Carboxylic acids and skeletal muscle chloride channel conductance: Effects on the biological activity induced by the introduction of an aryloxyalkyl group α to the carboxylic function of 4-chloro-phenoxyacetic acid

Article abstract of DOI:10.1016/S0014-827X(01)01127-2

2-(4-Chloro-phenoxy)propanoic and 2-(4-chloro-phenoxy)butanoic acids are compounds known to block chloride membrane conductance in rat striated muscle by interaction with a specific receptor. In the present study, a series of chiral analogues has been prepared and tested to evaluate the influence of a second aryloxy moiety introduced in the side-chain at a variable distance from the stereogenic centre. The results show that this chemical modification is detrimental for biological activity which, however, is increased by lengthening the alkyl chain up to three methylenic groups, then decreases to remain constant in the next analogues of the series. A possible explanation for this is proposed on the basis of steric effects and/or different approach of the molecules to the receptor.

Full text of DOI:10.1016/S0014-827X(01)01127-2

www.elsevier.com/locate/farmac
Il Farmaco 56 (2001) 749–754
Carboxylic acids and skeletal muscle chloride channel conductance:
effects on the biological activity induced by the introduction of an
aryloxyalkyl group a to the carboxylic function of
4
-chloro-phenoxyacetic acid
a
a
a,
c
Giuseppe Carbonara , Giuseppe Fracchiolla , Fulvio Loiodice *, Paolo Tortorella ,
b
b
b
Diana Conte-Camerino , Annamaria De Luca , Antonella Liantonio
a
Dipartimento Farmaco-Chimico, Uni6ersit a` di Bari, 6ia Orabona 4, 70126 Bari, Italy
Dipartimento Farmaco-Biologico, Uni6ersit a` di Bari, 6ia Orabona 4, 70126 Bari, Italy
b
c
Dipartimento di Scienze del Farmaco, Uni6ersit a` ‘G. D’Annunzio’, 6ia dei Vestini, 66100 Chieti, Italy
Received 30 March 2001; accepted 10 May 2001
Abstract
-(4-Chloro-phenoxy)propanoic and 2-(4-chloro-phenoxy)butanoic acids are compounds known to block chloride membrane
2
conductance in rat striated muscle by interaction with a specific receptor. In the present study, a series of chiral analogues has
been prepared and tested to evaluate the influence of a second aryloxy moiety introduced in the side-chain at a variable distance
from the stereogenic centre. The results show that this chemical modification is detrimental for biological activity which, however,
is increased by lengthening the alkyl chain up to three methylenic groups, then decreases to remain constant in the next analogues
of the series. A possible explanation for this is proposed on the basis of steric effects and/or different approach of the molecules
to the receptor. © 2001 Elsevier Science S.A. All rights reserved.
Keywords: Aryloxyalkanoic acids; Chloride channel conductance; Rat skeletal muscle; Myotonic-inducing effects
with abnormally low gCl can become hyperexcitable
1
. Introduction
and produce trains of action potentials as observed in
some forms of hereditary myotonia of goats [2] or
humans and in myotonia produced by certain drugs
In skeletal muscle, 65–85% of the resting membrane
conductance is due to chloride ions [1]. This large
chloride conductance (gCl) stabilizes the resting mem-
brane potential of mammalian muscle. In fact, muscles
[3–6]. In spite of the important role of resting gCl in
mammalian muscle excitability, relatively few studies
are available on the molecular mechanism underlying
this function.
In the past, clofibric acid [2-(4-chloro-phenoxy)-2-
methyl-propanoic acid] (1) (Fig. 1), the active metabo-
lite of the hypolipidemic drug clofibrate, has been
shown to specifically decrease membrane gCl of rat
skeletal muscle [7,8]. On the basis of these results, we
introduced various chemical modifications in the molec-
ular structure of clofibric acid and found out that,
among the numerous derivatives prepared, only chiral
Fig. 1. Clofibric acid (1) and two of its analogues, 2-(4-chloro-phen-
oxy)propanoic acid (2) and 2-(4-chloro-phenoxy)butanoic acid (3).
2
-(4-chloro-phenoxy)propanoic acid (2) and 2-(4-
chloro-phenoxy)butanoic acid (3) (Fig. 1) maintain a
*
Corresponding author.
E-mail address: floiodice@farmchim.uniba.it (F. Loiodice).
high activity in reducing gCl.
0
014-827X/01/$ - see front matter © 2001 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(01)01127-2

7
50
G. Carbonara et al. / Il Farmaco 56 (2001) 749–754
tanced from the stereogenic centre itself. We decided to
test these compounds, recently claimed in a patent as
hypolipidemic agents [12], to evaluate the possibility
that these clofibrate-like drugs were able, in the same
way, to interfere with gCl and, if so, to assess if a
second aryloxy moiety could represent an additional
interaction site with the receptor.
2
. Chemistry
Compound 4a [13] was prepared by simply refluxing
Fig. 2. Clofibric acid chiral analogues with an aryloxyalkyl group
alpha to the carboxylic function.
a mixture of 4-chlorophenol and ethyl 2,3-dibromo-
propanoate in the presence of NaOH (Scheme 1).
A different synthetic pathway was followed for the
preparation of acids 4b–f [12]. As shown in Scheme 2,
diethyl 2-(4-chloro-phenoxy)malonate (5) was reacted
with the suitable aryloxyalkylbromides 6b–f and the
condensation products hydrolyzed and decarboxylated
to give the desired compounds.
Starting materials 5 and 6b–f were obtained as re-
ported in Scheme 3, the former by reacting diethyl
chloromalonate with sodium 4-chlorophenate in reflux-
ing acetone, the latter by treating a mixture of phenol
and alkyldibromide with a boiling NaOH solution,
according to a procedure reported in literature for
compound 6c [14].
In these compounds, also, the absolute configuration
exerts a strong influence on the activity, with S-enan-
tiomers being much more potent than R-enantiomers
and clofibric acid itself [9]. On the contrary, R-enan-
tiomers produce a biphasic effect on chloride channel
conductance, increasing gCl at low concentrations and
decreasing it at higher concentrations. These data allow
the hypothesis of the existance of two opposing recep-
tor populations controlling chloride ion flux: S-isomers
would act as full agonists on an inhibitory site, whereas
R-isomers as full agonists on both the inhibitory and
excitatory sites [10,11].
In order to obtain more information on the struc-
tural requirements allowing a-aryloxyalkanoic acids to
interact with these receptors, we focused on compounds
3. Results and discussion
4a–f (Fig. 2) in which the substituent on the stereogenic
The effects of in vitro application of these new
centre contains a second phenoxy group variably dis-
synthesized clofibric acid derivatives on gCl of rat
Scheme 1.
Scheme 2.

G. Carbonara et al. / Il Farmaco 56 (2001) 749–754
751
ring of the side-chain. The choice of this substituent has
been made because of its different electronic effects, the
methoxy group being a strong electron donor which
contributes to make the benzene ring electron-rich. The
resulting effect on chloride conductance, however, was
similar to that of the related 4c, producing a 48%
reduction of gCl.
These results indicate that compounds 4a–f have a
reduced blocking activity on chloride ion flux of skele-
tal muscle membrane as compared with 2. A reasonable
explanation for this could be given in terms of steric
effects, that is, the aryloxyalkyl group bound to the
stereogenic centre, would be too bulky to interact prop-
erly with a receptor site where, probably, an hydropho-
bic pocket of limited size is present. Moreover, the
molecules of these acids could approach differently to
the receptor, as the phenoxy group of the side-chain is
able to mimic the aryloxy moiety a to the carboxylic
function. This alternative binding, however, would in-
crease the distance between the phenoxy and the car-
Scheme 3.
extensor digitorum longus (EDL) muscle are shown in
Table 1. In this preliminary experiment, we tested all
compounds in the racemic form at 100 mM concentra-
tion, a value close to the concentration required (80
mM) to produce a gCl 50% block from 2-(4-chloro-
phenoxy)propanoic acid (2), one of the most potent
modulators of chloride conductance in skeletal muscle
fibres. All of them showed a reduced potency in block-
ing gCl in comparison to racemic 2, but the different
blocking activity related to each compound suggests
that the length of the aliphatic chain markedly affects
the gCl block. In particular, compounds 4a and 4b,
having one or two methylenic groups on the side-chain,
were poorly effective producing only a 13 and 25%
decrease of gCl, respectively. Compound 4c was the
most effective derivative in this series, producing a 46%
block of gCl. A further increase in the distance of the
phenoxy group from the stereogenic centre led, again,
to a reduced potency. In fact, compounds 4d and 4e,
having one or two additional methylenic groups with
respect to compound 4c, were less effective, both
molecules producing only a 30% decrease of gCl.
boxylic
groups,
while
interacting
with
the
corresponding receptor sites, as a consequence of the
presence of the intermediate methylenic chain and this
would be detrimental for the activity. In previous stud-
ies, in fact, we reported that this distance is pivotal for
the pharmacological activity of this class of compounds
[15].
On the other hand, in this series of compounds, the
blocking activity is increased by lengthening the alkyl
chain up to three methylenic groups, then decreases to
remain constant in the next analogues of the series. It is
possible that the molecules of acids 4c and 4f, when
correctly oriented, are able to assume a conformation in
which the alkyl chain is folded in such a way that an
appropriate interaction with the hydrophobic pocket
occurs while placing the bulky phenoxy group far away
from it. Compounds 4a and 4b bind more weakly to the
receptor because the shorter alkyl chain would keep the
phenoxy group still too close to the pocket, whereas in
4d and 4e the alkyl chain would be too long to allow as
We also investigated the activity of compound 4f,
which differs from 4c only for the presence of a
methoxy group in place of chlorine on the aromatic
Table 1
Effect of in 6itro application of clofibric acid analogues 4a–f on gCl of rat skeletal muscle
2
Experimental condition
Dose (mM)
Number of fibres
gCl (mS/cm )
% Reduction of gCl
Control
2
63
20
28
19
37
16
39
21
2759969
11599113
2413999
20609101
14939102
1847986
1883991
1420979
a
100
100
100
100
100
100
100
5893.7
1393.0
2592.9
4693.4
3392.5
3292.9
4892.4
a
4a
4b
4c
4d
4e
4f
a
a
a
a
a
gCl, resting chloride conductance of skeletal muscle fibres. All tested compounds did not show any effect on the potassium conductance (gK), nor
produced remarkable modifications of the resting membrane potential of the examined fibres. The values of gK measured in normal solution and
2
after application of 4c (one of the most potent compounds) were 319960 and 323951 mS/cm , respectively.
a
Significantly different with respect to control value, PB0.005 or less.

7
52
G. Carbonara et al. / Il Farmaco 56 (2001) 749–754
an appropriate interaction as 4c. This hypothesis is
confirmed from the same activity of compounds 4c and
ethyl acetate. The combined organic extracts were
washed with brine, dried over sodium sulfate and con-
centrated to give 5.9 g of a crude oil which was purified
by column chromatography on silica gel eluting with a
9:1 mixture of petroleum ether/ethyl acetate. Pale yel-
low waxy solid (4.2 g, 77%).
4f; in these derivatives, in fact, the different substituent
(
Cl or CH O) on the aryloxy moiety of the side-chain,
3
being in a part of the molecule not involved in the
binding, would not affect the interaction with the
receptor.
+
1
MS, m/z (rel. abund.): 286 (M , 100), 141 (89). H
The preparation of the enantiomers of the more
active derivatives is in progress and their pharmacolog-
ical activity will be reported separately.
NMR (CDCl ): l 7.26–6.80 (m, 4H, aromatic); 5.14 (s,
3
1H, CH); 4.30 (q, 4H, 2CH ); 1.29 (t, 6H, 2CH ).
2
3
4.3. General procedure for the preparation of
aryloxyalkylbromides (6b–f)
4. Experimental
A 1.6 N NaOH solution (11 mmol, 7 ml) was added
dropwise, during 45 min, to a stirred boiling suspension
of the suitable phenol (10 mmol) and alkyldibromide
(13 mmol) in water (20 ml). The mixture was heated
under reflux for 4 h. After cooling, it was taken up with
chloroform and the aqueous layer was separated. The
organic layer was washed with 2 N NaOH and brine,
dried over sodium sulfate and evaporated under re-
duced pressure. The mixture was purified by column
chromatography on silica gel eluting with petroleum
ether.
Column chromatography was performed on ICN
,
silica gel 60 A (63–200 mm) as the stationary phase.
Melting points were determined on a Gallenkamp ap-
paratus and are uncorrected. Mass spectra were
recorded with a HP GC-MS 6890-5973 MSD spectrom-
eter, electron impact 70 eV, equipped with HP chemsta-
1
tion. Infrared and H NMR spectra were recorded on a
FT-IR spectrophotometer Perkin–Elmer, Spectrum
one, and a Bruker AM 300 WB (300 MHz) spectrome-
ter, respectively. Microanalyses were carried out with a
Carlo Erba mod. 1106 analyzer (the analytical results
are within 90.4% of theoretical values).
4.3.1. 4-Chloro-phenoxyethylbromide (6b)
+
Yield: 52%; MS, m/z (rel. abund.): 234 (M , 6), 107
4.1. 2,3-Bis(4-chloro-phenoxy)propanoic acid (4a)
(100).
A solution of NaOH (0.54 g, 13.4 mmol) in 1.5 ml of
water was added to a mixture of ethyl 2,3-dibromo-
propanoate (1.00 g, 3.73 mmol) and 4-chlorophenol
4.3.2. 4-Chloro-phenoxypropylbromide (6c)
Yield: 70%; MS, m/z (rel. abund.): 248 (M , 36), 128
(100).
+
(
1.24 g, 9.7 mmol) at 40 °C. The mixture was refluxed
with stirring for 3 h, treated with 1 ml of conc. HCl at
room temperature (r.t.) and extracted with chloroform.
The organic layer was dried over sodium sulfate and
the solvent removed under reduced pressure to give 1.5
g of a yellow solid which was crystallized from chloro-
form–hexane. White crystals, m.p.: 128–129 °C (0.98 g,
yield: 80%).
4.3.3. 4-Chloro-phenoxybutylbromide (6d)
Yield: 49%; MS, m/z (rel. abund.): 262 (M , 19), 128
(100).
+
4.3.4. 4-Chloro-phenoxypentylbromide (6e)
Yield: 62%; MS, m/z (rel. abund.): 276 (M , 18), 128
(100).
+
−
1
IR (KBr): 1718 cm
rel. abund.): 340 (M , 100). H NMR (CDCl ): l
(CꢀO). MS (methylester), m/z
+
1
(
4.3.5. 4-Methoxy-phenoxypropylbromide (6f)
Yield: 67%; MS, m/z (rel. abund.): 244 (M , 66), 124
3
+
7.27–7.20 (m, 4H, aromatic); 6.90–6.82 (m, 4H, aro-
matic); 5.48 (bs, 1H, exchange with D O, COOH); 4.98
(100).
2
(
t, 1H, CH); 4.42 (d, 2H, CH ). Anal. (C H Cl O )
2 15 12 2 4
C,H.
4.4. General procedure for the preparation of acids
4b–f
4.2. Diethyl 2-(4-chloro-phenoxy)malonate (5)
A solution of 5 (10 mmol) in dry DMF (25 ml) was
A mixture of chloromalonic acid diethyl ester (3.72 g,
9.1 mmol) and sodium 4-chlorophenate (3.02 g, 20.1
mmol), prepared from an equivalent amount of 4-
chlorophenol and sodium in absolute ethanol, was
stirred and heated under reflux in acetone (100 ml) for
added dropwise to a suspension of NaH (15 mmol, 95%
powder) in dry DMF (20 ml) at 0 °C. After stirring at
r.t. for 20 min, a solution of the suitable aryloxyalkyl-
bromide 6 (11.5 mmol) in dry DMF (15 ml) was added
dropwise and the resulting reaction mixture stirred at
55 °C for 20 h. The solvent was removed under reduced
pressure and the residue poured into water and ex-
1
3
.5 h. The solvent was removed under reduced pressure,
the residue was taken up with water and extracted with

G. Carbonara et al. / Il Farmaco 56 (2001) 749–754
753
tracted with diethyl ether. The organic layer was
4.4.5. 2-(4-Chloro-phenoxy)-5-(4-methoxy-phenoxy)-
washed with saturated ammonium chloride solution,
dried over sodium sulfate and the solvent evaporated in
pentanoic acid (4f)
−
1
Yield: 35%; m.p.: 119–121 °C. IR (KBr): 1726 cm
1
6
acuo. The residue was refluxed under stirring with 1 N
(CꢀO). H NMR (CDCl ): l 7.25–7.18 (m, 2H, aro-
3
NaOH (25 ml) in 95% ethanol (35 ml) for 4 h. The
organic solvent was distilled off under reduced pressure
and the remaining aqueous phase washed with diethyl
ether, acidified to pH 2 with 6 N HCl and extracted
with diethyl ether. The combined organic extracts were
dried over sodium sulfate and the solvent removed
under reduced pressure. The resulting products were
heated at 160 °C for 2 h affording the desired acids
which were obtained as pure white solids by crystalliza-
tion from chloroform–hexane.
matic); 6.90–6.70 (m, 6H, aromatic); 6.60–5.80 (bs, 1H,
exchange with D O, COOH); 4.66 (dd, 1H, CH); 3.95
2
(t, 2H, OCH ); 3.75 (s, 3H, OCH ); 2.25–2.10 (m, 2H,
2
3
CH CH); 2.08–1.92 (m, 2H, OCH CH ). MS
2
2
2
+
(methylester), m/z (rel. abund.): 364 (M , 47) 241
(100). Anal. (C H ClO ) C, H.
18
19
5
4.5. Pharmacology
4.5.1. Methods
The new synthesized compounds have been tested in
4
.4.1. 2,4-Bis(4-chloro-phenoxy)butanoic acid (4b)
6itro on membrane ionic conductance of EDL muscle
of adult male Wistar rats of 350–400 g. The muscle was
removed under urethane anaesthesia and placed in a
temperature controlled chamber at 30 °C and bathed
with a physiological solution or a chloride-free solution
in the absence and presence of the tested compounds.
The normal physiological solution had the following
composition (in mM): 148 NaCl, 4.5 KCl, 2.0 CaCl2,
−
1
Yield: 35%; m.p.: 118–119 °C. IR (KBr): 1729 cm
1
(
CꢀO). H NMR (CDCl ): l 7.26–6.77 (bs, 1H, ex-
3
change with D O, COOH); 7.26–7.17 (m, 4H, aro-
2
matic); 6.87–6.77 (m, 4H, aromatic); 4.91 (dd, 1H,
CH); 4.16 (t, 2H, OCH ); 2.51–2.40 (m, 2H, CH CH).
MS (methylester), m/z (rel. abund.): 354 (M , 15), 227
2
2
+
(
100). Anal. (C H Cl O ) C, H.
16 14 2 4
1
.0 MgCl , 0.44 NaH PO , 12 NaHCO , 5.5 glucose.
2 2 4 3
The chloride-free solution was prepared by equimolar
replacement of sulfate salts for NaCl and KCl and
nitrate salts for CaCl and MgCl . Both solutions were
4
.4.2. 2,5-Bis(4-chloro-phenoxy)pentanoic acid (4c)
−
1
Yield: 36%; m.p.: 112–114 °C. IR (KBr): 1709 cm
2
2
1
(
CꢀO). H NMR (CDCl ): l 7.25–7.17 (m, 4H, aro-
continuously bubbled with 95% O and 5% CO and
3
2 2
matic); 6.83–6.73 (m, 4H, aromatic); 5.94–5.78 (bs, 1H,
pH was maintained between 7.2 and 7.3. The total
resting ionic conductance of sarcolemma (gm) of mus-
cle fibres was calculated from the cable parameters, and
in particular from the membrane resistance (Rm) val-
ues, measured by standard cable analysis with the two
intracellular microelectrode technique. In brief, a
voltage sensitive microelectrode (3 M KCl) was used to
measure the membrane potential and the voltage deflec-
tion (electrotonic potential), monitored at two distances
(0.5 mm and about 1 mm), in response to a hyperpolar-
izing square wave current pulse passed through a sec-
ond electrode (2 M potassium citrate). Current pulse
generation, acquisition of the voltage records and cal-
culation of membrane resistance were carried out under
computer control as detailed elsewhere [11]. In each
fibre, the total membrane conductance (gm) was 1/Rm
in the normal physiological solution and is due for
exchange with D O, COOH); 4.68 (t, 1H, CH); 3.97 (t,
2
2
2
3
H, OCH ); 2.20–2.13 (m, 2H, CH CH); 2.05–1.96 (m,
H, OCH CH ). MS (methylester), m/z (rel. abund.):
68 (M , 20), 241 (100). Anal. (C H Cl O ) C, H.
2
2
2
2
+
17
16
2
4
4.4.3. 2,6-Bis(4-chloro-phenoxy)hexanoic acid (4d)
−
1
Yield: 50%; m.p.: 90–91 °C. IR (KBr): 1722 cm
1
(
CꢀO). H NMR (CDCl ): l 8.20–7.60 (bs, 1H, ex-
3
change with D O, COOH); 7.26–7.19 (m, 4H, aro-
2
matic); 6.84–6.76 (m, 4H, aromatic); 4.63 (t, 1H, CH);
3
.94 (t, 2H, OCH ); 2.06 (q, 2H, CH CH); 1.86–1.74
2 2
(m, 2H, OCH CH ); 1.74–1.70 (m, 2H, CH CH CH).
2 2 2 2
+
MS (methylester), m/z (rel. abund.): 382 (M , 38), 128
(
100). Anal. (C H Cl O ) C, H.
18 18 2 4
7
0–80% to the chloride conductance (gCl), the remain-
4
.4.4. 2,7-Bis(4-chloro-phenoxy)heptanoic acid (4e)
ing being mostly the resting conductance to potassium
ions (gK). Aqueous bicarbonate stock solutions of each
compound were prepared daily and the final concentra-
tions used were obtained by appropriate dilution with
normal physiological solution. Each drug was incu-
bated for at least 20 min before recordings to allow the
steady-state drug effect to be reached. The data are
expressed as mean9SEM [11]. Statistical difference
between means was evaluated by Student’s test.
−
1
Yield: 35%; m.p.: 111–112 °C. IR (KBr): 1706 cm
1
(
CꢀO). H NMR (CDCl ): l 7.24–7.17 (m, 4H, aro-
3
matic); 6.82–6.74 (m, 4H, aromatic); 5.10–4.52 (bs, 1H,
exchange with D O, COOH); 4.60 (t, 1H, CH); 3.89 (t,
2
2H, OCH ); 2.03–1.96 (m, 2H, CH CH); 1.79–1.73 (m,
2
2
2H, OCH CH ); 1.60–1.48 (m, 4H, CH CH CH CH).
2
2
2
2
+
2
MS (methylester), m/z (rel. abund.): 396 (M , 48), 81
100). Anal. (C H Cl O ) C, H.
(
1
9
20
2
4

7
54
G. Carbonara et al. / Il Farmaco 56 (2001) 749–754
skeletal muscle: an electrophysiologic study, Arch. Toxicol. 7
1984) 482–484.
Acknowledgements
(
[
9] G. Bettoni, F. Loiodice, V. Tortorella, D. Conte-Camerino, M.
Mambrini, E. Ferrannini, S.H. Bryant, Stereospecificity of the
chloride ion channel: the action of chiral clofibric acid analogues,
J. Med. Chem. 30 (1987) 1267–1270.
This work was accomplished thanks to the financial
support of MURST (Ministero dell’Universit a` e della
Ricerca Scientifica e Tecnologica).
[
[
10] D. Conte-Camerino, M. Mambrini, A. De Luca, D. Tricarico,
S.H. Bryant, V. Tortorella, G. Bettoni, Enantiomers of clofibric
acid analogs have opposite actions on rat skeletal muscle chlo-
ride channels, Pflugers Arch. 413 (1988) 105–107.
11] A. De Luca, D. Tricarico, R. Wagner, S.H. Bryant, V. Tor-
torella, D. Conte-Camerino, Opposite effects of enantiomers of
clofibric acid derivative on rat skeletal muscle chloride conduc-
tance: antagonism studies and theoretical modeling of two recep-
tor site interactions, J. Pharmacol. Exp. Ther. 260 (1992)
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