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On the Concept of a Bivalent Pharmacophore for SKCa Channel BlockersSynthesis Pharmacological Testing and Radioligand Binding Studies on Mono- Bis- and Tris-quinolinium Compounds.

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Galanakis. Ganellin. Dunii, and Jenkinson
On the Concept of a Bivalent Pharmacophore for SKca Channel
Blockers: Synthesis, Pharmacological Testing, and Radioligand Binding
Studies on Mono-, Bis-, and Tris-quinolinium Compounds
Dimitrios Galanakis,")') C. Robin Ganellin,"") Philip M. Dunn,b) and Donald H. Jenkinsonb)
'" University College London, Department
of Chemistry, Christopher Ingold Laboratories, 20 Gordon St., London WC 1H OAJ. U.K.
Department of Pharmacology, University College London, Cower Street, London W C l E 6BT. U.K.
Key Words: K' channels; ciparriiri, dequaliniunz; hivnlerit pharnzacoplzore; binding site
ing more potent non-peptidic compounds. Since there are two
quinolinium groups in the molecule of 2 one may question
whether both are required for SKca channel blockade['31.To
The dissociation equilibrium constants (Kd values) of dequalinium
address this issue, the monoquinolinium compounds l a and
(2) and the monoquinolinium compounds l a and l b have been
l b (Chart 1) were synthesized and tested in vitro for blockade
determined from competition equilibrium radioligand binding
the afterhyperpolarization (AHP, mediated by the opening
with ['251]apamin on rat brain synaptic plasma membrancs
of SKca channels) in rat sympathetic neurones" 13131. How(SPMs). Dequalinium binds to the channel with 2 orders of
ever, l a and l b proved to be less selective in their action than
magnitude higher affinity than l a or lb. suggesting that both
2 (and other bis-charged analo ues of 2), interfering with the
quinolinium groups are needed for potent and selective SKca
channel blockade. The trisquinolinium compound 3 (1.1'-[5-[4-(4- function of other ion channel$I3J. This low selectivity preaminoquinolinium-1-yl)but-1-yl]non-4-en- 1.9-diyl]-bis-(4-am- vented the determination of reliable IC50 values for SKca
inoquinolinium))has been synthesized and tested for inhibition of
channel blockade for l a and lb, leaving unanswered the
the afterhyperpolarization of rat sympathetic neurones and on the
question of the contribution of both quinolinium groups of 2
binding assay. Compound 3 shows approximately one order of
to SKca channel blockade[131.
magnitude higher potency than 2, being the most potent non-pepIn the present work, a radioligand binding assay has been
tidic SKca channel blocker reported so far (Kd = 30 nM). The
to compare the affinities of la, lb, and 2 for the SKca
higher affinity of 3 compared with 2 may be due to direct binding
using competition with ['*'II]apamin for the binding
of the third quinolinium group to the channel or may arise from a
brain synaptic plasma membranes (SPMs) to give
reduction of the unfavorable entropy of binding via an increase of
dissociation equilibrium constants (Kd values) for the blockthe "local concentration" of quinolinium groups.
ers. In addition, the trisquinoliniurn compound 3 (Chart 1) has
been synthesized and tested on the binding assay and for
blockade of the AHP in neurones.
Small conductance Ca*+-activated K+ (SKca) channels
comprise an important but relatively little studied class of K+
channelsl',21. Apamin, an 18-amino acid neurotoxin, isolated
from the venom of the honey bee (Apis mellfera) is a otent
and specific blocker of this Kf channel subtype13-' . The
finding that the binding site of apamin is expressed in the
muscle of patients with myotonic muscular dystrophy while
it is absent in normal human m ~ s c l e ~ ~
. ~ ] , a role for
the SKca channel in this disease. Furthermore, SKca channels
might be involved in EtOH intoxication[81. Thus, selective
blockers of this class of K+ channels may find therapeutic
Moreover, such blockers will be valuable
pharmacological tools for further studies on the physiology
and pathophysiology of thc SKca channel.
Dequalinium (2, Chart I ) , is much less potent than apamin
and we
but it is a selective blocker of the SKc3channel'''.'
have initiated studies towards identif ing the pharmacophore
of 2 for SKca channel blockadel "-17!
with the aim of design-
l a n=3
l b n=9
'' Present
address: Department of Pharinaceutical Chcinistry, School of
Pharmacy, Aristotelian University or Thessaloniki, Thessaloniki, 510 06,
Arch. Phann. Phurm. M e d Chetii.
Chart I
0 VCH Verlagsgesellschaft mbH. D-6945 1 Weinheini, 1996
0365-6233/96/1212-0524 $5.00 + .25/0
Pharmacophore for SKCa Channel Blockers
Scheme 1. Methods: (i) EhSiH, TFA, CH2C12, rt, 48 h; (ii) 4-aminoquinoline, abs. EtOH, reflux, 204 h, Ar.
Results and Discussion
Biological Testing
Inhibition of A H P
Compounds were tested for their ability to inhibit the afterhyperpolarisation (AHP) in cultured rat su erior cervical
ganglion neurones as described previously [ I R . Briefly, microelectrodes filled with l M KCl were used to obtain intracellular recordings from neurones that had been in culture for
3-10 days. Action potentials were evoked every 5 seconds,
and drugs were applied in the continuously flowing bathing
solution. The amplitude of the AHP was measured in the
absence and presence of the test compound and dose response
curves constructed. ICs0 values were obtained from non-linear least squares fit of the Hill equation to the data. Each
compound was tested at 3 or 4 concentrations on at least three
The requisite tribromide 3b for the synthesis of 3 was
obtained as shown in Scheme lr1*].The synthesis of the
tribromoalcohol 3a proceeded smoothly. Deoxygenation of
this using Et3SiH/TFA yielded a mixture of the tribromoalkene 3b and tribromoalkane 3c in the ratio of 4: 1. Since
we had already shown that rigidification of the alkyl chain of
dequalinium does not interfere with channel blockade [I3', 3b
was treated with 4-aminoquinoline to afford the trisquinolinium alkene 3. This was purified by reverse phase preparative HPLC.
Radioligand Binding Assay
80 -
5 .
? 405
The dissociation equilibrium constant (&) of ['2sI]apamin
binding to rat brain synaptic plasma membranes (SPMs) was
first obtained from saturation binding experiments and the
effect of compounds 1-3 on [1251]apaminbinding was then
examined in equilibrium competition experiments using the
procedure described p r e v i o u ~ l y . " ~A- ~typical
~ ~ graph showing the binding of [1251]apamin to rat brain SPMs in the
presence of increasing concentrations of 1-3 is shown in
Figure 1. Estimates of the concentration of the com ound that
causes 50% inhibition (IC50) of the specific [' 'Ilapamin
binding were obtained from non-linear least squares fitting of
the Hill equation to the data with the Hill coefficient constrained to unity. This provided a satisfactory fit of the displacement curves for all but the least active of the compounds.
The IC50 values were used to calculate dissociation equilibrium constants (Kd values) for the compounds, using the
Cheng-Prusoff equationr221and these are shown in Table 1.
In the saturation as well as competition experiments, triplicate
assays were performed.
Though the displacement curve for l a could be fitted more
satisfactorily with a Hill coefficient greater than unity, which
might indicate an allosteric interaction of some kind, the low
activity of this compound made further analysis unwarranted.
However, it adds uncertainty to the calculation of the K d value
from the ICso for la.
20 -
log (compound) (M)
Figure 1. ['251]apaminbinding to rat brain SPMs in the presence of compounds l a (0),
l h (O),2 (m),and 3 (A).
Membranes were incubated on ice
for 1 h in 10 mM KCI, 25 mM Tris, containing 0.1% ( d v ) BSA, at pH = 8.4,
in the presence of 10 pM ['251]apamin and varying concentrations of the
compounda. Following collection of the membranes by filtration, the amount
of specific [1251]apaminbound was measured and the extent of ['251]apamin
binding was expressed as a percent of total binding in the absence of any
competing compound. Data points are the means of triplicate determinations
?r SD, and the lines show least squares fits of the data using the Hill equation
with the Hill coefficient constrained to unity.
Arch. fhann.Phann. Med. Chem. 329,52&528 (1996)
Cialanakih, Ganellin. Dunn. and Jenkinson
Table 1. Biological results for the compound^
It i s believed that ion channels that conduct cations possess
rings of negative charge in their pore region, formed from the
Rat neuione AHP
Rat blain SPMI
side chains of aspartic and glutamic acids, one being contribCornpd
1Cs0 SD (phl)
lCi0 S D (PM)
K , (PM)
~ ~
uted from each subunit of the channel[3s1.Thus. the possibility exists that the quinolinium group interacts with a negative
60 i 7 . 5
ring on the channel in such a way that its positive ring-shaped
field complements the channel’s negative ring. In such a
21 i l
model, the second quinoliniuin group may be interacting with
0.69 i- 0.1 I
0.78 f 0.05
a second negative ring. Thus, one quinolinium group would
0.084 i- 0.02
0. I0 c! 0.005
0.03 1
bind “deeper” in the SKca channel than the other, with the
linking inethylene chain being placed along the axis of the
“Number of neuronea ksled. ’The experiments were performed on ;I inenichannel. A related possibility is that dequalinium may span
brane preparation froin 6 rats. Tlic LISC of a wcond membrane preparation
adjacent subunits making up the channel which is likely to be
gave similar results. ‘Data froin ref. ‘ I 3 ’ . The values are not reliable since la
a tetramer, in keeping with other K’channel subtypes, includand l b appear to act. at leaar in part, indirectly. “Uncertain because the v a l u a
ing voltage-dependent[361,ATP-~-egulated[~~],
inward rectifiwere poorly fitted when the Hill coefficient was constrained ro unity (see
ers1381and high conductance Ca2+-activated Kf ( B K c , ) ~ ’ ~ ~ ~ ” ]
To investigate whether a third quinolinium group in the
of the blocker would contribute to affinity via
All compounds were able to compete with [‘251]apa~minfor
the binding site on rat brain SPMs, albeit with very different interaction with a third binding site, compound 3 was synthepotencies. Thus, the monoquinolinium analogues l a and l b sized. In this analogue, each pair of quinolinium groups is
have =100-fold lower affinity for the apamin binding site separated by 9 carbon atoms ( I0 are present in dequalinium)
than the bisquino- and the ratio of aliphatic carbon atoms per quinolinium group
(presumed to be on the SKca
linium compound 2. The length of the aliphatic chain of the is similar to dequalinium. It should be noted that variation of
’ ~well
~ as
monoquinolinium compounds does not seem to be critical. the length of the alkylene chain of d e q ~ a l i n i u m [as
rigidification of this linker via introduction of two triple
However, it is clear that the presence of a second quinolinium
group in the molecule of the blocker contributes substantially: bonds[’31did not alter potency significantly. Hence, the presence of the double bond in the chain of 3 is not expected to
not only does it render the compound =2 orders of magnitude
more potent, it also confers higher selectivity for the SKca affect potency. In addition, the 2-Me group of dequalinium
was removed to facilitate the synthesis, since its contribution
channel, since dequalinium is a more selective SKca channel
to SKca channel blockade is minimall 14.151.Compound 3 was
blocker than are l a and l b
found to have approximately one order of magnitude higher
Dequalinium can (hen be considered as another example of
affinity for the SKca channel than dequalinium. Thus, it
the so-called “bivalent ligands”. Such compounds have
blocked the AHP with an IC50 of 84 nM (cf. ~ 0 . 7pM for
shown different selectivity (and in many cases higher podequa1iniumll3l) and competed with [1251]apaminwith a Kd
tency) for receptor subtypes than their monovalent counterof =30 nM.
parts in the area of opioid [24-26J, 5-HT [271, P-adrenergicL2’1,
It is questionable, however, whether the increase in potency
and muscarinicr291receptors. It is likely that the higher poresulting from the presence of the third quinolinium group in
tency and increased selectivity of the bivalent ligands is due the molecule of 3 is large enough to be attributed to binding
to bridging between proximal binding sites. It is reasonable
of this group to a third specific site in the channel. The
to hypothesize that dequalinium acts in a similar manner by possibility exists that the increase in affinity results from a
bridging two vicinal binding sites in the SKca channel macstatistical effect of 3 rather than 2 potential binding groups
romolecule. The pharmacophore for SKca channel blockade
being present in the molecule. This would increase the “local
as currently conceived incorporates two charged groups, e.g. concentration” of the quinolinium groups in the vicinity of
the guanidinium groups of the arginines 13 and 14 of the channel, resulting in a less unfavorable entropy for the
a p a m i n [ 3 w , the alkylammonium Groups of atracurium,
binding process. Alternatively, the third quinolinium group
tubocurarine or pancuroniumr23,33,3~?,
or the two charged
may be binding at a site which is chemically different from
heterocycles of dequalinium and analogues[13-171.
the other two, resulting in a lower free energy gain.
The quinolinium group is much superior to alkylammonium
groups and it has been suggested that this may be due to
differences represented by their electrostatic potential
maps.‘131 The positive field around an alkylammonium group
Competition e uilibrium binding studies have been conis spherical while the field of the quinolinium group is ringducted using [I2‘I]apamin and rat brain SPMs in order to
shaped and might be interacting with a putative ring of obtain dissociation equilibrium constants for dequalinium
negative charge on the channel. Alternatively, the stronger and the monoquinolinium analogues l a and lb. Dequalinium
binding of the quinolinium group may be due to n-n interacshowed 2 orders of magnitude higher affinity than l a or lb,
tions with aryl rings of the channel[”]. Furthermore. an stron ly supporting the suggested pharrnacophore1134
electronic effect probably operates in the binding of the
for SKca channel blockade which incorporates
quinolinium group since the activities of dequalinium ana- two charged groups. Furthermore, the trisquinolinium comlogues correlates quantitatively with the energies of the pound 3 has been synthesized and tested both on the funcLUMO of the c o m p o ~ n d s ~ l ~ , ~ ~ ~ .
tional rat neurone assay and on the binding assay. Compound
Pharmacophore for SKca Channel Blocker$
3 was approximately one order of magnitude more potent
than 2 in inhibiting [1251]apaminbinding to rat brain SPMs,
being the most potent non-peptidic SKca channel blocker
tested using this assay. The contribution of the third quinolinium group of this compound may arise from direct binding
to the channel, or may be the consequence of reducing the
unfavorable entropy of binding via increasing the "local
concentration" of quinolinium groups.
This work was partially supported by the Wellconie Trust (including a
fellowship to P.M.D.). We are most grateful to Drs P. N. Strong and J. D. F.
Wadsworth of the Neuromuscular Unit of Hammersmith Hospital for help
with and discussions of the binding studies. We also thank Ms K. B. Doorty
for the preparation of the rat brain SPMs.
Infrared (IR) spectra were run on a Perkin-Elmer 983 spectrophotometer.
Nuclear magnetic resonance (NMR) spectra were recorded on a Varian
VXR-400 (400 MHz) spectrometer, and chemical shifts (ppm) are reported
relative to the solvent peak (CHC13 in CDC13 at 7.24 ppm and DMSO in
DMSO-dh at 2.49 ppm). Signals are designated as follows: s, singlct: d,
doublet; t, triplet: q, quadruplet: m. multiplet. Mass spectra were run on a
ZAB SE or VG 7070H spectrometer. Analytical reverse phase high performance liquid chromatography (HPLC) was performed either on a Gilson or
Shimadzu HPLC apparatus with a UV detector at 2 I 5 nm and a Kromasil
C I 8 7pm column. Isocratic elutions using a solvent mixture of A = water +
0.1% TFA and B = MeOH + 0.1% TFA were performed. The ratio of A:B
is indicated. The flow rate was 1 mL/min. For preparative reverse phase
HPLC, a Kromasil C18 7 pm column was used, the solvent mixture being
the same as the one used for analytical HPLC and the flow rate being
15 mL/min.
5-(4-Bromobut-I -yl)-1,9-dihromonon-4-ene (3b)
117.08, 117.11, 118.1, 118.2, 118.24, 118.29, 118.5, 123.8, 126.58, 124.62,
124.72. 126.23, 126.27. 126.35, 126.39, 134.33, 134.45, 137.91, 137.93,
137.98, 139.06, 146.11, 157.78, 157.91, 157.95, 158.09, 158.41;MS (FAB,
MNOBA matrix) [M-2H]+ 609. fragments at m/z 465, 451: HPLC: A:B =
55:45, major peak at 8.98 min representing 98.3% of the absorption at 215
nm. Anal. (C46H47F9N6061.2CF3C02H) C, H, N.
Binding Studies
The saturation experiment to obtain the Kd ofapamin was performed using
a filtration assay as described
Briefly, aliquots of a membrane preparation (from 6 rats) containing 100 p$ of protein were incubated
on ice for 1 h with increasing concentrations of [ I 51]apamin. The incubation
medium (1 mL) consisted of 10 mM KC1,25 mM Tris at pH = 8.4, containing
0. I % w/v bovine serum albumin. The non-specific binding was determined
in the presence of 0.1 pM cold apamin. After rapid filtration through
Whatman GF/B FP-100 filters presoaked for 1 h in 0.5% v/v polyethyleneimine, filters were counted at 84% efficiency in a calibrated ycounter. The
Kd of apamin was 4.8 pM.
In the competition experiment^""^", rat brain SPMs were incubated on
ice with a fixed concentration of 10 pM ['*'I]aparnin in the presence or
absence of increasing concentrations of the blocker. The incubation medium,
time, filtration, and counting were as above. In both types of experiment
triplicate assays were performed. The concentration ofthe compound causing
50% inhibition (IC5o) of the specific ['251]apaminbinding was obtained by
non-linear least squares fitting of the Hill equation to the data, with the Hill
coefficient constrained to unity, using MicroCal ORIGIN (MicroCal Software, Inc.). The ICso values were then used to calculate Kd vales for the
compounds using the Cheng-Prusoff equation'**'.
D. G. Haylett, D. H. Jenkinson, in Potassium Channels (Ed.:
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G. M. Burgess, M. Claret, D. H. Jenkinson, J. Phl~siol.(Loud) 1981,
1.6 g, 3.66 mmol) and EtiSiH (0.58 mL, 3.66 mmol) in CHzClz (15 mL),
31 7, 67-90.
TFA (I-83 mL, 23.77 mmol) was added and the solution was stirred at room
temperature for 48 h. The solvents were evaporated in vacuo and the residue
M. Lazdunski, Cel/ Calcium 1983,4,421428.
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M. Lazdunski, Nature 1986, 319, 678-680.
NMR (400 MHz, C D C I ) 6 1.54 (in, 4H, CH2). 1.90 (in. 6H. CH2), 2.05 (m,
4H, CH2), 2.17 (q, J = 7.3 Hz, 2H, CHKH=C). 3.42 (m. 6H, CH2Br). 5. I 1
M. I. Behrens, C. Vergara, Am. J. PIzysiol. 1992.263, C794-C802.
( t , J = 7 . 2 H z , lH,CH=C); '3CNMR(100MHz,CUC1~)626.1,26.5,26.8,
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28.9, 32.3, 32.6, 32.9, 33.6, 33.7. 33.8, 35.7. 123.8, 139.7; MS (FAB,
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to yield a foam (63% based on HPLC). A portion of this was purified by
preparative HPLC: IR (KBr disc) vmax3370, 3 150, 2950, 1775, 1685, 1625
cm-'; 'H NMR (400 MI-Iz, DMSO-dh) v 1.32 (m. 4H, CH?), 1.70 (in, 6H,
CH2), 1.91 (m,
6H. CH2), 4.42 (1, J = 7.3 Hr. 2H, N+-CH*). 4.49 (t, J = 7.6
Hz. 4H. N+-CH?), 5.05 (t, J = 7.2 Hz, IH, CH=C), 6.79 (in, 3H, quinolineH3), 7.70 (m, 3H, quinoline), 8.01 (m. 6H, quinoline). 8.48 (m, 6H, quinoline),9.07(m.6H,NH2): '3CNMR(100MHz,DMSO-d~)621.0,
28.4, 28.6, 28.7, 29.1, 35.2, 38.5. 38.7, 45.7, 53.4, 53.7, 102.05, 102.08,
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Received: September 9. 1996 [FP149]
Arc k Plurt-m. Phunri Met/ Clieni 329. 524-528 (/996)
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channel, compounds, mono, trish, radioligand, testing, blockerssynthesis, skca, quinolinic, bivalent, concept, bis, studies, binding, pharmacological, pharmacophores
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