Chemical modifications of the N-methyl-laudanosine scaffold point to new directions for SK channels exploration

Article abstract of DOI:10.1016/j.bmcl.2014.10.083

An asparagine or a histidine are present in a similar position in the outer pore region of SK2 and SK3 channels, respectively. Therefore, this structural difference was targeted in order to develop selective blockers of SK channel subtypes. Following docking investigations, based on theoretical models of truncated SK2 and SK3 channels, the benzyl side chain of N-methyl-laudanosine (NML) was functionalized in order to target this specific amino-acid residues. Chiral butanamide and benzyloxy analogues were prepared, resolved and tested for their affinity for SK2 and SK3 channels. Isoquinolinium (NMIQ) derivatives have a higher affinity for both SK channel subtypes than the corresponding derivative with no functionalized side chain. This trend was observed also for the 1,2,3,4-tetrahydroisoquinoline (THIQ) analogues. A benzyloxy functionalized NML enantiomer has a higher affinity than NML stereoisomers. Otherwise, the conserved affinity of these analogues led to the opportunity to further investigate in terms of possible labeling for in vivo investigations of the role of SK channels.

Full text of DOI:10.1016/j.bmcl.2014.10.083

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5616–5620
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Chemical modifications of the N-methyl-laudanosine scaffold point
to new directions for SK channels exploration
Eduard Badarau a,b, , Sébastien Dilly a,b, , Johan Wouters c, Vincent Seutin b, Jean-François Liégeois a,
⇑
a Laboratory of Medicinal Chemistry & C.I.R.M., University of Liège, avenue de l’Hôpital, 1 (B36), B-4000 Liège 1, Belgium
b Laboratory of Pharmacology & GIGA-Neuroscience, University of Liège, avenue de l’Hôpital, 1 (B36), B-4000 Liège 1, Belgium
c Department of Chemistry, University of Namur, rue de Bruxelles, 61, B-5000 Namur, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
An asparagine or a histidine are present in a similar position in the outer pore region of SK2 and SK3
channels, respectively. Therefore, this structural difference was targeted in order to develop selective
blockers of SK channel subtypes. Following docking investigations, based on theoretical models of
truncated SK2 and SK3 channels, the benzyl side chain of N-methyl-laudanosine (NML) was functionalized
in order to target this specific amino-acid residues. Chiral butanamide and benzyloxy analogues were
prepared, resolved and tested for their affinity for SK2 and SK3 channels. Isoquinolinium (NMIQ)
derivatives have a higher affinity for both SK channel subtypes than the corresponding derivative with
no functionalized side chain. This trend was observed also for the 1,2,3,4-tetrahydroisoquinoline (THIQ)
analogues. A benzyloxy functionalized NML enantiomer has a higher affinity than NML stereoisomers.
Otherwise, the conserved affinity of these analogues led to the opportunity to further investigate in terms
of possible labeling for in vivo investigations of the role of SK channels.
Received 24 September 2014
Revised 24 October 2014
Accepted 27 October 2014
Available online 6 November 2014
Keywords:
Docking
Rational design
Butanamide
Benzyloxy
Enantiomers
Small conductance calcium-activated K+
channels
Ó 2014 Elsevier Ltd. All rights reserved.
Apamin
In vitro binding
Isoquinoline
Small conductance calcium-activated potassium channels or SK
(KCa2) channels are interesting and challenging targets in terms of
medicinal chemistry developments. Three subtypes have been
detected and cloned1 and are present both in the brain and the
periphery.1,2 By modulating the activity of neurons (firing rate,
firing pattern),3 blockers appear interesting for the treatment of
several CNS disorders including cognitive dysfunction, neuronal
hyperexcitability or dopamine related disorders.4 Cardiovascular
disorders or cancer are also potential applications for the SK
channel modulators.5–7 Until now, only some peptidic compounds
such as Lei-dab8 or tamapin,9 have more or less selectivity for SK2
channels. Non-peptidic molecules with high affinity have been
obtained10–13 (Fig. 1) but none possesses a high selectivity for SK2
or SK3 channel subtypes. Indeed, the nanomolar bis-quinolinium
cyclophane, UCL1684,13 is reported to be 34 times selective for
SK2 versus SK3,14 while in our hands, the corresponding ratio is
close to 5 as affinity for SK2 and SK3 channels are 0.21 nM and
1.1 nM, respectively. N-Methyl-laudanosine (NML), a N-methyl-
O
O
I
N
NH
N
NH
N
*
O
O
(+/-)-NML
O
. 2 HCl
UCL1684
N
O
N
NH2
N
(CH2)10
H2N
N
AG525E1
O
Dequalinium
1,2,3,4-tetrahydroisoquinoline (NMTHIQ) derivative, has
a
O
Figure 1. Chemical structure of some SK channel blockers interacting at the
apamine binding site.
⇑
Corresponding author. Tel.: +32 43 66 43 77; fax: +32 43 66 43 62.
E-mail address: JF.Liegeois@ulg.ac.be (J.-F. Liégeois).
These two authors contributed equally.
http://dx.doi.org/10.1016/j.bmcl.2014.10.083
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

E. Badarau et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5616–5620
5617
micromolar affinity for both SK2 and SK3 channels. It was shown to
be a useful tool for studying in vitro neurophysiology of SK
channels15 as a quick reversibility is observed following local appli-
cation.16 By comparison, apamin, or other high affinity compounds,
block the current for a long time because of their small kÀ1, which
makes their effect essentially irreversible in many systems.16 It
was also reported as radiotracer for biomedical imaging technique
positron emission tomography (PET) to image SKCa channels in the
studies of brain, heart and cancer diseases.17
Beside SK channel blockers interacting either with the apamine
binding site, or TEA binding site, molecules modulating the SK
channel gating properties have been described either as positive
modulators such as CyPPA, EBIO and NS309 (see Ref. 18 and
references associated) or as negative modulators such as
NS859319 and its related analogues20 (Fig. 2).
SK3 channels presents two different residues in this region. In
the SK2 protein, an asparagine (N) is present in position 368 while
in the SK3 subtype, the amino acid is replaced by a histidine (H) in
the equivalent position 522 (Fig. 3). This could be a potential
opportunity for developing more selective non-peptidic molecules.
Previous docking studies of apamin and NML revealed that NML
occupies a part of the binding site of apamin.26 An example of
docking results of R-enantiomer is illustrated in Figure 3. The
binding site of NML is very close to the discriminant residues N
368 for SK2 or H 522 for SK3 (Fig. 3). Therefore, we intended to
modulate NML in order to selectively target one SK channel
subtype. Additional docking studies allowed identifying different
functional groups able to specifically interact with the discriminant
residues. Thus, according to the best scoring results, for a putative
compound interacting with the N residue, an amide group was
chosen while for the compound interacting with the H residue, a
phenyl moiety because of its potential ability to interact with the
imidazole moiety of H 522 was used.
As an exploratory investigation, two groups of molecules were
synthesized with different intermediates (NMIQ, THIQ and
NMTHIQ) to be tested for their affinity for SK channels (Fig. 4).
The racemic mixtures of THIQ analogues were resolved by chiral
HPLC. These compounds were tested for their capacity to compete
with iodinated apamin on cloned SK2 and SK3 channels according
to the procedure previously reported.24–27
Targeted compounds were prepared according to previously
used synthetic pathways27,28 that involved Reissert’s compounds
as key intermediates. Both side chains were obtained from vanil-
line following two different chemical pathways (Scheme 1A and B).
In order to prepare the amide side chain, vanilline reacted by an
O-alkylation with ethyl 4-bromobutanoate (Scheme 1A). The alde-
hyde group was then reduced with sodium borohydride. The
halogenomethyl analogue (1) was prepared by the treatment of
the corresponding alcohol with thionyl chloride and used without
further purification.
In the present draft, we describe to our knowledge the first
report of a rational design based on the structure of the target.
Indeed, in our research program, we have reported additional
informations that indicate that apamin does not act as a pore
blocker, contrary to TEA but more likely binds in the outer pore
region according to recent reports.21–25 The sequence of SK2 and
As positive modulators
HN
Cl
H
H
N
Cl
N
N
O
O
N
N
N
N
N
HO
CyPPA
NS309
EBIO
As negative modulators
N
N
NH
NH
R
For the preparation of the benzyloxy side chain, vanilline was
O-alkylated on the phenol group using benzyl chloride
(Scheme 1B). The aldehyde moiety was then reduced with sodium
borohydride. The halogenomethyl analogue (2) was prepared by
reacting the corresponding alcohol with thionyl chloride and used
without further purification.
N
H
N
H
R'
Analogues of NS8593
NS8593
Figure 2. Chemical structure of some molecules modulating SK channel gating
properties.
Figure 3. (A) Extracellular view of docking results of R-NML into the pore region of SK2 and SK3 channels. R-NML is shown to interact with a part of the binding site of apamin
highlighted green. (B) Sequence alignment of the pore region of SK2 and SK3 channels. The discriminant residues N368 and H522 are highlighted red. The residues involved in
the interaction with NML are highlighted green.

5618
E. Badarau et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5616–5620
I
R
R
R
I
N
N
N
Isoquinolinium
NMIQ
1,2,3,4-tetrahydroisoquinoline
THIQ
1,2,3,4-tetrahydroisoquinolinium
NM-THIQ
Figure 4. Chemical entities to target SK channels from the isoquinoline scaffold.
The previously obtained chlorides were used for the alkylation
of the Reissert’s derivatives in anhydrous DMF (Schemes 2 and 3).
Then, the alkylated products were subsequently hydrolyzed in a
50% aqueous NaOH/EtOH solution. The aromatic analogue were
methylated with methyl iodide before reducing the isoquinolinium
(NMIQ) derivative to a 1,2,3,4-tetrahydroisoquinoline (THIQ) by
using sodium borohydride. For the amide side chain (Scheme 2),
the acid derivative was firstly esterified to synthesize the amide
group in a second time before the treatment with methyl iodide.
The rest of the sequence was the same than that for the benzyloxy
analogue (Scheme 3).
A. for potentially selective SK2 channel blockers
O
O
Br
COOEt
O
O
3
H
H
NaBH4
K2CO3, TBAI
OEt
MeOH
1h, 25°C
OH
O
ACN, 12h, 85°C
O
OH
Cl
O
O
O
O
SOCl2
OEt
O
OEt
CHCl3
2h, 25°C
O
1
The racemic mixtures of THIQ derivatives (7a–b, 11a–b) were
resolved by a preparative HPLC method with a chiral stationary
phase to get both enantiomers. Due to limited solubility, the amide
analogue was resolved in more polar conditions than those previ-
ously used.27 Subsequent treatment of THIQ enantiomers (7a, 7b,
11a, 11b) with methyl iodide gave the NMTHIQ derivatives (8a,
8b, 12a, 12b). The absolute configuration was determined for one
enantiomer of each series by X-ray analysis. For compound 8a
and 12b, the crystal structure has been deposited at the Cambridge
Crystallographic Data Centre and the CCDC deposition number is
979360 and 979359, respectively.
Regarding the affinity for SK2 and SK3 channels, in the series of
NML, experimental data are reported in Table 1. Some data were
reported previously in the literature but they concern affinity on
rat brain preparations.28–31 The NMIQ analogue, N-methyl-papav-
erine, and the THIQ enantiomers (laudanosine enantiomers) pres-
ent a low affinity as determined during the screening evaluation.
Among this series of compounds, the enantiomers of NML have
B. for potentially selective SK3 channel blockers
O
O
O
O
BnCl
NaBH4
H
H
MeOH
2h, 0-25°C
K2CO3, TBAI
OH
O
ACN, 12h, 85°C
OH
Cl
O
O
O
O
SOCl2
CHCl3
2h, 50°C
2
Scheme 1. Synthesis of intermediates in order to functionalize side chains.
O
O
O
1
NaOH (50%)
N
N
NaH, DMF
2h, -10°C
O
Bz
EtOH
Bz
CN
4h, 100°C
CN
O
O
COOEt
3
O
O
O
SOCl2
7N NH3
N
N
O
MeOH
1h, 25°C
MeOH
O
O
O
O
48h, 100°C, closed vial
4
3
3COOH
3COOMe
O
O
O
MeI
NaBH4
I
N
N
O
DMF
5h, 50°C
MeOH
O
O
O
30min, 0-25°C
5
6
O
CONH2
3CONH2
3
O
O
O
O
Chiral resolution
O
MeI
I
N
N
ACN
4h, 80°C
O
7a-b
8a, 8b
O
3 CONH2
O
3CONH2
Scheme 2. Synthesis of target compounds aimed at interacting with SK2 channels.

E. Badarau et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5616–5620
5619
O
O
Table 2
O
O
2
NaOH (50%)
Affinity of butanamideoxy derivatives for SK2 and SK3 channels (Ki in
l
M; mean SD)
NaH, DMF
2h, -10°C
N
N
Bz
EtOH
4h, 100°C
Bz
O
CN
CN
O
O
I
N
O
O
O
O
O
O
MeI
NaBH4
I
N
N
O
CONH2
DMF
3h, 60°C
MeOH
30min, 0-25°C
3
O
O
O
O
9
10
Compounds
Chemical entity
SK2
SK3
6
7a
7b
8a
8b
NMIQ
THIQ E1
THIQ E2
NMTHIQ E1
NMTHIQ E2
11.515 5.872
26.843 4.017
32.690 9.014
1.044 0.154
1.115 0.138
11.167 1.993
23.300 16.994
20.442 16.552
1.726 0.182
1.210 0.045
O
O
O
Chiral resolution
MeI
I
N
N
O
ACN
4h, 80°C
O
O
O
11a-b
12a, 12b
O
Table 3
Affinity of benzyloxy derivatives for SK2 and SK3 channels (Ki in
lM; mean SD)
Scheme 3. Synthesis of target compounds aimed at interacting with SK3 channels.
O
I
N
O
Table 1
O
Affinity of NML derivatives for SK2 and SK3 channels (Ki in
10 M)
lM or % of displacement at
l
O
O
I
N
*
O
Compounds
Chemical entity
SK2
7.905 0.780
19.957 9.845
18.630 1.998
0.897 0.148
0.772 0.022
SK3
5.824 2.768
29.118 5.046
15.746 8.971
0.967 0.100
1.426 0.396
O
O
10
11a
11b
12a
12b
NMIQ
THIQ E1
THIQ E2
NMTHIQ E1
NMTHIQ E2
Compounds
Chemical entity
SK2
SK3
N-Methylpapaverine
(S)-Laudanosine
(R)-Laudanosine
(S)-NML
NMIQ
THIQ
THIQ
NMTHIQ
NMTHIQ
10%
13%
À2%
NT
35%
35%
1.886 0.344
1.715 0.125
Following these chemical modifications of NML structure, dif-
ferent informations can be put forward. For the NMIQ analogues
(6, 10), it appears that the presence of both functionalized arms
has a favourable impact in terms of affinity for SK channels. The
THIQ stereoisomers (7a–b, 11a–b) have a weak affinity that limits
further experiments for exploring CNS targets. Among the NMTHIQ
enantiomers (8a, 8b, 12a, 12b), globally the presence of the
additional side chain does not modify significantly the affinity for
both channels in comparison with enantiomers of NML except
the benzyloxy enantiomer (12b) which present a higher affinity
for SK2. In previous works,29 we had shown the superiority in
terms of interaction of 6,7-dimethoxy analogues in comparison
with the unsubstituted derivatives and therefore, we were focused
on these types of molecules for further developments. In this work,
the unsubstituted analogue of 10 was prepared and tested. This
0.941 0.169
1.391 0.120
(R)-NML
the highest affinity in the
slightly higher affinity for SK2 than SK3 channels.
In the series of butanamide analogues (Table 2), the NMIQ ana-
logue 6 has an affinity close to 10 lM thus higher than that
observed for the corresponding analogue in the NML series. No
SK2 versus SK3 selectivity is observed. For the THIQ enantiomers
7a and 7b, the affinity of both compounds is lower than that of
the NMIQ analogue 6 and they interact almost equally on both
channel subtypes. For the NMTHIQ enantiomers 8a and 8b, the
affinity is significantly increased in comparison with the NMIQ
analogue 6. Both enantiomers interact almost similarly on both
channel subtypes except 8a which have a slightly higher affinity
for SK2 channels. The affinity of the enantiomers is quite similar
to that of NML enantiomers.
lM range. The S-enantiomer shows a
compound has an affinity of ꢀ4.7 and 3.1
lM for SK2 and SK3
channels, respectively. This is interesting and could mean that a
possible competition between the 6,7-dimethoxy moiety and the
functionalized arm would appear during the interaction with
the target. In the unsubstituted analogue, the absence of
6,7-dimethoxy would be compensated by the interaction of the
arm and the protein. Currently, these results are not explained
by further docking experiments. This point was also recently
reported in a separate work32 and this might be related to the
limited size of the pore region examined in the theoretical model.
In silico models will be strongly improved when more complete
structure of the target will be available. Indeed, an X-ray crystal
structure of the channel or at least a larger part of the pore region
should facilitate the design of new molecules and this represents a
fascinating challenge.
In the series of benzyloxy analogues (Table 3), the affinity of the
NMIQ analogue 10 is ꢀ7.9 and 5.9
lM for SK2 and SK3 channels.
This is higher than the value observed for the corresponding ana-
logue in the NML series and also slightly higher than that of com-
pound 6. For the THIQ enantiomers 11a and 11b, the affinity is
lower than that of NMIQ analogue 10 and in a similar range than
enantiomers 7a and 7b. For the NMTHIQ enantiomers 12a and
12b, the affinity is significantly increased in comparison with the
NMIQ analogue 10. Both enantiomers interact almost similarly
on both channel subtypes except 12b which has a slightly higher
affinity for SK2 channels even higher than that of the correspond-
ing NML enantiomer.

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E. Badarau et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5616–5620
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Otherwise, the current chemical modifications have permitted to
keep the affinity for SK channels and in some cases to increase it.
As a consequence, this work raises the opportunity to further
functionalized NML structure to prepare labeled compounds such
as fluorescent probes for in vitro cellular investigations of the role
of SK channels.
Acknowledgments
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Supported in part by Grants of the Fonds de la Recherche
Scientifique - FNRS (F.R.S.-FNRS) Grant FRSM3.4533.09 (Belgium),
the Fonds Spéciaux pour la Recherche of the University of Liège
(Belgium) and the SPW DGO6 PPP NEUREDGE convention 816859.
J.-F.L. is Research Director of the F.R.S.-FNRS. S.D. was supported
financially by a post-doctoral fellowship of the F.R.S.-FNRS and a
collective Grant of the University of Liège. J. Ghiotto and E.B. were
supported financially by the SPW DGO6 PPP NEUREDGE convention
816859. For medicinal chemistry studies, the technical assistance of
S. Counerotte and J. Ghiotto is gratefully acknowledged. For cell cul-
ture, membrane preparation and in vitro binding experiments,
C. Gillissen is gratefully acknowledged. B. Norberg is gratefully
acknowledged for assistance in X-ray diffraction data collection.
20. Sørensen, U. S.; Strøbæk, D.; Christophersen, P.; Hougaard, C.; Jensen, M. L.;
Nielsen, E. Ø.; Peters, D.; Teuber, L. J. Med. Chem. 2008, 51, 7625.
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Biochem. Pharmacol. 2013, 85, 560.
Supplementary data
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295.
24. Lamy, C.; Goodchild, S. J.; Weatherall, K. L.; Jane, D. E.; Liégeois, J.-F.; Seutin, V.;
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.10.
083.
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