Effects of linker elongation in a series of N-(2-benzofuranylmethyl)- N′-(methoxyphenylalkyl)piperazine σ1 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2011.08.029

In our continued exploration of disubstituted piperazine derivatives as sigma (σ) receptor ligands with central nervous system (CNS) activity, a series of N-(2-benzofuranylmethyl)-N′-(methoxyphenylalkyl)piperazines (16-21 and 26-31) were synthesized, anti

Full text of DOI:10.1016/j.bmcl.2011.08.029

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5707–5710
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Effects of linker elongation in a series of N-(2-benzofuranylmethyl)-
N0-(methoxyphenylalkyl)piperazine r1 receptor ligands
Iman A. Moussa a, Samuel D. Banister a, Fady N. Akladios 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
Article history:
In our continued exploration of disubstituted piperazine derivatives as sigma (
r
) receptor ligands
with central nervous system (CNS) activity,
oxyphenylalkyl)piperazines (16–21 and 26–31) were synthesized, anticipating that these ligands would
better suit the structural requirements of the current 1 pharmacophore. Affinities of these ligands for r1
and r2 receptors were investigated by means of radioligand binding assays, with the identification of
N-(2-benzofuranylmethyl)-N0-[3-(4-methoxyphenyl)propyl]piperazine (29, Ki = 3.1 nM, r2
1 = 45) as a
selective 1 ligand. The 1 affinities and subtype selectivities of piperazines 16–21 and 26–31 were gen-
a
series of N-(2-benzofuranylmethyl)-N0-(meth-
Received 18 July 2011
Revised 3 August 2011
Accepted 4 August 2011
Available online 12 August 2011
r
/
r
Keywords:
Piperazines
Sigma receptors
CNS
Structure–affinity relationships
r
r
erally comparable to the corresponding benzylic analogs. Additionally, the affinities of 16–21 and 26–31
for the 5-HT2B receptor were much lower than the relatively nonselective methoxybenzylic analogs 2–4,
indicating that elongation of the alkyl tether generally improved selectivity for r1 receptors.
Ó 2011 Elsevier Ltd. All rights reserved.
Sigma (
r
) receptors were first proposed as an opioid receptor
The r2 receptor has yet to be cloned, but a molecular weight of
subtype by Martin et al. in the mid-1970s.1 Since that time, exten-
sive pharmacological and behavioral studies have revealed that
these sites are, in fact, biochemically and topographically distinct
approximately 21.5 kDa has been suggested based on the photo-
affinity labeling of pheochromocytoma (PC12) cell membranes.6,8
Compared to
r1, much less is known about the function of r2
from all previously characterized mammalian proteins.2–5 Two
receptor subtypes, namely r1 and r2
r
receptors, however, they are highly implicated in the regulation
5,6
,
have been pharmacologi-
of cell proliferation and viability.20
cally characterized and are widely distributed in both the central
The ability of r receptors to regulate the neurotransmission
and peripheral nervous system (CNS and PNS, respectively).7,8
mediated by acetylcholine,21 dopamine,22–24 glutamate25 and 5-
hydroxytryptamine,26 accounts for their implication in a diverse
spectrum of CNS disorders.27,28 On the basis of their neuroregulato-
ry and neuroprotective functions, agents acting at r1 have been
proposed for the treatment of depression,29,30 drug abuse31,32 and
psychiatric disorders.33 Ligands selective for the r2 receptor, on
the other hand, are proposed to act as novel antineoplastic agents.34
Work in our laboratory has focused on the rational design and
Many historical, high affinity
1,3-di-o-tolylguanidine (DTG), display little to no subtype selectiv-
ity.9,10 However,
receptor subtypes exhibit enantiodiscrimination
r ligands, including haloperidol and
r
toward certain structural classes, such as the benzomorphans. For
example, [3H](+)-pentazocine is the ligand of choice for in vitro
r1 binding assays, displaying very high selectivity for the r1 sub-
type,11 while (–)-pentazocine displays a preference for the r2
receptor.5
development of increasingly
r subtype selective ligands, based
The r1 receptor has been cloned from numerous mammalian
tissues, including human brain,12 and the amino acid sequence is
highly conserved, with greater than 90% homology across spe-
cies.13–15 Although r1 receptors primarily reside at the interface
between the endoplasmic reticulum (ER) and mitochondria—the
mitochondria-associated ER membrane (MAM)—and control Ca2+
flux by acting as molecular chaperones for type 3 inositol-1,4,5-tri-
phosphate receptors, they are also able to translocate to the plasma
membrane where they regulate Ca2+ and K+ channels.16–19
on the differential arylalkyl disubstitution of 1,4-piperazine. We
recently reported a series of N-(2-benzofuranylmethyl)-N0-benzyl-
piperazines (1–4, Fig. 1) as selective r1 receptor ligands.35 The
simple benzylic analog 1 was a highly selective
r1 receptor ligand
(Ki = 5.2 nM, r2 1 = 46), with lower affinity for other CNS
/r
receptors, transporters, and ion channels. However, addition of a
2-, 3-, or 4-methoxy substituent (2, 3, and 4, respectively)—while
retaining moderate to high affinity for the
r1 receptor—also intro-
duced concomitant high affinity for the 5-HT2B receptor subtype,
and micromolar affinity for the D2 dopamine receptor.
The high degree of symmetry present in benzylpiperazines 1–4
provided little insight into the structural interactions important
⇑
Corresponding author.
E-mail address: michael.kassiou@sydney.edu.au (M. Kassiou).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.029

5708
I. A. Moussa et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5707–5710
The desired piperazines were prepared according to the syn-
O
thetic methods shown in Schemes 1 and 2. Benzofuranyl amine
5, previously prepared in our laboratory,35 was subjected to an
amide coupling with the appropriate carboxylic acid in the pres-
ence of EDC and HOBt to furnish phenylacetamides (6–9), phenyl-
butyramides (10 and 11), and (E)-cinnamamides (12–15). Treating
bisamides 6–15 with lithium aluminum hydride reduced both
amide functionalities to give the corresponding piperazines
16–25 in moderate yields. The (E)-cinnamylamines (22–25),
underwent hydrogenation to give saturated piperazines 26–29 in
good yields.
N
N
N
O
N
O
1
2
σ
σ1
1 Ki = 5.2 nM
σ2 Ki = 240 nM
5-HT2B Ki = 497 nM
Ki = 198 nM
σ2 Ki = 89 nM
5-HT2B Ki = 9.7 nM
D2 Ki = 5122 nM
D
2 Ki > 10000 nM
An alternative synthetic strategy was undertaken to synthesize
the remaining arylbutylpiperazines 30 and 31 (Scheme 2). Iodoani-
soles 32 and 33 were each subjected to Sonogashira cross-coupling
with 3-butynol to give the corresponding arylalkynes 34 and 35,
followed by hydrogenation to yield 4-arylbutanols 36 and 37 in
high yields. Appel bromination of alcohols 36 and 37 afforded their
respective arylalkyl bromides 38 and 39,40 which were subjected
to amination using the previously described N-(2-benzofuranylm-
ethyl)piperazine,35 giving the desired phenylbutylpiperazines 30
and 31.
O
N
N
N
N
O
O
O
3
4
σ1 Ki = 16 nM
σ2 Ki = 80 nM
5-HT2B Ki = 28 nM
2 Ki = 5728 nM
σ1 Ki = 2.7 nM
σ2 Ki = 103 nM
5-HT2B Ki = 15 nM
D2 Ki = 2700 nM
D
Figure 1. Examples of
r
selective N-(2-benzofuranylmethyl)-N0-benzylpiperazines
ligands.
Binding affinities for newly synthesized compounds 16–21 and
26–31 at
r1 and r2 receptors were determined from in vitro com-
petition assays, using a modification of the protocol reported by
Kovacs and Larson,41 and are summarized in Table 1. Competitive
displacement of [3H](+)-pentazocine in a rat brain homogenate
preparation was used to determine r1 receptor affinities, while
competitive displacement of [3H]DTG from a PC12 cell preparation
provided r2 receptor affinities. Ki determinations and extensive
CNS binding profiles were generously provided by the National
Institute of Mental Health’s Psychoactive Drug Screening Program
(NIMH PDSP).
Like parent compound 1, most analogs within this series
showed a distinct preference for the r1 receptor. Extending the
length of the alkyl tether of 1–4 by a single carbon gave the corre-
sponding phenethyl analogs 16–19, which retained the high r1
receptor affinities (r1 Ki = 7.3–17 nM), generally observed for the
benzylic series (excepting 2). When compared to 2-methoxybenzyl
derivative 2 (r1 Ki = 198 nM), 2-methoxyphenethyl 17 possessed
affinity for r1 that was more than an order of magnitude greater
(Ki = 17 nM), resulting in a compound that was selective for r1
for optimal r1 binding. However, Glennon et al. have generated a
1 receptor pharmacophore accounting for most of the structurally
diverse family of
1 ligands (Fig. 2).36 This pharmacophoric model
requires a basic nitrogen flanked by two hydrophobic motifs; a pri-
mary hydrophobic region (typically an aryl group) at a distance of
6–10 Å from the central amine, and a sterically-tolerant secondary
hydrophobic region 2.5–3.9 Å from the central nitrogen atom. The
simplicity of the pharmacophore allows it to encompass most
r
r
known r1 ligands, and guide the optimization of
r1-binding
chemotypes.36,37
The benzofuranyl group of 1 and its congeners are likely to oc-
cupy the secondary hydrophobic site of the Glennon pharmaco-
phore, and extending the distance to the substituted phenyl ring
should furnish ligands more congruent with the structural require-
ments of
r1 receptor binding. Additionally, it was anticipated that
deviation from the core structure of regioisomers 2–4 might atten-
uate off-target interactions with the 5-HT2B and D2 receptors.
In order to produce analogs of 1 with improved
r1 binding, we
rather than
comparable r1 affinity to the corresponding benzylic analog 3,
but an increased 2 affinity, resulting in a lack of subtype selectiv-
r2. The 3-methoxyphenethyl derivative 18 showed
sought to elongate the alkyl chain represented by the dashed line
in Figure 2, thereby extending the distance between the central
piperazine and the phenyl ring. Utilizing 1 as a lead compound,
2-, 3-, and 4-methoxyphenyl analogs tethered to the piperazine
nitrogen by a chain of 2, 3, or 4 methylene units were generated
r
ity overall (r1 Ki = 13 nM, r2 Ki = 14 nM). A 4-methoxy substitu-
tion pattern within the phenethyl series (19) conferred no
advantage to r2 binding over the same substitution in the benzyl
to explore the effect of linker elongation on
and subtype selectivity.
r receptor affinity
series (4), and reduced
r1 Ki = 9.4 nM, r2 1 = 11). Much like their benzylic analogs, the
most 1-selective members of the phenethyl series were the
simple phenethyl derivative 16 (r1 Ki = 7.3 nM, r2 1 = 18) and
the 4-methoxy-substituted 19 r1 Ki = 9.4 nM, r2 1 = 11),
r1 affinity, to give a less r1-selective ligand
(
/r
r
/r
Secondary
hydrophobic
region
Central
basic
Primary
hydrophobic
region
(
/r
although levels of r1 selectivity for both compounds were lower
than the corresponding benzyl derivatives.
nitrogen
Phenylpropyl analogs 26–29 retained high affinity for the r1
receptor (r1 Ki = 3.1–8.3 nM), comparable to those of the corre-
sponding phenethyl derivatives (r1 Ki = 7.3–17 nM), along with
moderate to high r2 affinities (r2 Ki = 18–138 nM). Consequently,
26–29 generally possessed poor r1 selectivity, with the notable
N
2.5–3.9 Å
6–10 Å
exception of 4-methoxy substituted 29
(r1 Ki = 3.1 nM, r2/
r
1 = 45). The binding profile of 29 closely resembled that of the cor-
N
responding benzylic derivative 4, making it one of the most selec-
tive r1 ligands identified within this series. Moreover, 29 showed
substantially reduced off-target affinity (5-HT2B Ki = 155 nM, D2 Ki
>10,000 nM) when compared to 4 (5-HT2B Ki = 15 nM, D2 Ki
>2700 nM).
R
O
N
Figure 2. The Glennon r1 receptor pharmacophore and proposed orientation of
binding for elongated N-(2-benzofuranylmethyl)-N0-arylalkylpiperazines.37–39

I. A. Moussa et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5707–5710
5709
O
R
R
a
b
NH.HCl
N
N
n
N
N
O
n
O
N
O
O
O
5
6:
16:
n = 1, R = H
7: n = 1, R = 2-OCH3
8:
n = 1, R = H
17: n = 1, R = 2-OCH3
18:
n = 1, R = 3-OCH3
9: n = 1, R = 4-OCH3
10:
n = 1, R = 3-OCH3
19: n = 1, R = 4-OCH3
20:
n = 3, R = H
n = 3, R = H
a
11: n = 3, R = 4-OCH3
21: n = 3, R = 4-OCH3
O
N
N
N
b
c
N
N
R
N
O
O
R
O
R
O
12:
22:
26:
R = H
13: R = 2-OCH3
14:
R = H
23: R = 2-OCH3
24:
R = H
27: R = 2-OCH3
28:
R = 3-OCH3
15: R = 4-OCH3
R = 3-OCH3
25: R = 4-OCH3
R = 3-OCH3
29: R = 4-OCH3
Scheme 1. Reagents and conditions: (a) RPh(CH2)nCOOH or RPhCH@CHCOOH, NMM, EDCꢀHCl, HOBt, DMF, rt, 20 h, 61–88%; (b) LiAlH4, Et2O, 0 °C to reflux, 16 h, 61–82%; (c)
H2, HCl, 10% w/w Pd/C, MeOH, rt, 20 h, 78–82%.
R
a
R
b
d
R
R
N
X
3
I
3
N
HO
O
32: R = 2-OCH3
33:
34: R = 2-OCH3
35:
36: X = OH, R = 2-OCH3
30: R = 2-OCH3
31:
R = 3-OCH3
37:
R = 3-OCH3
R = 3-OCH3
X = OH, R = 3-OCH3
c
38:
X = Br, R = 2-OCH3
39: X = Br, R = 3-OCH3
Scheme 2. Reagents and conditions: (a) 3-butynol, Pd(PPh3)2Cl2 (5 mol %), CuI (5 mol %), Et3N, reflux, 20 h, 34: 60%, 35: quant.; (b) H2, 10% w/w Pd/C, MeOH, rt, 20 h, 36:
quant., 37: 88%; (c) CBr4, PPh3, Et2O, rt, 16 h, 38: 75%, 39: quant.; (d) N-(2-benzofuranylmethyl)piperazine, K2CO3, NaI, DMF, reflux, 20 h, 30: 72%, 31: 74%.
Table 1
In vitro binding data for N-(2-benzofuranylmethyl)-N0-(methoxyphenylalkyl)piperazine derivatives 16–21 and 26–31
R
N
n
N
O
Cmpd
n
R
Ki SEMa (nM)
NMDA/PCP
5-HT2B
D2
r1
r2
r2/r1
16
17
18
19
26
27
28
29
20
30
31
21
1
1
1
1
2
2
2
2
3
3
3
3
H
310 18
NA
1648 130
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
7.3 0.4
131 10
18
5
1
11
3
6
7
45
4
8
28
7
2-OCH3
3-OCH3
4-OCH3
H
2-OCH3
3-OCH3
4-OCH3
H
120
6
17
13
1
1
81
14
101
18
53
40
4
1
9
2
7
5
290 16
463 29
NA
9.4 0.5
5.7 0.3
8.3 0.6
5.7 0.4
3.1 0.2
4.2 0.3
147
9
1025 87
5866 920
556 54
NA
89 10
432 41
484 47
5791 921
628 31
243 12
155
7
138 13
18
275 27
332 26
343 13
352 21
2
2-OCH3
3-OCH3
4-OCH3
16
7.6 0.7
13
1
130 15
211 25
1
87
8
a
Affinities for r1 were determined in rat brain homogenates using [3H](+)-pentazocine, and for r2 in PC12 cells using [3H]DTG. The values in this table represent the
mean SEM from triplicate assays. NA = less than 50% inhibition at primary assay concentration (10 M).
l

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I. A. Moussa et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5707–5710
Compounds 20, 21, 30, and 31, featuring a four-carbon linker,
Acknowledgements
displayed high r1 affinities (r1 Ki = 4.2–16 nM), with a simple
phenylbutyl group conferring the greatest r1 affinity (20, r1
Ki = 4.2 nM). Although 20 showed good r1 affinity, it also pos-
sessed high affinity for r2 receptors (r2 Ki = 18 nM), with a net
binding profile akin to the subtype nonselective phenylpropyl ana-
Ki determinations 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/.
log 26, and contrasting the high
r1 selectivity of the corresponding
benzyl (1) and phenethyl (16) congeners. In stark contrast to 4 and
29, a 4-methyl ether did not confer high r1 selectivity within the
phenylbutyl series, and compound 21 (r1 Ki = 13 nM, r2
showed a binding profile similar to that of the corresponding phen-
ethyl analog 19 (r1 Ki = 9.4 nM, r2 1 = 11). However, 3-meth-
oxyphenylbutyl derivative 31 showed reasonable r1 selectivity
r1 Ki = 7.6 nM, r2 1 = 28), unlike the 3-methoxy substituted
/r1 = 7)
Supplementary data
/r
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.08.029.
(
/r
members of the previous series (3, 18, and 28).
Excepting butyl analog 21, derivatives comprising a methoxy
group at the 4-position of the distal phenyl ring appear to be well
tolerated at the r1 site, a trend similarly observed in our previous
work.35 The 4-methoxy-substituted derivative containing a propyl
linker (29) showed the highest r1 affinity and selectivity
References and notes
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5-HT2B receptor, and negligible affinity (Ki >10
dopamine receptor, relative to 4.
lM) for the D2
The range of
r2 affinities of 16–21 and 26–31 were more widely
varied than those of 1–4 at the same site. Although the 3-methoxy-
phenethyl analog showed the greatest r2 affinity (18, r2
Ki = 14 nM), the next most prominent
r2 interactions were demon-
strated by the simple phenylpropyl and phenylbutyl derivatives
(26 and 20, respectively), with each possessing a r2 Ki value of
18 nM. Within the current series it appears that methoxy-subsitu-
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/r2
affinity, and may be generally detrimental to 2 binding. A conclu-
r
sive r2 receptor pharmacophore has not yet been proposed,
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those for r1 binding, thereby accounting for the myriad of high
affinity r2 ligands displaying less than 10 times subtype selectiv-
ity—including 18, 20, and 26.42
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Considered together, the r1 affinities and subtype selectivities
of piperazines 16–21 and 26–31 (Ki = 3.1–17 nM) were comparable
to benzylic analogs 1, 3, and 4 (Ki = 2.7–16 nM). Moreover, the
affinities of 16–21 and 26–31 for the 5-HT2B receptor (Ki = 120–
628 nM) were similar to
r1-selective 1 (Ki = 497 nM); much lower
than the relatively nonselective methoxybenzylic analogs 2–4
(Ki = 9.7–28 nM). However, several ligands from the present work
showed increased off-target interaction with D2 dopamine recep-
tors compared to the micromolar affinities of 1–4 at the same site,
most notably 20, 28, 30, and 31 (Ki = 89–556 nM).
We have developed a series of subtype selective
gands by amalgamating lead structure 1 with the r1 pharmaco-
phore proposed by Glennon et al.37–39 The
receptor affinities of
these linker-elongated arylalkylpiperazines revealed that 4-
methoxyphenyl groups are generally well tolerated at 1, with
r receptor li-
r
r
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the 4-methoxy-substituted phenylpropylpiperazine 29 was identi-
fied as a high-affinity r1 receptor ligand (Ki = 3.1 nM, r2/r1 = 45),
with lower affinity for other CNS receptors. The binding profile of
compound 29 suggests that it may be suitable for the development
of a carbon-11-labeled tracer for imaging r1 receptors using posi-
tron emission tomography (PET).