Two new phenylpiperazines with atypical antipsychotic potential

Article abstract of DOI:10.1016/j.bmcl.2007.08.066

Two new series of substituted arylpiperazines with heterocyclic 3-propoxy-benzimidazole or 3-propoxy-benzimidazole-2-thione groups were synthesized and their in vitro binding affinities for the D₂, 5-HT_1A, 5-HT_2A, and α

Full text of DOI:10.1016/j.bmcl.2007.08.066

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5749–5753
Two new phenylpiperazines with atypical antipsychotic potential
a,
a
a
b
*
´
´
´
´
Mirko Tomic, Djurdjica Ignjatovic, Gordana Tovilovic, Deana Andric,
b
c
´
´
´
Goran Roglic and Sladjana Kostic-Rajacˇic
aDepartment of Biochemistry, Institute for Biological Research, Bul. Despota Stefana 142, 11060 Belgrade, Serbia
bFaculty of Chemistry, 11000 Belgrade, Serbia
cInstitute for Chemistry, Technology and Metallurgy, 11000 Belgrade, Serbia
Received 14 June 2007; revised 22 August 2007; accepted 28 August 2007
Available online 31 August 2007
Abstract—Two new series of substituted arylpiperazines with heterocyclic 3-propoxy-benzimidazole or 3-propoxy-benzimidazole-2-
thione groups were synthesized and their in vitro binding affinities for the D2, 5-HT1A, 5-HT2A, and a1-adrenergic receptors deter-
mined. Among them, only two compounds with phenyl aryl-constituent (8a and 9a) showed 5-HT2A/D2 pKi binding ratios proposed
for atypical neuroleptics. As to their behavioral screening on rodents, both compounds exhibited a non-cataleptic action in rats and
antagonized D-amphetamine-induced hyperlocomotion in mice, suggesting their possible atypical antipsychotic potency.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Schizophrenia is an overwhelming mental illness for
which there is currently no ideal therapy. Classical anti-
psychotic drugs, exhibiting the mechanism of the central
dopamine (DA) D2 receptors blockade in the limbic
forebrain, are useful for the treatment of the positive
symptoms, but failed to manage the negative symptoms
of schizophrenia.1 Moreover, antipsychotics with prom-
inent DA D2 antagonist potency were shown to cause
tardive dyskinesia and extrapyramidal side effects
(EPS) in humans, presumably by simultaneous blockade
of striatal DA receptors.1,2 Limited efficacy and undesir-
able side effects of typical antipsychotics have driven the
development of improved ‘‘atypical’’ antipsychotic
agents, like the prototype antipsychotic drug—cloza-
pine, which are in general effective for both positive
and negative symptoms of schizophrenia, more
efficacious than classical antipsychotics in treatment-
refractory patients, and have a low incidence of extrapy-
ramidal side effects.1,2 A number of current approaches
for the development of superior antipsychotic agents in-
volve the mechanisms based on the reduction of the DA
neurotransmission with partial D2 agonists or DA auto-
receptor agonists, together with antagonism at the cen-
tral serotonin 5-HT2A and partial agonism at 5-HT1A
receptors.1–4 The blockade of 5-HT2A receptors has been
implicated in both the enhanced efficacy against negative
symptoms of schizophrenia and improved EPS profile of
the atypical antipsychotics,3 while the 5-HT1A receptor
agonists are believed to attenuate some D2 receptor-
mediated side effects.4 Thus, new compounds may retain
antipsychotic efficacy, while having reduced liability for
severe movement disorders often developed upon acute
and long-term treatments, and could potentially allevi-
ate certain negative schizophrenia-associated symp-
toms.1,2 Additionally, upon modulation of the central
5-HT neurotransmission, these compounds may also ex-
hibit certain anxiolytic and/or antidepressant effects.1,5
During the last decade, we have formulated the strategy
on drug design and synthesis of mixed DA-/5-HT-ergic
heterocyclic arylpiperazines, with different specific struc-
ture of heteroaryl-group that mimics catechol moiety of
the dopamine,6,7 and may exhibit atypical neuroleptic
potential. In previous papers, we have presented some
of the most appealing compounds upon alteration of
heterocyclic and aryl groups.7 Here, we present some
selected newly synthesized ligands containing benzimid-
azole or benzimidazole-2-thione linked by propyloxy
bridge to four different arylpiperazines, already charac-
terized by improved interaction with the D2 receptors.7
Aryl parts of the ligands were chosen in accordance to
their best pharmacological profiles6–8 and our intention
was also to further evaluate the influence of the propyl-
oxy linker of the new ligands (instead of ethyloxy linker
Keywords: Arylpiperazines; Dopamine receptors; Serotonin receptors;
Atypical antipsychotics.
*
Corresponding author. Tel.: +381 11 2078306; fax: +381 11
2761433; e-mail: mitomic@ibiss.bg.ac.yu
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.08.066

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M. Tomic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5749–5753
5750
found in our previously synthesized compounds) on the
receptor binding profiles.
ties (pK i, Table 1) of the new arylpiperazines and cloza-
pine were determined by measuring the extent of
displacement of 3H-labeled specific ligands from rat stri-
atal or cortical synaptosomes with a range of concentra-
tions of selected compounds.7,11 Based on their high
pKi’s 5-HT2A/D2 receptor binding ratio, two of the com-
pounds were selected to be assayed in simple animal
behavioral models relevant to atypical antipsychotic
activity. These compounds (8a, 9a) were applied to ro-
dents in 2–3 single doses (in the range 1–10 mg/kg bw;
ip) and their possible cataleptic effects were evaluated
in rats,12 while their influence on spontaneous locomo-
tion and amphetamine-induced hyperactivity was
assessed in mice with an open-field test.13
Synthetic pathways, similar to previously described
procedure,8 of the two sets of ligands, 5-[3-(4-arylpipera-
zin-1-yl)propoxy]-1,3-dihydro-2H-benzimidazole-2-thi-
ones (8a–d) and 6-[3-(4-arylpipera-zin-1-yl)propoxy]-
1H-benzimidazoles (9a–d), submitted to pharmacological
exploration in the present study, are shown in
Scheme 1. Yield and chemical characterization of the
compounds 8a–d and 9a–d are given under Notes.9,10
Eight new compounds (8a–d, 9a–d) and clozapine were
initially evaluated for cytotoxicity by MTT (3-[4,5-di-
methyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium
bro-
mide) colorimetric assay,11 performed on the stable
transfected CHO hD2L cell line. Concentrations of the
compounds killing 50% of the cells (EC50) were esti-
mated from the curves obtained with a series of ligand
concentrations in culture media. The eight new ligands
were also evaluated by in vitro assays for binding affin-
ities at the specific DA (D2), 5-HT (5-HT1A, 5-HT2A),
and a1-adrenergic receptors. These receptors were cho-
sen concerning their anticipated role in the action of
atypical antipsychotic drugs.1–4 Specific binding affini-
The MTT assay revealed that all compounds had a low
cytotoxic potential, mainly weaker than that of cloza-
pine (EC50 = 56 lM). Compound 9c expressed the high-
est cytotoxicity among the examined ligands
(EC50 = 43 lM), while the EC50 values for the remaining
ligands ranged from 139 to 859 lM. Binding affinities of
arylpiperazines 8a–d, 9a–d for the D2, 5-HT1A, 5-HT2A
,
and a1–adrenergic receptors are listed in Table 1. The
binding affinities of these new compounds appeared to
be somewhat decreased for D2 and 5-HT1A receptors,
OH
O
Cl
O
Cl
O
Cl
2) a,b
1)
3)
O2N
3
4
NO2
NO2
NHAc
4)
NHAc
1
2
O
N
O
Cl
5)
N
Ar
O2N
O2N
NH2
6(a-d)
NH2
Ar
5
6)
O
N
O
N
8)
N
N
Ar
H2N
N
7(a-d)
NH
NH2
9(a-d)
7)
O
N
Ar: a = phenyl-,
b = 2-methoxyphenyl-,
c = naphthyl-,
N
Ar
d = 3-(trifluoromethyl)phenyl-
HN
S
NH
8(a-d)
Scheme 1. Synthetic pathways of the new arylpiperazines. Reagents: (1) Cl(CH2)3Br, MEK, Na2CO3, 93%; (2) a—SnCl2, (CH3)2 CHOH b—Ac2O,
(CH3)2CHOH, 94%; (3) Ac2O, H2SO4/HNO3, 68%; (4) 4 N HCl, 93%; (5) DMF, Na2CO3, arylpiperazine, 78–90%; (6) RaNi, N2H4; (7) CS2, KOH;
(8) 98% HCO2H, 4 N HCl.

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M. Tomic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5749–5753
5751
Table 1. Binding affinities of the new compounds and clozapine
Compound
Ar
pKi
5HT1A
D2
5HT2A
a1
5-HT2A/D2
O
N
N
Ar
HN
S
NH
8a
8b
8c
8d
Phe
7.38
8.77
7.02
6.44
8.69
7.72
6.72
6.50
6.03
6.75
6.26
7.00
7.53
8.71
6.37
6.31
1.18
0.88
0.96
1.01
2-MeOPhe
Naphthyl
3-CF3Phe
O
N
N
Ar
N
NH
9a
9b
Phe
7.12
8.06
7.38
7.82
6.84
7.86
7.10
7.29
6.99
7.88
6.19
7.82
7.22
6.41
7.02
7.58
8.23
7.20
6.92
7.65
1.10
0.88
0.99
0.89
1.15
2-MeOPhe
Naphthyl
3-CF3Phe
9c
9d
Clozapine
*Values are means of at least 3 experiments (SEM were less than 5%).
when compared to the previously synthesized arylpiper-
azines of the similar structure and with the ethyloxy
linker.7 SAR analysis of the present compounds demon-
strated that 2-methoxyaryl substitutions improved bind-
ing affinity at D2 and a1 receptors, while reducing it at
5-HT2A receptors, and this was more obvious for thi-
ones. On the other hand, only phenylpiperazines shifted
the preferred affinity of the ligands from D2 toward
5-HT2A receptors, where the pKi’s 5-HT2A/D2 ratios of
8a and 9a were 1.10 and 1.18, respectively, which is close
to that of clozapine (1.15). Although Meltzer and colle-
gues3 suggested pKi’s 5-HT2A/D2 ratios over 1.14 as the
criterion for a possible atypical neuroleptic action of
new ligands, both the mentioned compounds were cho-
sen here for behavioral screening of their atypical anti-
psychotic potency. In the first instance, it was noticed
that neither of the two selected ligands provoked cata-
lepsy in rats (0/5 animals following 1.0 or 10.0 mg/kg
bw of 8a or 9a, observed after 30, 60, 90, or 180 min),
the same as 1.0 mg/kg clozapine (0/5 animals at the same
time points), while haloperidol induced catalepsy at
1.0 mg/kg (3/5 animals after 30 min and 5/5 after 60,
90, and 180 min). In addition, the individual effects of
the compounds on the spontaneous mice locomotion
and amphetamine-induced hyperlocomotion were esti-
mated in an open-field test (Fig. 1).13 One way ANOVA
indicated a significant influence of the treatments on the
two observed parameters: (a) activity time (F13,70 = 7.76,
p < 0.001) and (b) the distance traveled by heads of ani-
mals (F13,70 = 19.71, p < 0.001). Post hoc analysis
revealed non-significant variation (p > 0.05) of these
parameters following two 8a or 9a doses (1.0 and
10 mg/kg ip) when compared to the basal activity of
saline controls. However, apparent, although non-sig-
nificant, decrements of both parameters were noticed
after the lower 9a dose, suggesting its attenuating action
on locomotion at lower concentrations. While this is
similar to the pattern of behavioral action of an antide-
pressant roxindole,5 it might be suggested that 9a could
also express antidepressant effects. Since it is not the to-
pic of the present initial behavioral screening, this possi-
bility will be tested in the future, more advanced study.
Nonetheless, it is noticeable in this survey that almost all
treatments generated a significant decline of the amphet-
amine-induced hyperlocomotion in mice. Even though
the doses of the ligands in this behavioral test were cho-
sen according to in vitro binding data (Table 1), with the
expectation that the active threshold dose should be be-
tween 1.0 and 10 mg/kg ip, it appeared that these
compounds, especially 9a, may calm down the hyperlo-
comotion even after the lowest dose applied (1.0 mg/kg).
Compound 9a seems to be a stronger blocking agent for
amphetamine hyperactivity, but differently from 8a, it
did not show a clear dose response relation. This could
not be partially explained by the interaction of 9a with
D2 or 5-HT2A receptors, since it expressed lower binding
affinities for these receptors comparing to 8a (Table 1).
Both compounds showed similarly low affinity at the
5-HT1A receptors, which should exclude any significant
participation of this interaction in their behavioral
action. While high affinity of neuroleptics at the a1-
adrenergic receptors was explained as partially benefi-
cial for their antipsychotic action, but also undesirable
at high extent, because of their contribution to the side
effects,14 it seems that moderate affinity of 8a and 9a at
this receptor (pKi ꢀ7.5), that is almost equal to that of

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M. Tomic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5749–5753
5752
Figure 1. The effects of 8a, 9a, and clozapine (5 mg/kg) on spontaneous (+saline) and amphetamine-stimulated locomotor activity in mice. Animal
locomotion was determined by (a) the cumulative time of activity and (b) total distance traveled by head of animals in an open field during 60-min
registration period (for details see Ref. 13). *p < 0.001 versus saline + amphetamine (3 mg/kg) control group, by Bonferroni’s post ANOVA test.
clozapine (Table 1), could be at the reasonable level
and optimal for their complete antipsychotic action.
However, as it is well known that arylpiperazine tem-
plate may show decent affinity for a number of recep-
tors coupled to G protein, it cannot be excluded that
significant interaction of our compounds with some
other CNS receptors would participate in their total
behavioral effects. These interactions with certain
receptor classes (e.g. D1, D3, 5-HT2C) would be eluci-
dated soon.
In summary, we have described here the synthesis and
binding affinity of new heterocyclic arylpiperazines, with
benzimidazole and benzimidazole-2-thione linked to
N-arylpiperazines by a propyloxy-bridge. Two of the
compounds with phenyl constituent, that showed appro-
priate pKi’s 5-HT2A/D2 ratio suggested for atypical anti-
psychotics, have also expressed certain behavioral
pattern of atypical antipsychotics in experimental
rodents. Consequently, together with few other aryl-
piperazines already found to have atypical antipsychotic
potency,7 compounds 8a and 9a are subjected to a
thorough preclinical profiling. More pharmacological
details will be published in the near future.
The new compounds in this study show the most of
structural similarities with aripiprazole, among official
neuroleptics, but they did not share a comparable
receptor binding profile according to the published
pharmacological data of aripiprazole.15 Aripiprazole
displays a combination of much higher affinity for the
D2, 5-HT2A, and especially 5-HT1A receptors than any
of our compounds. While it shows a partial agonism
at D2 and 5-HT1A and antagonism at 5-HT2A recep-
tors,15 the question arises whether the new arylpipera-
zines may exhibit the same functional activity. It was
found that 8a and 9a may act as D2 partial agonists
by initial in vitro studies on hD2L receptor-mediated
inhibition of forskoline-stimulated cAMP accumulation
in CHO cells (to be published). However, as postulated
D2 partial agonism of aripiprazole has been contradicto-
rily replicated and it was proposed that this compound
might function as a D2 antagonist, agonist, or partial
agonist depending on the precise complement of D2
receptors and G-proteins in a particular cell,16 this set
of new arylpiperazines is also currently submitted to
the more comprehensive assessment upon clarification
of their exact functional activity.
Acknowledgment
This work was supported by the Ministry for Science,
Technology and Environmental Protection of Serbia,
Grants #143032 (authors 1–4) and #142009 (authors
5,6).
References and notes
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J = 3.6 Hz, ArH), 7.38–7.56 (m, 5H, ArH), 7.79–7.84 (m,
1H, ArH), 8.00 (s, 1H, CH). MS: m/e 387 (100), 387 (M+).
C24H26N4O; (9d): Yield: 88%; mp 187 ꢁC; 1H NMR: d
2.22–2.30 (m, 2H), 3.25–3.33 (m, 4H), 3.60 (s, 6H), 4.15 (t,
2H, J = 5.8 Hz), 6.87–6.91 (m, 1H, ArH), 7.16 (d, 2H,
J = 6.2 Hz, ArH), 7.30 (d, 2H, J = 7.8 Hz, ArH), 7.44–7.55
(m, 2H, ArH), 8.32 (s, 1H, CH). ). MS: m/e 405 (100), 405
(M+). C21H23F3N4O.
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´
´
ˇ ´
´
´
12. Test for catalepsy was done on adult Mill-Hill hooded rat
males (bw 200–250 g). Catalepsy was scored by the
ˇ
´
(b) Kostic-Rajacic, S.; Soskic, V.; Joksimovic, J. Arch.
Pharm. (Weinheim) 1998, 331, 22.
ˇ ´
ˇ
´
´
7b
horizontal bar test. Details are given in ref.
.
´
´
7. (a) Tomic, M.; Kundakovic, M.; Butorovic, B.; Vasilev,
V.; Dragovic, D.; Roglic, G.; Ignjatovic, D.; Soskic, V.;
´
13. Open-field test. A total of 84 adult CPU mice males (30–
40 g) were divided into 14 experimental groups (each
consisting of 6 animals). Six groups were used to evaluate
the effects of test compounds on spontaneous locomotor
activity. Compounds 8a and 9a were originally dissolved
in DMSO (final conc. up to 2%), diluted with saline, and
ip injected (1.0 mg, or 10.0 mg in 2.0 ml per kg bw) 20 min
before another injection of saline. The controls received
first saline/DMSO and the comparison drug’s group was
primary treated with clozapine (5 mg/kg). Remaining eight
groups of mice were employed to assess the effects of the
first treatment on amphetamine-induced hyperactivity.
They received (by the same schedule as above) either
1.0 mg, 4.0 mg, or 10.0 mg of 8a or 9a, saline/DMSO or
clozapine (5 mg/kg), 20 min prior to D-AMPH sulphate
(3.0 mg/kg). Each animal was positioned in the center of
the plastic open-box (40 · 40 · 30 cm) immediately after
the second injection and for the next 15 min they were
allowed to adapt to the environment. The test room with
the acoustic isolation was dimly illuminated (indirect
2 · 40 W light). During the following 60 min interval,
locomotion was registered by a web-camera connected to
PC and controlled by ANY-maze software (ANY-maze
Video Tracking System 4.30, Stoelting Co., USA). The
same program was also used to calculate two parameters
chosen to illustrate total animal locomotion. (1) Time of
activity (in seconds) was the sum of periods when animals
moved in space. (2) Total head distance (in meters)
demonstrated both the total locomotion in space and the
head movements made in place, also representing a
measure of some stereotype behaviors. Crude data was
analyzed by GraphPad Prysm (4.00) using one-way
ANOVA followed by Bonferroni’s multiple group com-
parison test.
ˇ
´
´
´
ˇ ´
´
Kostic-Rajacic, S. Pharmazie 2003, 58, 677; (b) Tomic, M.;
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9. Compound (8a): Yield: 69%; mp 141 ꢁC; 1H NMR
(DMSO-d6): d 2.00 (t, 2H, J = 6 Hz), 2.85 (s, 6H), 3.24–
3.39 (m, 4H), 4.02 (t, 2H, J = 6 Hz), 6.70–6.84 (m, 3H,
ArH), 6.94–7.06 (m, 3H, ArH), 7.23 (t, 2H, J = 7.4 Hz,
ArH), 12.41 (d, 2H, J = 8.2 Hz, NH). MS: m/e 163 (100),
369 (M+). C20H24N4OS; (8b): Yield: 53%; mp 195 ꢁC; 1H
NMR (DMSO-d6): d 1.92 (s, 2H), 2.46–2.54 (m, 6H), 2.97
(s, 4H), 3.77 (s, 3H, OCH3), 4.00 (t, 2H, J = 6.4 Hz), 6.68–
6.76 (m, 2H, ArH), 6.87–6.95 (m, 4H, ArH), 7.04 (d, 1H,
J = 8.8 Hz, ArH), 12.40 (s, 2H, NH). MS: m/e 397 (100),
397 (M+). C21H26N4O2S; (8c): Yield: 61%; mp 221 ꢁC; 1H
NMR (d6DMSO): d 2.13 (s, 2H), 2.50–2.53 (m, 6H), 3.22
(s, 4H), 4.07 (t, 2H, J = 6 Hz), 6.73–6.79 (m, 2H, ArH),
6.73 (s, 1H, ArH), 6.90 (d, 1H, J = 2.4 Hz, ArH), 7.10 (d,
1H, J = 6.8 Hz, ArH), 7.16 (d, 1H, J = 7 Hz, ArH), 7.41–
7.66 (m, 4H, ArH), 7.89–7.94 (m, 1H, ArH), 8.11–8.16 (m,
1H, ArH), 12.45 (d, 2H, J = 10.2 Hz, NH). MS: m/e 242
(100), 419 (M+). C24H26N4OS; (8d): Yield: 68%; mp
223 ꢁC; 1H NMR (DMSO-d6): d 1.98 (s, 4H), 2.51–2.56
(m, 4H), 3.24 (s, 4H), 4.00 (t, 2H, J = 6 Hz), 6.69–6.76 (m,
2H, ArH), 7.02–7.09 (m, 2H, ArH), 7.17–7.24 (m, 2H,
ArH), 7.42 (t, 1H, J = 8 Hz, ArH), 12.41 (d, 2H,
J = 6.8 Hz, NH). MS: m/e 437 (100), 437 (M+).
C21H23F3N4OS.
10. Compound (9a): Yield: 83%; mp 136 ꢁC; 1H NMR: d 2.04
(t, 2H, J = 7 Hz), 2.58–2.72 (m, 6H), 3.20–3.25 (m, 4H),
4.07 (t, 2H, J = 6.2 Hz), 6.82–6.96 (m, 3H, ArH), 7.11 (s,
1H, ArH), 7.23–7.31 (m, 2H, ArH), 7.53 (d, 1H,
J = 8.4 Hz, ArH), 7.98 (s, 1H, CH). MS: m/e 221 (100),
337 (M+). C20H24N4O; (9b): Yield: 90%; oil; 1H NMR: d
2.02 (t, 2H, J = 6.8 Hz), 2.59–2.70 (m, 6H), 3.12 (s, 4H),
3.85 (s, 3H, OCH3), 4.03 (t, 2H, J = 6.2 Hz), 6.84–7.12 (m,
6H, ArH), 7.53 (d, 1H, J = 7.4 Hz, ArH), 7.99 (s, 1H, CH).
MS: m/e 251 (100), 367 (M+). C21H26N4O2; (9c): Yield:
78%; mp 241 ꢁC; 1H NMR: d 2.05 (t, 2H, J = 6.6 Hz),
2.65–2.78 (m, 6H), 3.15 (s, 4H), 4.05 (t, 2H, J = 6 Hz), 6.94
(d, 1H, J = 8.6 Hz, ArH), 7.04 (s, 1H, ArH), 7.09 (d, 1H,
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