Discovery of bishomo(hetero)arylpiperazines as novel multifunctional ligands targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors

Article abstract of DOI:10.1021/jm100294b

As a continuation of our efforts to develop innovative ligands for D ₃, 5-HT_1A, and 5-HT_2A receptors with low propensity to block hERG channels, we propose a series bishetero(homo) arylpiperazines 5a-m as novel and potent multifunctional ligands characterized by low occupancy at D₂ and 5-HT_2C receptors.

Full text of DOI:10.1021/jm100294b

J. Med. Chem. 2010, 53, 4803–4807 4803
DOI: 10.1021/jm100294b
Discovery of Bishomo(hetero)arylpiperazines as Novel Multifunctional Ligands Targeting Dopamine
D3 and Serotonin 5-HT1A and 5-HT2A Receptors
Stefania Butini,†,‡ Giuseppe Campiani,*,†,‡ Silvia Franceschini,†,‡ Francesco Trotta,†,‡ Vinod Kumar,†,‡ Egeria Guarino,†,‡
Giuseppe Borrelli,†,‡ Isabella Fiorini,†,‡ Ettore Novellino,†,§ Caterina Fattorusso,†,§ Marco Persico,†,§ Nausicaa Orteca,†,§
Karin Sandager-Nielsen,^ Thomas Amos Jacobsen,^ Kim Madsen,^ Jorgen Scheel-Kruger,^ and Sandra Gemma†,‡
†
‡
European Research Centre for Drug Discovery and Development, Universita di Siena, 53100 Siena, Italy, Dipartimento Farmaco Chimico
ꢀ
Tecnologico, Universita di Siena, Via Aldo Moro, 53100 Siena, Italy, Dipartimento di Chimica delle Sostanze Naturali and Dipartimento di
§
ꢀ
Chimica Farmaceutica e Tossicologica, Universita di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy, and ^NeuroSearch A/S,
ꢁ
Pederstrupvej 93, Ballerup DK-2750, Denmark
Received March 5, 2010
As a continuation of our efforts to develop innovative ligands for D3, 5-HT1A, and 5-HT2A receptors
with low propensity to block hERG channels, we propose a series bishetero(homo)arylpiperazines
5a-m as novel and potent multifunctional ligands characterized by low occupancy at D2 and 5-HT2C
receptors.
Chart 1. Reference and Title Compounds
Introduction
Schizophrenia is a chronic mental disorder that globally
affects ∼1% of the world population.1 “Typical” antipsycho-
tics (e.g., haloperidol), potent dopamine D1 receptor (D1Ra)
and D2 receptor (D2R) antagonists, are effective in the treat-
ment of the positive symptoms of schizophrenia but fail to
manage the negative symptoms and the cognitive impairment
and induce side effects such as extrapyramidal symptoms
(EPS) and hyperprolactinemia.2 “Atypical” antipsychotics
(e.g., clozapine (1) and olanzapine (2), Chart 1), characterized
by a multireceptor affinity profile, are effective on therapy-
resistant schizophrenic patients3 although accompanied by a
series of unwanted effects. Olanzapine may precipitate
diabetes4 and increase appetite,5 and clozapine may induce
agranulocytosis, while other antipsychotics (ziprasidone, ris-
peridone, andquetiapine) mayinducelong QTsyndrome(risk
of malignant ventricular arrhythmia). Recently, aripiprazole
(3, Chart 1), a potent D2R ligand,6,7 characterized by low risk
of side effects, has been launched.8
The unmet clinical needs such as the treatment of refractory
patients, poor treatment of negative symptoms, and cognitive
dysfunction boosted us to exploit a novel paradigm9-13 for
developinginnovativeantipsychotics basedona unique multi-
receptor affinity profile.14 Our pharmacological approach
combines occupancy at dopamine D3 receptor (D3R), 5-HT2A
receptor (5-HT2AR), and 5-HT1A receptor (5-HT1AR) with low
affinity for D2R (no liability of EPS at antipsychotic doses) and
5-HT2C receptor (5-HT2CR) (reducing the risk of obesity under
chronic treatment). Our original design strategy14 was based on
the hypothesis that dopamine/serotonin competitive ligands,
although characterized by different structural scaffolds, are able
to interact with similar clusters of key receptor residues by
adopting multiple binding modes.9-14 We hypothesized that the
flexible arylpiperazine skeleton could allow the proper orienta-
tion of the pharmacophoric moieties (i.e. the two aromatic
rings, the protonated nitrogen, the H-bond donor/acceptor
atom(s)) to settle into different dopamine/serotonin receptor
sites. Structure-activity relationships (SARs) of the original
arylpiperazines were associated (i) with the variation of the
aromatic systems at the “head” and “tail” (Chart 1) of the stru-
cture, (ii) with the length of the methylene linker, and (iii) with
*To whom correspondence should be addressed. Phone: 0039-0577-
234172. Fax: 0039-0577-234333. E-mail: campiani@unisi.it.
a Abbreviations: D1R, dopamine D1 receptor; D2R, dopamine D2
receptor; D3R, dopamine D3 receptor; EPS, extrapyramidal symptoms;
5-HT2AR, serotonin 5-HT2A receptor; 5-HT1AR, serotonin 5-HT1A
receptor; 5-HT2C, serotonin 5-HT2C receptor; SARs, structure-activity
relationships; hERG, human ether-a-go-go-related gene; PCP, phency-
clidine; MAMP, methamphetamine; AUC, area under the curve; TEA,
triethylamine.
r
2010 American Chemical Society
Published on Web 05/19/2010
pubs.acs.org/jmc

4804 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12
Butini et al.
Table 1. Binding Affinities for D2, D3, 5-HT1A, 5-HT2A, and 5-HT2C Receptors (Ki, nM)a and hERG Channels (Ki, μM)b of Compounds 5a-m and
Reference Antipsychotics
a Each value is the mean of three determinations, and all SD were within 10% of the mean. b Each value is the mean of two determinations, and all SD
were within 10% of the mean. c Tests performed as in ref 14. d NT: not tested.
the replacement of the amide bond with an ether function.14
According to our binding mode hypothesis, we rationalized
SARs on the basis of dopamine/serotonin receptor homology
by using 3D receptor models. This approach allowed us to
identify the key structural elements responsible for achieving the
fine balancing of activity and selectivity toward the receptors of
interest and led to the identification of innovative atypical
antipsychotics.14 Furthermore, to improve the drugability of
the novel antipsychotics, we directed our design strategy at
limiting human ether-a-go-go-related gene (hERG) potassium
channel inhibition by up to 1 μM, thus minimizing the risk of
long QT syndrome and cardiac side effects.
In an effort to identify new scaffolds for the development of
multifunctional ligands for the same panel of receptors, we
applied the lessons learned from our previous studies and we
developed novel bishomo(hetero)arylpiperazines as flexible
ligands for specific occupancy of D3R, 5-HT1AR, and 5-HT2AR.
The bishomo(hetero)arylpiperazines 5a-m (Chart 1 and Table 1)
described herein demonstrated the predicted receptor affinity
profile, being potent and selective for D3R, 5-HT1AR, and
5-HT2AR (with low binding affinity for D2R and 5-HT2CR).
Our design strategy also proved to be successful for reducing
hERG occupancy. In fact, most compounds showed a low
propensity to block hERG potassium channels.
Chemistry
For the synthesis of the bishomoarylpiperazines 5a-e
(Scheme 1) 2 equiv of the correspondent arylpiperazines
6a-e were reacted with 1,6-dibromohexane in the presence
of a base. Unsymmetrical bisarylpiperazines 5f-m were
synthesized by a two-step synthesis. Bromo derivatives 7a-c
were at first synthesized using an excess of the 1,6-dibromo-
hexane (2 equiv) in the presence of the appropriate arylpiper-
azine (6a-c). Bromo derivatives 7a-c were then used as the
alkylating agents of the appropriate arylpiperazine (6b,d,e,
10a,b) to afford 5f-m.
The noncommercially available arylpiperazines 10a,b were
synthesized (Scheme 2) starting form N-Boc-piperazine (8)
that was N-substituted with the appropriate heteroaryl bro-
mide following a standard palladium catalyzed protocol.15,16
Deprotection of derivatives 9a,b by trifluoroacetic acid af-
forded 10a,b as trifluoroacetates.
Structure-Activity Relationships of Compounds 5a-m
Compounds 5a-m showed a receptor affinity profile
similar to that of our original arylpiperazine series,14 being,
on average, more selective for the desired panel of receptors
(i.e., D3R, 5HT1AR, 5HT2AR; Table 1). These results

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12 4805
Scheme 1a
a Reagents and conditions: (a) 1,6-dibromohexane (0.5 equiv), TEA,
MeCN, 12 h, room temp; (b) 1,6-dibromohexane (2.0 equiv), TEA,
MeCN, 12 h, room temp; (c) arylpiperazine (6b,d,e, 10a,b), TEA,
MeCN, 12 h, room temp.
Scheme 2a
Figure 1. (A) Transversal view of serotonin and dopamine 3D
receptor models. D2R (yellow), D3R (white), 5-HT2AR (cyan),
and 5-HT2CR (green), and 5-HT1AR (magenta) are superimposed
by CR atoms. Key residues on TM3, TM5, TM6, and TM7 are
displayed. Amino acids involved in subtype selectivity are high-
lighted by white circles. Ser residues on TM5 are labeled. (B)
Transversal view of 5a (green) and 4 (magenta), superimposed by
fitting their pharmacophoric moieties (i.e., “head” ring centroid,
protonated piperazine nitrogen hydrogen, H-bond donor group,
“tail” ring centroid). The hypothesized interactions with TM3,
TM5, TM6, and TM7 receptor helices are indicated.
a Reagents and conditions: (a) 2-bromo-6-methylpyridine or 4-bro-
moquinoline, Pd2(dba)3, (()-BINAP, NaOtBu, toluene, 90 min, 70 ꢀC;
(b) trifluoroacetic acid, dichloromethane, 1 h, room temp.
validated our design strategy and binding mode hypothesis.
Indeed, our previous studies14 indicated that an intramole-
cular H-bond between the carbonyl oxygen and the proto-
natable nitrogen of 4 (and its analogues) stabilized a
conformation that could fit the dopamine/serotonin receptor
pharmacophore. Molecular modeling calculations per-
formed on the bishomo(hetero)arylpiperazine scaffold also
indicated that 5a-m (Table 1) tend to adopt a similar
conformation (Figure 1; Figure 1 SI and Table 1 SI of the
Supporting Information).
Indeed, conformational search results pointed out that
most of the low energy conformers (i.e., ΔEGM e 5 kcal/mol)
of 5a-m presented an intramolecular H-bond between their
protonated and unprotonated aliphatic nitrogens (Figure 1 SI,
Table 1 SI). At physiological pH, apparent estimated pKa
values of the new compounds (Table 2 SI) predicted a 50:50
equilibrium between the mono- and the diprotonated forms
(pKa1 ≈ 8.2, pKa2 ≈ 7.4, SD = (0.40). In the case of 5i and 5l,
this equilibrium involved the diprotonated and the triproto-
nated forms because the first protonation was estimated to
occur on the 4-aminoquinoline moiety. However, taking into
account the observed conformational behavior of 5a-m and
the presence an intramolecular H-bond that engages one
aliphatic nitrogen lone pair, water protonation of both ali-
phatic nitrogens was disfavored. Taken together, our results
indicated that at physiological pH, the monoprotonated
(diprotonated for 5i and 5l) forms of 5a-m tend to prevail
because of the internal proton exchange between the two
(equally basic) aliphatic nitrogens. As a consequence, 5a-m
were predicted to adopt a conformation able to fulfill the
dopamine/serotoninpharmacophore reproducing the binding
mode of 414 (Figure 1, Figure 1 SI, Table 1 SI), placing (i) the
protonated N in contact with the Asp residue on TM3, (ii) the
two aromatic rings on the aromatic pockets on TM6 and TM7
(or TM4), and (iii) the H-bond donor groups close to the donor/
acceptor residues on TM5 and (in D3R and 5HT1AR) on
TM7.14 Accordingly, the bishomo(hetero)arylpiperazine scaf-
fold was designed to support our hypothesis of multiple binding
modes related to the pseudosymmetry of the receptor binding
sites. Resulting affinity profiles of 5a-m (Table 1) proved this
hypothesis, with 5a (bearing two unsubstituted phenyl
groups) being one of the most potent and selective ligands
of the series. In agreement with our previous SARs,14 the low
occupancy at D2R and 5HT2CR (5a, Table 1) could be related
to (i) the constraint due to the H-bond acceptor groups
hypothesized to interact with TM5 in a bulky piperazine ring
(Figure 1), (ii) the increased length of the alkyl chain, and (iii)
the consequent optimal distance between the aromatic ring
binding to the relevant aromatic pocket on TM6 and the
protonated N binding to TM3 (Table 3 SI: Y-N2 distance).
Because of the higher tolerance of D3R, 5HT1AR, and
5HT2AR to the mentioned structural modifications,14 5a
maintained the desired affinity profile on these receptors.

4806 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12
Butini et al.
Since 5a was found to be a weak hERG potassium channel
ligand (hERG Ki = 8.0 μM, Table 1), this indicated14 that
hERG affinity was strongly influenced by the dipole of the
phenyl ring at the “tail”. In our original series we observed
that a meta-substituent on the phenyl ring at the “tail”
(Chart 1) of the arylpiperazine moiety, such as in 4, led to
an optimal balance in receptor affinity profile.14 Conse-
quently, different substituents at the meta position of the
phenyl rings were investigated (5b-d,h,j-m, Table 1). Elec-
tron rich nitrogen containing aromatic rings (5e-g,i-l,
Table 1) were also introduced to further reduce hERG
channel interaction, according to the observation that elec-
tron-withdrawing atoms at the “tail” of arylpiperazines
strongly increased hERG affinity.14 The tight correlation
between the electron density at the aromatic rings and hERG
affinitywas confirmedin the new series (5d > 5m> 5b and5e,
f > 5a; Table 1). Furthermore, comparing hERG occupancy
in the subseries 5a-c (5b ∼ 5c > 5a), 5f,g,i (5i > 5g > 5f), and
5j-l (5l > 5k > 5j), we observed that, besides electronic
effects, hERG interaction was dependent on the steric hin-
drance at the meta position. With respect to receptor interac-
tion, the methyl groups of 5b reduced affinity for D3R and
Table 2. Pharmacokinetic Results for Compounds 5a,e-h,k and 4 after
Administration of 3 mg/kg (ip) in Mouse
AUCa
Cmax
(ng mL-1
compd
(h ng mL-1
)
Tmax (h)
)
T1/2 (h)
3
3
3
71
5a
5e
5fb
5g
5h
5k
4
198
84
0.5
1.0
1.0
0.3
0.5
2.0
0.5
NA
NA
NA
2.5
26
50
58
362
147
243
128
121.3
41
58
NA
NA
NA
155
a Area under the curve. b Exposure was only observed for one animal.
the compounds only reduced spontaneous exploratory
locomotor activity in relatively high doses (between 10 and
30 mg/kg, sc). These data indicated a low potential for
inducing sedation and extrapyramidal side effects consistent
with low D2R occupancy. When locomotor activity was
increased by phencyclidine (PCP), all tested compounds
produced a potentiation of PCP-induced locomotor activity
at doses between 3 and 10 mg/kg (data not shown). The
antipsychotic potential of the compounds was also assessed in
mice rendered hyperactive by methamphetamine (MAMP) or
MK801 pretreatment. 5a caused a nonsignificant reduction in
MAMP-induced hypermotility at 30 mg/kg, whereas 5g and
5f significantly reduced the MK801-induced hypermotility at
10 and 30 mg/kg, respectively. For 5g this represents a dose
that is 3 times lower than the doses able to reduce spontaneous
locomotor activity, whereas for 5f, it is a dose that is 3 times
higher than that able to reduce exploratory lomotor activity.
At the lower doses (1-0.3 mg/kg), 5k and 5j moderately
increased MK801- and MAMP-induced hypermotility, re-
spectively. Taken together, these preliminary data indicate
that the new compounds, although possessing a valuable in
vitro profile, fail to show an effect in animal models sensitive
to antipsychotic treatment.
5-HT1AR while increasingaffinity for 5-HT2AR and 5-HT2C
R
(5b vs 5a). Analogous to what occurred at the “tail” of our
original arylpiperazines, the replacement of the methyl groups
of 5b with chlorine atoms (5d) improved potency at D3R,
worsening affinity for 5-HT2AR. Introduction of methoxy
groups (5c) was tolerated at the three receptors of interest,
while the introduction of two 2-pyridine systems was detri-
mental for D3R affinity (5e). Interestingly, in the heterodimer
series (5f-m), the combination of the phenylpiperazine func-
tionality with the 2-pyridinylpiperazine (5f), together with 5a,
provided the best affinity profile of the series. A bulky
6-methyl substituent at the pyridine (5g) provided a com-
pound equally active at D3R and 5-HT2AR with respect to 5f
while increasing occupancy at 5-HT1AR and 5-HT2CR. Ex-
ploration of other combinations (5h and 5i) did not improve
the original profile of 5a and 5f. Introduction of a bicyclic
system as in 5i was well tolerated by the three receptors of
interest, as well as the combination of the m-tolylpiperazine
with different pyridinylpiperazines (5k and 5j). Occupancy of
5HT2CR increased with the introduction of a methyl substi-
tuent on the phenyl and the pyridine ring (5a vs 5b, 5f vs 5g, 5j
vs 5k), and 5k was the most potent compound of the series. As
discussed above, when the m-tolylpiperazine was combined
with the bulky 4-quinolylpiperazine (protonated at physiolo-
gical pH, Table 2 SI), hERG affinity was highly increased (5l).
When a m-methoxyphenylpiperazine was combined with a
3-chlorophenylpiperazine system (5m), an excellent ligand for
D3R, 5-HT1AR, and 5-HT2AR was obtained. These SARs
proved that the bisheteroarylpiperazine represents a new
scaffold for selective interaction with D3R, 5-HT1AR, and
5-HT2AR. Except for 5d, the other members of the series
showed micromolar affinity for hERG potassium channels
with 5f that combines the desired binding profile to the lowest
occupancy at hERG (Table 1).
In parallel we measured plasma concentration of 5a,e-h,k
after administration of 3 mg/kg (ip) in mice. Compound 4,
characterized by an amide moiety linked to an arylpiperazine
system, was tested as a reference analogue. In Table 2 and in
Figure 2 SI, 4 showed an AUC (0-6 h interval, h ng mL-1
)
3
3
of 128 while all the other tested compounds showed an AUC
between 58 and 362. Tmax was higher for 5e,f,k, while all the
other tested compounds displayed a similar value compared
to 4. While Cmax for 4 was 155 ng/mL, the values of the other
analogues were 26-121 ng/mL. These data suggest that the
new bisarylpiperazines do not possess an improved pharma-
cokinetic profile over 4. By comparison of the plasma
level profiles of 5g,h,k, it emerges that after administration
of 3 mg/kg ip in mice, the plasma concentration was higher for
5g than for 5k and 5h, probably indicating a different meta-
bolic stability of these analogues.
In summary, following our strategy for developing innova-
tive antipsychotics we generated novel bisarylpiperazinehex-
anes for a specific interaction with D3R, 5-HT1AR, and
5-HT2AR, minimizing occupancy at D2R and 5-HT2CR.
Among the compounds synthesized the multireceptor affinity
profile of 5a,f,j was particularly intriguing.
Since the risk of drug-induced cardiac arrhythmia is recog-
nized as a major hurdle in the successful development of new
drugs, investigation of hERG channel blockade is a key step
for the drug discovery process. We decided to include hERG
channel interaction evaluation at the early stage of the design
process. While 5d and 5l showed a submicromolar activity on
The intriguing multireceptor affinity profile of 5a,e-h,k,j
prompted us to further explore the antipsychotic potential by
means of standard animal models (Table 3 SI). In parallel to
these studies preliminary pharmacokinetic parameters were
also evaluated (Table 2 and Figure 2 SI).
Preliminary tests performed to evaluate the ability of our
compounds to inhibit spontaneous exploratory locomotor
activity indicated that, with the exception of 5j (Table 3 SI),

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12 4807
hERG, compounds 5a,f,g,j showed low liability to block
hERG channels. When tested in vivo to investigate their
behavioral effects, the novel compounds did not show the
expected antipsychotic potential. Compound 5g was able to
slightly reduce MK801-induced locomotor activity at 10 mg/kg,
and in other cases, at the lowest doses tested, a potentiation of
PCP-induced locomotor activity was observed. Although this
novel series of compounds shows the desired affinity profile,
the lack of antipsychotic potential in vivo might be explained
assuming a different intrinsic activity with respect to 4 and
analogues.14 Furthermore, the different orientation of the
H-bond donor/acceptor group(s), supposed to interact with
the Ser/Thr residues on TM5, with respect to the aromatic ring,
supposed to contact TM6 (such as in 5a and 4, Figure 1), might
affect receptor activation, thus contributing to the results
obtained when measuring in vivo antipsychotic efficacy.
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Experimental Section
Standard Synthesis of Symmetrical Compounds 5a-e. To a
solution of the appropriate 1-arylpiperazine (1.0 mmol) in dry
acetonitrile (30.0 mL), 1,6-dibromohexane (0.5 mmol) and TEA
(0.5 mmol) were added. The mixture was stirred at room
temperature for 12 h. The crude was extracted with dichloro-
methane (3 Â 20 mL), dried, and evaporated. The residue was
purified by means of flash chromatography (10% methanol in
chloroform) to give the pure compound.
Standard Synthesis of Unsymmetrical Compounds 5f-m. To a
solution of the 1-(6-bromohexyl)arylpiperazine (1.0 mmol) in
dry acetonitrile (30.0 mL), the appropriate 1-arylpiperazine
(1.3 mmol) and TEA (1.3 mmol) were added. The mixture was
stirred at room temperature for 12 h. The crude was extracted
with dichloromethane (3 Â 20 mL), dried, and evaporated. The
residue was purified by means of flash chromatography (10%
methanol in chloroform) to give the pure compound.
Acknowledgment. The authors thank MIUR;Rome,
Italy (PRIN), and NeuroSearch A/S Ballerup, Denmark, for
financial support.
Supporting Information Available: Tables 1-3 SI, Figures 1 SI
and 2 SI, experimental procedures for intermediates and char-
acterization of final compounds, experimental procedures for
molecular modeling studies, in vivo tests, and pharmacokinetic
studies and elemental analysis results for final compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A
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