1 gave 6 in 65% yield.
The hemiaminals thus synthesized (4–6) were subjected to
binding assays against a panel of CNS receptors (see Table S1 for
full binding profiles). The Ki values for 4–6 at r1 and r2 receptors,
and D1–D5 dopamine receptor subtypes are shown in Table 1. Rat
brain homogenates were used as the source of r1 receptors, whilst
PC12 cells were used as the r2 receptor source. All dopamine
receptor assays employed transfected human embryonic kidney
O
O
HO
O
O
O
O
NO2
a
b
H
H
O
15
16
17
18
c
d, e, f
O
O
O
O
NH2
OH
N
5
g
O
O
N
2
Scheme 3. Reagents and conditions: (a) PhCH2CH2Br, K2CO3, DMF, 50 °C, 19 h, 90%; (b) CH3NO2, NH4OAc (cat.), AcOH, reflux, 4 h, 95%; (c) LiAlH4, Et2O/THF (80:20), reflux,
42 h, 68%; (d) 7, EtOH, 100 °C, 18 h; (e) NaBH4, rt, 8 h; (f) aq 4 M HCl, acetone, rt, 12 h, 50% over three steps; (g) CH3CH2CHO, NaBH(OAc)3, rt 18 h, 96%.

S. D. Banister et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3622–3626
3625
O
O
O
O
NH2
OH
OH
N
H
H
N
a
b, c, d
N
O
O
19
20
6
Scheme 4. Reagents and conditions: (a) CDI, THF, rt, 1 h, then H2NCH2CH2NH2 (20 equiv), 19 h, 95%; (b) 7, EtOH, 100 °C, 18 h; (c) NaBH4, rt, 8 h; (d) aq 4 M HCl, acetone, rt,
12 h, 65% over three steps.
Table 1
Binding affinities of compounds 4–6 for
r
receptors (r1 and
r
2) and dopamine receptors (D1–D5)
Ki (nM SEM)a
Compound
r1
r2
D1
D2
D3
D4
D5
4
5
6
27
20
7.6 1.0
0.90–10
1.03
2
1
55
93
225 18
7.93–78
212
4
5
209 36
>10000
ND
1724 316
>10000
>10000
1
1958 146
ND
>10000
29
ND
3760
93
ND
ND
5
ND
ND
8
>10000
ND
ND
48
ND
Haloperidol (1)b
NE-100 (2)c
RHM-2 (3)d
25
>10000e
ND
>10000e
2850
10412
13.3
ND
ND = not determined.
a
Ki values represent the mean SEM of four experiments.
Data extracted from Refs. 34–40.
Data extracted from Refs. 41–42.
Data extracted from Refs. 43–44.
IC50 (nM SEM).
b
c
d
e
Ki = 5 nM).37 However, the reduction in binding of 4 at D3 and D5
receptors (D3 Ki = 1958 nM, D5 Ki >10 M) compared to haloperidol
Jamie Driscol at NIMH, Bethesda MD, USA. For experimental details
please refer to the PDSP web site http://pdsp.med.unc.edu/.
l
was more significant, approximately 67-times and more than 200-
times, respectively. Most notable was the diminished binding of 4
at D2 receptors, a key pharmacological target for the activity of 1,
where a greater than 1700-fold reduction in binding was observed
(D2 Ki = 1724 nM).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.04.098.
NE-100 analog 5 displayed moderate r1 affinity (Ki = 20 nM),
and modest subtype selectivity (r2
100 itself, 5 showed a decrease in r1 affinity, and higher levels of
/r1 = 4.7). Compared to NE-
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