Consequences of linker length alteration of the α7 nicotinic acetylcholine receptor (nAChR) agonist, SEN12333.
ABSTRACT 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 article published by Elsevier in Bioorganic & Medicinal Chemistry Letters
Consequences of linker length alteration of the α7
nicotinic acetycholine receptor (nAChR) agonist
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
aSchool of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia; bBrain and Mind Research
Institute, Sydney, NSW 2050, Australia; cSchool of Pharmacy, The University of Sydney, Sydney, NSW 2006,
Australia; dDepartment of Pharmacology and Physiology, Georgetown University, Washington, DC 20057,
USA; eDiscipline of Medical Radiation Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
Abstract—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
virtually identical, 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 μM), and only SEN12333 itself
exhibited functional activity at the α7 nAChR.
Keywords: α7 nicotinic receptors; molecular modeling; CNS; structure-activity relationships.
Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated cation
channels distributed throughout the central 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 subtypes are known to exist, with each
subtype comprising a homo- or heteropentameric combination of twelve possible subunits;
α2-α10 and β2-β4. The two most abundant nAChRs in the human brain are the α4β2 and α7
subtypes, the latter distinguished from other subtypes by its unique pharmacology and
relatively extreme Ca2+ permeability.4, 5
The α7 subtype has been implicated in schizophrenia, with specific regions of the
postmortem brains of schizophrenic patients showing a reduction in α7 nAChR mRNA
expression, and a concomitantly reduced density of α7 nAChR protein.6-8 Moreover,
polymorphisms within the α7 nAChR subunit gene CHRNA7 have been linked to auditory
gating deficits in schizophrenia, an aberrance that is normalized by nicotine, possibly
accounting for the high rate of tobacco use among schizophrenic patients.9-11 Selective α7
nAChR agonists have shown excellent in vivo efficacy in the normalization of auditory
gating in rats, indicating potential utility in the treatment of the cognitive deficits associated
Reduced expression of α7 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, β-amyloid (Aβ) peptides, were found
to interact with α7 nAChRs with picomolar affinity.17, 18 The exogenous nAChR agonist
nicotine shows protective effects against the neurotoxicity of Aβ peptides, and this
neuroprotection can be blocked by selective α7 nAChR antagonists.19 Moreover, inhibition of
α7 mRNA and protein expression using siRNA transfection exacerbated the toxicity of Aβ
peptides in neuroblastoma SH-SY5Y cells.20 Consistent with the aforementioned findings,
selective stimulation of α7 nAChRs was shown to attenuate Aβ-induced cell death,
suggesting a therapeutic role for α7 nAChR agonists in the treatment of AD.19, 20
Although α7 nAChRs represent a promising target for therapeutic intervention in
schizophrenia and AD, few structural classes of selective α7 nAChR agonists are known,
with reported ligands predominantly based on anabaseine, quinuclidine, or diazabicyclic
scaffolds. One of the first functionally α7-selective agents described was the partial agonist,
dimethoxybenzilidene anabasein (DMXB-A, 1, Figure 1), a natural product derivative with
only micromolar potency at α7 nAChRs and off-target activity at α4β2 nAChRs 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
The potential therapeutic applications of α7 agonists have generated 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 demonstrates several
hundred-fold in vitro selectivity for rat α7 over rat α4β2 nAChRs.24 AR-R17779 has
undergone extensive pharmacological profiling in vivo, and improves learning and memory in
several rat models, consistent with the anticipated cognition-enhancing effects of selective α7
nAChR agonists.25, 26 However, even minor structural changes to AR-R17779 attenuated α7
affinity, limiting its use as a lead for the further development of α7 agonists.24
Sanofi-Aventis has also reported the diazabicyclic SSR180711 (3) as a potent partial agonist
of recombinant human α7 nAChRs, with greater than 250-fold selectivity over other nAChR
subtypes, and neglibile affinity for 100 other receptors.27, 28 SSR180711 was able to
ameliorate the cognitive deficits induced by repeated phencyclidine administration in mice
and, like many α7 nAChR agonists, has shown promise in animal models of the cognitive
aspects schizophrenia.29, 30
Selective α7 nAChR agonists represent promising candidates for the alleviation of cognitive
dysfunction in schizophrenia (CDS), and neuroprotection in AD.31-33 Indeed, many α7
nAChR agonists are 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 However, known α7 ligands display relatively little
structural diversity, having been developed through lead optimization of few chemotypes,
and most possess cross-reactivity with other sites.
Figure 1. Selected α7 nAChR agonists evaluated in preclinical and clinical studies.
High-throughput screening by Siena Biotech and Wyeth identified piperazine 6 (Figure 2) as
a novel chemotype with weak partial agonist activity at α7 nAChRs,34 and investigation of
the piperazine, biaryl, and amide regions of 6 led to the discovery of SEN12333 (7).35
SEN12333 is a potent and selective α7 nAChR agonist, exhibiting high selectivity for α7 over
other nAChR subtypes, 5-HT3 receptors, and hERG.35, 36 In addition to its promising in vitro
profile, 7 also showed reasonable bioavailability and good brain 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
Figure 2. Activity of SEN12333 and its parent structure, 6, at α7 nAChRs.
The development of SEN12333 was focused on improving both potency and drug-like
properties. As a result, only limited structure-activity relationships are available for this class
of α7 nAChR ligands. Alteration of the mopholine group of 7 revealed that a reasonable
diversity of heterocycles was tolerated, with small, aliphatic azacycles being optimal.
Similarly, replacement of the arylanilide with other aromatic moieties had little effect on α7
nAChR activity, but biaryls were generally preferred over monoaromatic groups. The butyl
chain tethering the morpholine and pyridylanilide groups allows a large degree of
conformational freedom, and little is known about the optimal orientation of these two
To determine the most favorable distance between the morpholine 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 methylene units (8a-
d, Scheme 1), were synthesized from the corresponding ω-bromoalkanoic acids (9a-d,
respectively). The 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 anilides 10a-d in acceptable yield. Alkylation of morpholine
by bromoalkanes 10a-d was achieved in the presence of catalytic iodide to give compounds
11a-d in good yields. Subjecting bromoarenes 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-bromopentanoic acid (9e), for direct
comparison with the new analogs.
Scheme 1. Reagents and conditions: (a) (COCl)2, rt, 45 min; (b) 4-bromoaniline, Et3N or K2CO3,
CH2Cl2, –78 °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%.
Molecular modeling was undertaken to predict possible variation of binding modes for
ligands 7 and 8a-d. Firstly, a homology model of the α7 nAChR was generated by using the
‘prime’ suite in Maestro.37 The crystal structure of the acetylcholine binding protein
(AChBP)38 from L. stagnalis (PDB code: 1UW6) was used as a template for generating the
model. The sequence of α7 nAChR (accession code: AAA83561) as obtained from NCBI
was aligned on the template. Five subunits of the α7 nAChR were individually made and
merged to form an α7 nAChR pentamaric model. The OPLS_2005 all-atom force field was
used for energy scoring of the protein, and surface generalized Born (SGB) continuum
solvation 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 disulphide bonds created. Finally the corrected structure was
optimized by restrained minimization using “impref minimization” 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 between two
adjacent α7 monomers. The ligands under study were minimized using OPLS_2005
forcefield, with water as solvent and “constant dielectric” as electrostatic treatment, in the
Macromodel 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 understand the ligand- receptor interactions of α7 nAChR receptor agonists, three known
ligands with agonist activity were docked into the α7 nAChR model; AR-R177796,
acetylcholine, and nicotine. Interestingly, all three ligands showed comparable interactions
with the receptor (Figure 3). The protonated nitrogen of these ligands was found to make
cation-π interactions with one of the five aromatic amino acids that comprise the wall of the
hydrophobic pocket (ChainA: Trp77 and ChainB: Tyr115, Trp171, Tyr210, and Tyr217). The
other important common feature is that all compounds made a hydrogen bond interaction
with hydroxyl group of Ser172 (ChainB). These two interactions seem to be very important
for the agonistic activity of α7 nAChR ligands.
Figure 3. AR-R17779, acetylcholine, and nicotine docked into the active site of the α7 nAChR
model. Hydrogen bonding with Ser172 is also shown. Image drawn using ICM browser.
Compounds 7 and 8a-d were docked into the α7 nAChR active site to predict the effect of
chain length variation on α7 nAChR 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 alternative 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-π 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 –10.59 to –11.13. Compound 8a (n = 1) was predicted to be least active, with a
G-score of –0.67, having a relative large, negatively contributing ‘penalty’ for polar atom
burial, desolvation, and intra-ligand contacts.
Figure 4. Compounds 7 and 8a-d docked into the active site of the α7 nAChR model. Hydrogen
bonding with Gln139 is also shown. Image drawn using ICM browser.
To confirm the validity of the modeling, 7 and 8a-d were subjected to competition binding
measurements against racemic [3H]epibatidine. The binding assays were performed using
membrane homogenates of stably transfected HEK293 cells expressing rat α7, α4β2, or α3β4
nAChR subtype.41-43 The binding affinities of these analogues are shown in Table 1. Contrary
to the predictions of the docking studies, 7 and 8a-d displayed Ki values ranging from 0.50
μM to greater than 10 μM, a difference of more than two orders of magnitude. The highest
affinity was displayed by SEN12333 itself (5, Ki = 0.50 μM). Extending the distance of the
alkyl tether of SEN12333 by a single methylene unit, to give 8d, resulted in more than an
order of magnitude reduction in α7 nAChR binding (Ki > 10 μM), contradicting the improved
affinity anticipated by the docking studies. Compared to SEN12333, the ethylene- and
propylene-linked congeners (8b and 8c) also showed diminished α7 nAChR binding (Ki > 10
μM in both cases). However, 8a (Ki = 3.9 μM), containing the shortest linker, exhibited α7
affinity less than 8 times lower than that of SEN12333 itself, despite the contrary predicitions
of the docking studies.
Table 1. Binding affinities of 7 and 8a-d for multiple nAChR subtypes.
α4β2 α7 α3β4
3.9 ± 1.5 >10
>10 >10 >10
>10 >10 >10
>10 >10 >10
0.50 ± 0.03 >10 >10
aKi values represent the mean ± SEM of three independent experiments.
Compounds 8a-d and SEN12333 (7) were also evaluated on rat recombinant α7 receptors
expressed in Xenopus oocytes. Only SEN12333 exhibited partial agonist activity, activating
the receptor by approximately 11% compared to the maximal ACh response with an EC50 of
9.5 µM (95% Confidence interval 3.4-26) (Figure 5). The remaining analogues did not
exhibit any agonist or antagonist activity when tested at 100 µM (data not shown).
Figure 5. Effect of SEN12333 (7) on rat recombinant α7 receptors expressed in Xenopus oocytes.
SEN12333 (7) exhibited partial agonist activity, activating the receptor by approximately 11%
compared to the maximal ACh response. The EC50 value was 9.5 µM (95% CI 3.4-26). Data are mean
± SEM from 4 oocytes.
Contraction and elongation of the alkyl chain in SEN12333 produces distinct changes in α7
affinity, and optimal binding is conferred by a 4 methylene unit linker, as found in SEN12333
itself. However, the variation of binding affinity is not predicted by molecular docking to a
α7 nAChR homology model, demonstrating the limited predictive utility of this model for the
rational design of α7 receptor agonists. A 4-carbon chain appears to offer ideal inter-
functional group distances for interaction with α7 nAChRs, and future work could focus on
the functionalization or conformational restriction of this tether.
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