Exploration of ring size in a series of cyclic vicinal diamines with σ1 receptor affinity

Article abstract of DOI:10.1016/j.bmcl.2012.07.026

Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl- N′-(4-alkoxybenzyl)piperazines were prepared to explore the effect of ring contraction and expansion on σ receptor affinity and subtype selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vicinal diamines possessed affinity and selectivity for σ₁ receptors. The imidazolidines possessed nanomolar σ₁ affinities (K_i = 6.45-53.5 nM), and relatively low levels of subtype selectivity (σ₂/σ₁ = 58-237). However, the piperazines and diazepanes achieved picomolar σ₁ interactions, with K_i ranges of 0.05-10.28 and 0.10-0.194 nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimination over the σ₂ receptor, with σ₁ selectivities of 143-16140 and 220-11542, respectively.

Full text of DOI:10.1016/j.bmcl.2012.07.026

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5493–5497
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Exploration of ring size in a series of cyclic vicinal diamines with r1
receptor affinity
Iman A. Moussa a, Samuel D. Banister a,b, Miral Manoli b,c, Munikumar Reddy Doddareddy d, Jinquan Cui e,
Robert H. Mach e, 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
d Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia
e Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
a r t i c l e i n f o
a b s t r a c t
Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl-N0-(4-alkoxybenzyl)piperazines
Article history:
Received 8 June 2012
Revised 3 July 2012
Accepted 6 July 2012
Available online 14 July 2012
were prepared to explore the effect of ring contraction and expansion on
selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vic-
inal diamines possessed affinity and selectivity for 1 receptors. The imidazolidines possessed nanomolar
r1 affinities (Ki = 6.45–53.5 nM), and relatively low levels of subtype selectivity (r2 1 = 58–237). How-
r receptor affinity and subtype
r
/
r
ever, the piperazines and diazepanes achieved picomolar r1 interactions, with Ki ranges of 0.05–10.28
and 0.10–0.194 nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimi-
nation over the r2 receptor, with r1 selectivities of 143–16140 and 220–11542, respectively.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Sigma receptor
Piperazine
Imidazolidine
Diazepane
Diamine
Sigma (
of two subtypes, r1 and r2
in the central nervous system (CNS) and, to a lesser extent, in the
periphery.2–5 The
subtypes are differentiated by their anatomical
distribution, apparent molecular weight, and ligand discrimination
profiles.6 While the r1 receptor has been cloned from numerous
species and tissues, including human brain,7 much less is known
about the r2 receptor. In fact, it was only very recently that the
r2 binding site was putatively identified as progesterone receptor
membrane component 1 (PGRMC1).8
r
) receptors are unique mammalian proteins comprised
The diverse pharmacology of r1 receptors is consistent with
their implication in virtually all major disorders of the CNS. Indeed,
there is compelling evidence that r1 receptors are involved in the
pathophysiology of anxiety, depression, neurodegeneration, motor
dysfunction, and substance abuse.19,20 Efforts have been directed
1
,
both of which are widely distributed
r
towards the development of selective agents targeting r1 receptors
as potential anxiolytics, antidepressants, and neuroprotective
agents with novel modes of action.20,21
Various N,N0-disubstituted piperazines have been reported as
selective
r receptor ligands. One of the earliest examples was SA-
One of the most well-characterized roles of
r
1 receptors is their
4503 (1, Fig. 1), a r1 selective ligand (r1 Ki = 4.6 nM, r2
ability to modulate Ca2+ flux by acting as molecular chaperones for
type 3 inositol-1,4,5-triphosphate (IP3) receptors at the interface
between the endoplasmic reticulum (ER) and mitochondria, the
mitochondria-associated ER membrane (MAM).9,10 However r1
receptors are also known to translocate to the plasma membrane,
where they regulate voltage-dependent Ca2+ channels and K+ chan-
Ki = 63 nM),22,23 which has demonstrated efficacy in animal models
of amnesia, depression, and ischemia.24 Related piperazine YZ-185
(2) also shows a preference for r1 receptors (r1 Ki = 1.4 nM, r2
Ki = 10.2 nM), and attenuates cocaine-induced convulsions in mice
at doses as low as 0.01 mg/kg.25,26 The subtype non-selective
r
li-
gand CM156 (3, r1 Ki = 1.3 nM, r2 Ki = 0.6 nM) diminishes the stim-
nels.11,12 Moreover,
r1 receptors are known to modulate the activity
ulatory and toxic effects of both cocaine and methamphetamine in
mice, and was able to reduce cocaine-induced conditioned place
preference (CPP) by reversing cocaine-effected alterations of gene
expression.27–29 Other N,N0-disubstituted piperazines with selectiv-
ity for r1 receptors include 4 (r1 Ki = 34.4 nM, r2 Ki = 1870 nM),30
and even simple N,N0-dibenzylpiperazine (5, r1 Ki = 5.81 nM, r2
Ki = 1274 nM), which also shows anticocaine activity in mice.31
of several neurotransmitter systems, including those of dopa-
mine,13–15 5-hydroxytryptamine (5-HT),16 and norepinephrine.17,18
⇑
Corresponding author.
E-mail address: michael.kassiou@sydney.edu.au (M. Kassiou).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.026

5494
I. A. Moussa et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5493–5497
R
N
N
N
O
N
N
S
S
SA-4503 (1, R = OCH3)
CM156 (3)
2
YZ-185 ( , R = H)
O
N
N
N
N
4
5
N
N
O
OR
6
(R = CH3)
7 (R = CH2CH3)
8
9
(R = CH2CH2F)
(R = CH2CH2CH3)
10 (R = CH2CH2CH2F)
Figure 1. N,N0-Disubstituted piperazines with affinity for r1 receptors.
We recently reported a series of 4-alkoxybenzyl-substituted
N-(2-benzofuranyl)methylpiperazines, including 6–10 (Fig. 1),
which displayed higher r1 affinity (r1 Ki = 2.6–53.8 nM) and sub-
tools for evaluating the role of r1 receptors in CNS disease
states.32,34
To further extend the structure-affinity relationship (SAfiR) pro-
type selectivity (r2/r1 = 37–187) than their 2- or 3-alkoxybenzyl
file of this class of N,N0-disubstituted 1,4-piperazines, the influence
regioisomers.32,33 Additionally, 6 and 8 were found to possess suit-
able lipophilicity for use as potential r1 receptor PET imaging
agents. Isotopologues [11C]6 and [18F]8 were synthesized and eval-
uated as PET tracers in Papio hamadryas, showing good brain per-
meation and distribution in brain regions consistent with
established r1 expression patterns.32,34 The promising pharmaco-
kinetic profiles of [11C]6 and [18F]8 in vivo makes them attractive
of ring size on r affinity and subtype selectivity was explored by
preparing analogs of 6–10 comprising 5- or 7-membered cyclic
vicinal diamine cores. The synthesis of imidazolidines 11–15 and
1,4-diazepanes 16–20 is shown in Scheme 1 and Scheme 2, respec-
tively. The 4-alkoxybenzyl substituents of 6–10 were retained in
these new congeners to promote enhanced r1 affinity and selectiv-
ity, as previously demonstrated in SAfiR studies.32,33
OR
a
b
O
O
O
OH
NH
NHBoc
NH
NH2
HO
O
O
O
O
24
: R = CH3
22
23
21
25: R = CH2CH3
26: R = CH2CH2F
27
: R = CH2CH2CH3
28: R = CH2CH2CH2F
c
OR
OR
OR
d
e
O
N
N
O
O
NH HN
NH HN
O
O
11
34
29
: R = CH3
: R = CH3
: R = CH3
12: R = CH2CH3
13: R = CH2CH2F
35: R = CH2CH3
36: R = CH2CH2F
30: R = CH2CH3
31: R = CH2CH2F
14
37
32
: R = CH2CH2CH3
33: R = CH2CH2CH2F
: R = CH2CH2CH3
: R = CH2CH2CH3
15: R = CH2CH2CH2F
38: R = CH2CH2CH2F
Scheme 1. Reagents and conditions: (a) H2NCH2CH2NHBoc, NMM, EDCꢀHCl, HOBt, DMF, rt, 20 h, 83%; (b) 4 M HCl in dioxane, rt, 0.5 h, basic work-up, 100%; (c) NMM,
EDCꢀHCl, HOBt, DMF, rt, 20 h, 69–80%; (d) AlH3, THF, 0 °C, 16 h, 51–72%; (e) 37% aq CH2O, H2O, 0 °C, 2 h, 62–78%.

I. A. Moussa et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5493–5497
5495
OR
O
O
O
b
d
f
HN
NR
N
NR
N
NH
N
N
O
39
40
41
42
43
44
: R = H
: R = Boc
: R = H
: R = H
a
c
g
e
17
18
: R = Boc
: R = CH2CH3
: R = CH2CH2F
OCH3
19: R = CH2CH2CH3
20
: R = CH2CH2CH2F
O
N
N
16
Scheme 2. Reagents and conditions: (a) Boc2O, CH2Cl2, rt, 20 h, 65%; (b) 21, NMM, EDCꢀHCl, HOBt, DMF, rt, 20 h, 87%; (c) 4 M HCl in dioxane, rt, 0.5 h, basic work-up, 100%; (d)
AlH3, THF, 0 °C, 2 h, 77%; (e) 4-methoxybenzaldehyde, NaBH(OAc)3, ClCH2CH2Cl, rt, 4 h, 80%; (f) 4-hydroxybenzaldehyde, NaBH(OAc)3, ClCH2CH2Cl, rt, 4 h, 81%; (g) ROTs,
K2CO3, DMF, reflux, 16 h, 60–62%.
O
O
O
a
H
H
b
OH
F
F
HO
O
O
n
n
45
46
: n = 1
47: n = 2
26
: n = 1
28: n = 2
Scheme 3. Reagents and conditions: (a) FCH2CH2OTs or FCH2CH2CH2OTs, K2CO3, DMF, 40 °C, 16 h; (b)(i) 30% aq H2O2, 50% aq KOH, CH3OH, reflux, 1 h; (ii) 2 M aq HCl, 100%
over 3 steps.
The synthesis of imidazolidines 6–10 commenced with the cou-
pling of benzofuran-2-carboxylic acid (21) and N-tert-butoxycar-
bonylethylenediamine, the latter prepared by monoprotection of
ethylene diamine with di-tert-butyl dicarbonate, to give amide
22. Acidolysis of carbamate 22, followed by basic work-up, quanti-
tatively afforded primary amine 23. The newly liberated amine of
23 was coupled to the appropriately substituted 4-alkoxybenzoic
acids (24–28) under standard amide formation conditions to fur-
nish the respective bisamides (29–33), which were reduced to
the corresponding diamines (34–38) using aluminum hydride.
Transannular condensation of diamines 34–38 with aqueous form-
aldehyde afforded imidazolidines 11–15 in overall yields of 21–
32% for the 5-step sequence.
The binding affinities (Ki values) of compounds 6–20 for
2 receptors were determined using well-established in vitro com-
petition assays and are presented in Table 1. For consistency, pre-
viously reported compounds 6–10 were screened under the same
r1 and
r
conditions to enable meaningful interpretation of changes to
r
receptor affinity and subtype selectivity arising from heterocycle
variation. Homogenates of guinea pig brain membranes and rat
liver were used as the source of r1 and r2 receptors, respectively.
Binding affinities for r1 receptors were determined from displace-
ment of
r
1-selective [3H](+)-pentazocine, while those for r2
utilized the subtype non-selective radioligand, [3H]DTG, in the
presence of cold (+)-pentazocine (1 lM) to mask r1 sites.
In contrast to the late-stage heterocyclization of Scheme 1, the
synthesis of the diazepane series started with the monoprotection
of 1,4-diazepane (1,4-diazacycloheptane, 39) as its tert-butylcarba-
mate (40), the remaining amine of which was coupled to benzofu-
ran-2-carboxylic acid under standard conditions to yield amide 41.
Cleavage of the tert-butoxycarbonyl protecting group was accom-
plished with hydrogen chloride, followed by basic workup to fur-
nish 42. Reduction of amide 42 using aluminum hydride gave
common precursor 43 in moderate yield, and reductive alkylation
of 43 with anisaldehyde or 4-hydroxybenzaldehyde using sodium
triacetoxyborohydride afforded diazepane 16 and phenol 44,
respectively. Alkylation of the latter with the tosylates derived
from ethanol, 2-fluoroethanol, n-propanol or 3-fluoropropanol32
furnished 1,4-diazepane congeners 17–20 in acceptable yields.
Although benzoic acids 24, 25, and 27 were commercially avail-
able, 4-fluoroethoxybenzoic acid (26) and 4-fluoropropoxybenzoic
acid (28) were synthesized according to Scheme 3. Alkylation of
4-hydroxybenzaldehyde (45) with the appropriate fluoroalkyl tos-
ylate32 gave 4-fluoroalkoxybenzaldehydes 46 and 47, which were
transformed to the corresponding carboxylic acids, 26 and 28,
respectively, by Dakin oxidation.
Table 1
Binding affinities of compounds 6–20 for r1 and r2 receptors
Compound
Ki (nM SEM)a
r1 selectivityb
r1
r2
6
7
8
0.18 0.05
167.2 4.2
1115 65
807 91
929
6194
16140
143
842
58
123
237
121
175
220
1505
881
4605
11542
0.18 0.01
0.05 0.02
10.28 1.74
1.61 0.07
43 4.2
19.3 1.2
6.45 1.32
53.5 5.7
9
1469 47
1355 155
2497 283
2377 279
1529 129
6473 346
3643 270
118.9 2.2
292 39.6
88.1 2.8
700 95
10
11
12
13
14
15
16
17
18
19
20
20.8 2.6
0.54 0.04
0.194 0.02
0.10 0.02
0.152 0.024
0.12 0.026
1385 327
a
Ki values represent the mean SEM of four experiments.
r1 selectivity presented as the ratio of r2 Ki over r1 Ki.
b

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I. A. Moussa et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5493–5497
Consistent with previously identified SAfiRs,32 piperazines 6–10
all showed high affinity for r1 receptors (Ki = 0.05–10.28 nM) and
excellent selectivity over 2 sites (r2 1 = 143–16140). Homologa-
Table 2
Predicted acid dissociation constants and pH 7.4 microspecies distributions for 6, 11,
and 16
r
/r
tion of the simple methoxy derivative 6 to the corresponding ethyl
ether 7 had little influence on r1 binding (Ki = 0.18 nM for each),
but produced a several-fold increase in subtype selectivity. Further
homologation of 7 to give propyl ether 9 resulted in a small de-
OCH3
1 N
N 2
n
O
crease in both r1 affinity and selectivity (Ki = 10.28 nM, r2
1 = 143), but otherwise indicated that alkyl ethers of up to 3 car-
bon atoms in length are tolerated at this position.
/
r
Compound Predicted
Predicted
pKa2 (N-
2)
Ionization
state
Predicted microspecies
distribution at pH 7.4
(%)
pKa1 (N-
1)
Subjecting the ethoxy group of 7 to a terminal hydrogen-for-
fluorine bioisosteric replacement, as occurs in 8, resulted in further
improvement to r1 binding, providing the most potent and selec-
N-1 N-2
6 (n = 2)
8.03
6.42
9.03
2.29
1.71
4.75
N
N
N
19.03
64.37
NH+
N
tive member r1 ligand within this series (Ki = 0.05 nM, r2
1 = 16140). This trend was retained for the propyl ether of 9, with
terminal fluorine substitution imparting improved r1 affinity and
selectivity to 10 (Ki = 1.61 nM, r2 1 = 842). Taken together, this
/
NH+ 16.60
r
NH+ NH+
0.00
90.51
7.12
2.38
0.00
11 (n = 1)
16 (n = 3)
N
N
/r
NH+
N
N
NH+
information suggests that a distal electrostatic interaction may
be important for interaction of the alkoxybenzyl group with the
r1 binding site within this class of piperazines.
Ring-contracted imidazolidines 11–15 displayed a reduction in
r1 affinity of approximately one to two orders of magnitude com-
pared to their piperazine analogs (Ki = 6.45–53.5 nM). A terminal
fluorine atom on the alkyl ether, present in imidazolidines 13
and 15, conferred improved r1 affinity compared with the corre-
sponding non-fluorinated analogs, 12 and 14. As with the pipera-
NH+ NH+
N
N
N
2.30
NH+
N
77.47
NH+ 20.01
NH+ NH+
0.22
As could be expected for both 6 and 16, the predicted major
species at pH 7.4 is that in which only a single nitrogen atom is
protonated (benzofuranyl-proximal N-1), representing 64.37%
and 77.47% distribution, respectively. By contrast, the poor basicity
of imidazolidine 11 results in 7.12% distribution of the correspond-
ing protonated species at pH 7.4, with the unprotonated form pre-
dominating (90.51%). If the summative monoprotonated species
are considered in each case, singly ionized ligands are predicted
to represent 80.97% and 97.48% of those in solution at assay pH
for 6 and 16, respectively, but only 9.5% for 11 (>90% unprotonat-
ed), suggesting a dramatic difference in the basicity of a piperazine
or diazepane core compared to imidazolidine. Based on the differ-
ential basicities of each vicinal diamine core, it is probable that a
similar distribution might be predicted at pH 7.4 even if N-2 were
to prove more basic than N-1.
zine congeners, the most
imidazolidine series was fluoroethyl ether 13 (Ki = 6.45 nM, r2
1 = 237), however, compared to corresponding piperazine 8, r1
r1-selective member of the
/
r
affinity was more than 120 times lower, and subtype selectivity
was reduced approximately 70-fold.
Diazepanes 16–20, ring-expanded homologs of piperazines 6–
10, showed comparable r1 affinities to their piperazine counter-
parts, with Ki values in the subnanomolar range (Ki = 0.10–0.54
nM). Alkyl ethers featuring two or three carbons possessed high
selectivity for the
20 (r2 1 = 11542) showing
1 = 16140). Within the diazepane series, r2 affinities varied even
r1 subtype (r2/r1 = 881–11542), with diazepane
/r
r
1 selectivity akin to piperazine 8 (r2
/
r
more widely than those of the piperazines and imidazolidines,
ranging from low nanomolar to high micromolar affinities (r2
Ki = 88.1–6473 nM), with no clear trend obvious from differential
alkyl ether length.
The primary determinant of the differential r1 receptor affini-
ties of the imidazolidines, piperazines, and diazepanes described
above appears to be basicity of the central heterocyclic ring, with
a piperazine or diazepane core conferring subnanomolar affinity
The differences in
an imidazoline to a piperazine or diazepane core prompted us to
investigate the protonation state at the in vitro binding assay
r1 affinity and selectivity when moving from
for r1 receptors. In each series, a two carbon ether at the 4-position
r
of the benzyl ring confers comparable or greater r1 affinity than a
methyl ether, but a three carbon chain is nearly equally well toler-
ated. Additionally, terminal hydrogen-for-fluorine substitution of
the ethoxy and propoxy groups in each series improves both the
r1 affinity and selectivity over the r2 subtype, suggesting that an
electrostatic interaction may be important at the complementary
region of the r1 receptor binding site.
Further improvement to these ligands may be achieved by
rigidification of the diamine core, and the preparation of bridged
piperazines and diazepanes is currently underway. It is possible
that N-2 does not contribute significantly to r1 interactions, and
the synthesis of analogous piperidines and homopiperidines to
confirm or refute this hypothesis is in progress.
pH of 7.4. The predicted pKa and predicted microspecies distribu-
tions of the simple methoxy-substituted member of each series
(6, 11, and 16) were determined using the relevant calculator plu-
gins in ChemAxon’s Marvin software suite35 and are presented in
Table 2. The pKa and microspecies distribution calculations per-
formed by Marvin have been described and validated previ-
ously,36–40 however, all resultant data was interpreted cautiously
due to a relative lack of experimental information about the differ-
ential basicity of systems typified by 6, 11, and 16.
The most basic nitrogen atom in each of 6, 11, and 16 was pre-
dicted to be that proximal to the benzofuranyl group (N-1),
although the basicity of the distal nitrogen atom (N-2) is likely to
be extremely close. The predicted first acid dissociation constant
for imidazolidine 11 (pKa1 = 6.42), is more than a single log unit
lower than that of piperazine 6 (pKa1 = 8.03), and more than 2 units
lower than diazepane 16 (pKa1 = 9.03), with the respective pre-
dicted second acid dissociation constants (pKa2) following the
same general trend. Regardless of the specific assignment of the
most basic nitrogen atom within each system, it seems likely that
the rank order of basicity for each diamine core decreases from dia-
zepane, to piperazine, to imidazolidine.
The N-(2-benzofuranyl)methyl-substituted piperazine and dia-
zepane scaffolds allow the development of subnanomolar
tor ligands, with excellent selectivity over 2 receptors, pending the
r1 recep-
r
judicious incorporation of N0-(4-alkoxy)benzyl substituents. It is
possible that similar improvements to r1 affinity and selectivity
may be attained by substituting 1,4-diazepane for the 1,4-pipera-
zine core of structurally related r1 ligands 1–5, and their analogs,
representing a promising potential direction for exploration by
other researchers working with piperazine-derived r1 ligands.

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