Consequences of linker length alteration of the α7 nicotinic acetylcholine receptor (nAChR) agonist, SEN12333

Article abstract of DOI:10.1016/j.bmcl.2012.02.052

A series of ligands based on SEN12333, containing either contracted or elongated alkyl chains, were synthesized and evaluated in molecular docking studies against a homology model of the α7 nicotinic acetylcholine receptor (nAChR) subtype. The predicted binding of all ligands was highly similar, with the exception of the analog containing a 5 methylene unit spacer. However, in vitro competition binding assays revealed that the ligands possessed dissimilar binding affinities, with a K_i range of more than an order of magnitude (K_i = 0.50 to >10 μM), and only SEN12333 itself exhibited functional activity at the α7 nAChR.

Full text of DOI:10.1016/j.bmcl.2012.02.052

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2380–2384
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Consequences of linker length alteration of the
receptor (nAChR) agonist, SEN12333
a7 nicotinic acetylcholine
Corinne Beinat a, Samuel D. Banister a,b, Saundra van Prehn b, Munikumar Reddy Doddareddy c,
David Hibbs c, Michael Sako c, Mary Chebib c, Thao Tran d, Nour Al-Muhtasib d, Yingxian Xiao d,
Michael Kassiou a,b,e,
⇑
a School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
b Brain and Mind Research Institute, Sydney, NSW 2050, Australia
c School of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia
d Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20057, USA
e 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 ligands based on SEN12333, containing either contracted or elongated alkyl chains, were syn-
Received 23 January 2012
Revised 13 February 2012
Accepted 16 February 2012
Available online 24 February 2012
thesized and evaluated in molecular docking studies against a homology model of the a7 nicotinic ace-
tylcholine receptor (nAChR) subtype. The predicted binding of all ligands was highly similar, with the
exception of the analog containing a 5 methylene unit spacer. However, in vitro competition binding
assays revealed that the ligands possessed dissimilar binding affinities, with a Ki range of more than
an order of magnitude (Ki = 0.50 to >10
the 7 nAChR.
l
M), and only SEN12333 itself exhibited functional activity at
Keywords:
a
a7 Nicotinic receptors
Ó 2012 Elsevier Ltd. All rights reserved.
Molecular modeling
CNS
Structure–activity relationships
Neuronal nicotinic acetylcholine receptors (nAChRs) are a fam-
ily of ligand-gated cation channels distributed throughout the cen-
tral and peripheral nervous systems (CNS and PNS, respectively),
and have generated much interest as potential therapeutic targets
for the treatment of cognitive disorders.1–3 Multiple nAChR sub-
types are known to exist, with each subtype comprising a homo-
or heteropentameric combination of twelve possible subunits;
utility in the treatment of the cognitive deficits associated with
schizophrenia.12–14
Reduced expression of
a7 nAChR protein has also been observed
in the hippocampus of Alzheimer’s disease (AD) patients.15,16
A
component of the neuritic plaques that characterize AD and are
thought to contribute to neurodegeneration, b-amyloid (Ab) pep-
tides, were found to interact with a7 nAChRs with picomolar affin-
a
2–
a
10 and b2–b4. The two most abundant nAChRs in the human
4b2 and 7 subtypes, the latter distinguished from
ity.17,18 The exogenous nAChR agonist nicotine shows protective
brain are the
a
a
effects against the neurotoxicity of Ab peptides, and this neuropro-
other subtypes by its unique pharmacology and relatively extreme
tection can be blocked by selective
Moreover, inhibition of 7 mRNA and protein expression using siR-
a
7 nAChR antagonists.19
Ca2+ permeability.4,5
a
The
cific regions of the postmortem brains of schizophrenic patients
showing a reduction in 7 nAChR mRNA expression and a concom-
itantly reduced density of
7 nAChR protein.6–8 Moreover, poly-
morphisms within the 7 nAChR subunit gene CHRNA7 have
a
7 subtype has been implicated in schizophrenia, with spe-
NA transfection exacerbated the toxicity of Ab peptides in neuro-
blastoma SH-SY5Y cells.20 Consistent with the aforementioned
a
findings, selective stimulation of a7 nAChRs was shown to attenu-
a
ate Ab-induced cell death, suggesting a therapeutic role for a7
a
nAChR agonists in the treatment of AD.19,20
been linked to auditory gating deficits in schizophrenia, an aber-
rance that is normalized by nicotine, possibly accounting for the
high rate of tobacco use among schizophrenic patients.9–11 Selec-
Although
tic intervention in schizophrenia and AD, few structural classes of
selective 7 nAChR agonists are known, with reported ligands pre-
dominantly based on anabaseine, quinuclidine, or diazabicyclic
scaffolds. One of the first functionally 7-selective agents
a7 nAChRs represent a promising target for therapeu-
a
tive
a7 nAChR agonists have shown excellent in vivo efficacy in
the normalization of auditory gating in rats, indicating potential
a
described was the partial agonist, dimethoxybenzilidene anabasein
(DMXB-A, 1, Fig. 1), a natural product derivative with only micro-
molar potency at a7 nAChRs and off-target activity at a4b2 nAChRs
⇑
Corresponding author.
E-mail address: michael.kassiou@sydney.edu.au (M. Kassiou).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.02.052

C. Beinat et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2380–2384
2381
O
Br
O
O
N
N
O
NH
N
O
O
N
N
1: DMXB-A
2: AR-R17779
3: SSR180711
O
H
N
O
N
N
N
O
N
N
NH
4: TC-5619
5: ABT-107
Figure 1. Selected a7 nAChR agonists evaluated in preclinical and clinical studies.
and 5-HT3 receptors.21,22 DMXB-A subsequently entered a proof-
of-concept trial where it improved neurocognitive measures in
non-smoking schizophrenic patients,23 and has progressed to
Phase II studies.3
permeation in vivo.36 Preliminary evaluation of SEN12333 in
animal models of episodic memory revealed its ability to reverse
both scopolamine- and MK-801-induced amnesia.35,36
The development of SEN12333 was focused on improving both
potency and drug-like properties. As a result, only limited struc-
The potential therapeutic applications of a7 agonists have gen-
erated much interest within the pharmaceutical industry. An early
example disclosed by AstraZeneca was the quinuclidine-derived
spiro-oxazolidinone, AR-R17779 (2), a potent full agonist that
ture–activity relationships are available for this class of a7 nAChR
ligands. Alteration of the morpholine group of 7 revealed that a
reasonable diversity of heterocycles was tolerated, with small, ali-
phatic azacycles being optimal. Similarly, replacement of the ary-
demonstrates several hundred-fold in vitro selectivity for rat
a7
over rat
a
4b2 nAChRs.24 AR-R17779 has undergone extensive
lanilide with other aromatic moieties had little effect on a7
pharmacological profiling in vivo, and improves learning and
nAChR activity, but biaryls were generally preferred over monoaro-
matic groups. The butyl chain tethering the morpholine and
pyridylanilide groups allows a large degree of conformational free-
dom, and little is known about the optimal orientation of these two
pharmacophic units.
To determine the most favorable distance between the morpho-
line ring and the pyridylanilide group in SEN12333, analogs of 7
containing contracted or elongated alkyl tethers were synthesized.
The desired ligands contained an alkyl linker of 1, 2, 3, or 5 meth-
ylene units (8a–d, Scheme 1), were synthesized from the corre-
memory in several rat models, consistent with the anticipated cog-
nition-enhancing effects of selective
ever, even minor structural changes to AR-R17779 attenuated
a
7 nAChR agonists.25,26 How-
a7
affinity, limiting its use as a lead for the further development of
a
7 agonists.24
Sanofi-Aventis has also reported the diazabicyclic SSR180711
(3) as a potent partial agonist of recombinant human
a7 nAChRs,
with greater than 250-fold selectivity over other nAChR subtypes,
and negligible affinity for 100 other receptors.27,28 SSR180711
was able to ameliorate the cognitive deficits induced by repeated
sponding
x-bromoalkanoic acids (9a–d, respectively). The
phencyclidine administration in mice and, like many
a
7 nAChR
commercially available acids were converted to the corresponding
acid chlorides using oxalyl chloride, and subsequent treatment
with 4-bromoaniline in the presence of a suitable base gave ani-
lides 10a–d in acceptable yield. Alkylation of morpholine by
bromoalkanes 10a–d was achieved in the presence of catalytic io-
dide to give compounds 11a–d in good yields. Subjecting bromo-
arenes 11a–d to Suzuki coupling with 3-pyridyl boronic acid
gave the desired ligands 8a–d. SEN12333 (7, n = 4) was synthesized
analogously, starting from commercially available 5-bromopenta-
noic acid (9e), for direct comparison with the new analogs.
Molecular modeling was undertaken to predict possible varia-
tion of binding modes for ligands 7 and 8a–d. Firstly, a homology
agonists, has shown promise in animal models of the cognitive as-
pects schizophrenia.29,30
Selective
the alleviation of cognitive dysfunction in schizophrenia (CDS), and
neuroprotection in AD.31–33 Indeed, many
7 nAChR agonists are
a7 nAChR agonists represent promising candidates for
a
progressing through clinical trials and proving efficacious for the
treatment of CDS, including TC-5619 (4, Phase II), ABT-107 (5,
Phase I), and MEM-3454 (structure undisclosed, Phase II).3 How-
ever, known a7 ligands display relatively little structural diversity,
having been developed through lead optimization of few chemo-
types, and most possess cross-reactivity with other sites.
High-throughput screening by Siena Biotech and Wyeth identi-
fied piperazine 6 (Fig. 2) as a novel chemotype with weak partial
model of the a7 nAChR was generated by using the ‘prime’ suite
in Maestro.37 The crystal structure of the acetylcholine binding
agonist activity at
zine, biaryl, and amide regions of 6 led to the discovery of
SEN12333 (7).35 SEN12333 is a potent and selective
7 nAChR ago-
a
7 nAChRs,34 and investigation of the pipera-
protein (AChBP)38 from L. stagnalis (PDB code: 1UW6) was used
as a template for generating the model. The sequence of
(accession code: AAA83561) as obtained from NCBI was aligned on
the template. Five subunits of the 7 nAChR were individually
made and merged to form an 7 nAChR pentamaric model. The
OPLS_2005 all-atom force field was used for energy scoring of
a7 nAChR
a
nist, exhibiting high selectivity for
a
7 over other nAChR subtypes,
a
5-HT3 receptors, and hERG.35,36 In addition to its promising in vitro
a
profile, 7 also showed reasonable bioavailability and good brain

2382
C. Beinat et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2380–2384
N
N
H
N
O
N
N
O
O
N
N
H
O
O
6: EC
50 = 2.84 µM
(SEN12333): EC50 = 1.65 µM
7
Figure 2. Activity of SEN12333 and its parent structure, 6, at a7 nAChRs.
Br
Br
O
n
O
n
O
O
a, b
c
Br
Br
N
OH
N
H
N
H
n
9a:
b:
10a-e
11a-e
n = 1
n = 2
c: n = 3
d
d:
e:
n = 5
n = 4
N
8a: n = 1
8b:
8c:
n = 2
n = 3
O
O
n
N
8d: n = 5
N
H
7:
n = 4
Scheme 1. Reagents and conditions: (a) (COCl)2, rt, 45 min; (b) 4-bromoaniline, Et3N or K2CO3, CH2Cl2, À78 °C to rt, 1 h, 54–94% over 2 steps; (c) morpholine, NaI, Et3N, DMF,
reflux, 16 h, 64–85%; (d) Pd(PPh3)4, pyridine-3-boronic acid, MeCN–0.4 M aq Na2CO3 (50:50), reflux, 18 h, 67–83%.
the protein, and surface generalized Born (SGB) continuum solva-
tion model for treating solvation energies and effects. The
predicted model was then prepared for docking by using protein
preparation wizard, wherein hydrogens were added, bond orders
assigned, and disulfide bonds created. Finally the corrected struc-
ture was optimized by restrained minimization using ‘impref min-
imization’ by selecting hydrogens only so that heavy atoms were
left untouched.
Docking studies were conducted by using ‘Glide’ software as
provided in Maestro.39 A docking model was generated by forming
a receptor grid around nicotine, the ligand from the template,
which was included in the model as a reference for the active site
activity. As seen in Figure 4, all five ligands docked in a similar
way, with the exception of 8d (n = 5), which docked in an alterna-
tive orientation to accommodate the elongated chain. The docking
poses and the XP40 docking summary (see Table S1) show that all
ligands except 8a (n = 1) make cation–p interactions with the
receptor, all but 8d form a hydrogen bond with Gln139, and none
interact with Ser172. The docking results predict an increase in
activity within this series when chain length is increased from 4
(SEN12333, 7) to 5 methylene units (8d), as indicated by the G-
score increase from À10.59 to À11.13. Compound 8a (n = 1) was
predicted to be least active, with a G-score of À0.67, having a
relative large, negatively contributing ‘penalty’ for polar atom bur-
ial, desolvation, and intra-ligand contacts.
between two adjacent
a7 monomers. The ligands under study
were minimized using OPLS_2005 forcefield, with water as solvent
and ‘constant dielectric’ as electrostatic treatment, in the Macro-
model module of Maestro. Finally they were protonated at pH
7.4 and docked flexibly in to the active site using extra-precision
(XP) mode.40
To confirm the validity of the modeling, 7 and 8a–d were sub-
jected to competition binding measurements against racemic
[3H]epibatidine. The binding assays were performed using mem-
brane homogenates of stably transfected HEK293 cells expressing
rat
a7, a4b2, or a
3b4 nAChR subtype.41–43 The binding affinities
To understand the ligand–receptor interactions of
receptor agonists, three known ligands with agonist activity were
docked into the 7 nAChR model; AR-R177796, acetylcholine,
and nicotine. Interestingly, all three ligands showed comparable
interactions with the receptor (Fig. 3). The protonated nitrogen of
a
7 nAChR
of these analogs are shown in Table 1. Contrary to the predictions
of the docking studies, 7 and 8a–d displayed Ki values ranging from
a
0.50
ders of magnitude. The highest affinity was displayed by
SEN12333 itself (5, Ki = 0.50 M). Extending the distance of the al-
kyl tether of SEN12333 by a single methylene unit, to give 8d, re-
sulted in more than an order of magnitude reduction in 7 nAChR
binding (Ki >10 M), contradicting the improved affinity antici-
lM to greater than 10 lM, a difference of more than two or-
l
these ligands was found to make cation–p interactions with one
of the five aromatic amino acids that comprise the wall of the
hydrophobic pocket (Chain A: Trp77 and Chain B: Tyr115,
Trp171, Tyr210, and Tyr217). The other important common feature
is that all compounds made a hydrogen bond interaction with hy-
droxyl group of Ser172 (ChainB). These two interactions seem to be
a
l
pated by the docking studies. Compared to SEN12333, the ethyl-
ene- and propylene-linked congeners (8b and 8c) also showed
diminished
a7 nAChR binding (Ki >10
lM in both cases). However,
very important for the agonistic activity of
Compounds 7 and 8a–d were docked into the
site to predict the effect of chain length variation on
a
7 nAChR ligands.
7 nAChR active
7 nAChR
8a (Ki = 3.9
l
M), containing the shortest linker, exhibited a7
a
affinity less than 8 times lower than that of SEN12333 itself, de-
spite the contrary predictions of the docking studies.
a

C. Beinat et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2380–2384
2383
Figure 3. AR-R17779, acetylcholine, and nicotine docked into the active site of the a7 nAChR model. Hydrogen bonding with Ser172 is also shown. Image drawn using ICM
browser.
Figure 4. Compounds 7 and 8a–d docked into the active site of the
a7 nAChR model. Hydrogen bonding with Gln139 is also shown. Image drawn using ICM browser.
Table 1
by approximately 11% compared to the maximal ACh response
Binding affinities of 7 and 8a–d for multiple nAChR subtypes
with an EC50 of 9.5
The remaining analogs did not exhibit any agonist or antagonist
activity when tested at 100 M (data not shown).
Contraction and elongation of the alkyl chain in SEN12333 pro-
duces distinct changes in 7 affinity, and optimal binding is con-
lM (95% confidence interval 3.4–26) (Fig. 5).
Compound
Kia
(
l
M)
a
7
a
4b2
a3b4
l
8a
8b
8c
8d
3.9 1.5
>10
>10
>10
0.50 0.03
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
a
ferred by a 4 methylene unit linker, as found in SEN12333 itself.
However, the variation of binding affinity is not predicted by
7 (SEN12333)
molecular docking to a
the limited predictive utility of this model for the rational design of
7 receptor agonists. A 4-carbon chain appears to offer ideal inter-
functional group distances for interaction with 7 nAChRs, and fu-
a7 nAChR homology model, demonstrating
a
Ki values represent the mean SEM of three independent experiments.
a
Compounds 8a–d and SEN12333 (7) were also evaluated on rat
a
recombinant
a
7 receptors expressed in Xenopus oocytes. Only
ture work could focus on the functionalization or conformational
SEN12333 exhibited partial agonist activity, activating the receptor
restriction of this tether.

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C. Beinat et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2380–2384
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2012.02.052.
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