Discovery of highly potent and selective D4 ligands by interactive SAR study

Article abstract of DOI:10.1016/j.bmcl.2013.07.033

A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with K_i 3.9 nM. An interactive SAR approach was adopted and lead to compound 14a with K_i (D4) as low as 0.03 nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands' arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure.

Full text of DOI:10.1016/j.bmcl.2013.07.033

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of highly potent and selective D4 ligands by interactive SAR
study
Mohamed A. O. Abdelfattah a,b, Jochen Lehmann b, Ashraf H. Abadi a,
⇑
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
b Institut für Pharmazie, Pharmazeutische/Medizinische Chemie, Friedrich Schiller Universität Jena, Philosophenweg 14, D-07743 Jena, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five sub-
types of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors;
analogue 5e showed the highest affinity to D4 receptors with Ki 3.9 nM. An interactive SAR approach was
adopted and lead to compound 14a with Ki (D4) as low as 0.03 nM. Molecular docking studies showed a
potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands’
arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of
the compound structure.
Received 2 June 2013
Revised 3 July 2013
Accepted 16 July 2013
Available online xxxx
Keywords:
Dopamine
D4 receptors
D4 ligands
Ó 2013 Elsevier Ltd. All rights reserved.
Interactive SAR study
Phenylpiperazins
The catecholamine dopamine neurotransmitter controls diverse
activities in CNS such as cognitive, motor, and emotional func-
tions.1 It mediates its action through interacting with five subtypes
of G-protein coupled receptors that referred to as dopaminergic
receptors.2–4 These receptors are classified into D1-like subfamily
that includes D1 and D5 receptor subtypes and D2-like subfamily
having D2, D3, and D4 as its own characteristic members.5,6
D4 agonists and partial agonists are of value in counteracting
Parkinson’s disease, and proved to be of benefit in relieving Attention
Deficit Hyperactivity Disorder, and other mood disturbances.7–9 This
is related to the contribution of this receptor subtype in some per-
sonality traits such as novelty seeking or impulsive, compulsive,
and addictive behavior.10 Moreover, other D4 selective agonists have
been reported to induce penile erection in rats when administered
in vivo, an action that is inhibited by concurrent ingestion of selec-
tive D4 antagonist confirming the mechanistic pathway.11
target protein. Ligands bearing the arylmethylphenylpiperazin
scaffold are known with their remarked selectivity and affinity to-
wards D4 receptor subtype.
As an example of these ligands, comes PD-168077 (1) that was
demonstrated to be unstable in acidic solution, precluding its
chances for oral administration.14 L-745870 (2) is another member
that is induced for clinical trials but failed to exert clinical effi-
cacy.15 Structure of these compounds and other D4 selective
ligands such as FAUC 113 (3) are shown in Chart 1.
In this work, we have started with synthesizing a series of thi-
enylmethylphenylpiperazin derivatives bearing the thiophene as
the heterocyclic arene moiety and different phenylpiperazin units
to serve as the recognition element for the target D4 receptor.
Thinking about centrally acting dopaminergic ligands, thiophene
system would serve as an optimum aromatic heterocycle moiety
as a start for this set of compounds for being more or less electron-
ically similar to the catechol ring of the endogenous dopamine.
Such similarities lead to close molar refractivities for the two sys-
tems, where molar refractivity of thiophene is 2.6 versus 3.0 for the
catechol system, (calculated with molar refractivity descriptor of
MOE16), so that thiophene system would provide this area of the
compound’s scaffold with the optimum polarizability to ensure
the affinity of the designed candidates to the target receptor.17 Fur-
thermore, the thiophene containing Rotigotine, Chart 1, has dem-
onstrated enhanced affinity and selectivity towards D3/D4
dopamine receptor subtypes.18
Compounds with high affinity to D4 receptors and antagonistic
functional activity are considered among the powerful marketed
antipsychotic drugs that show minimal Parkinson’s like side effects
that characterize the classical non selective members mainly work-
ing by antagonizing dopamine at D2 receptors.12
Unlike D3 receptor subtype,13 the exact molecular structure of
the D4 binding pocket is still not characterized by X-ray crystallog-
raphy leaving the field in a still need for selective chemical probes
that might help in identifying the binding fashion to this valuable
As for the phenylpiperazin part of the scaffold, we decided to
use different substituents on the phenyl ring to investigate the
⇑
Corresponding author.
E-mail address: ashraf.abadi@guc.edu.eg (A.H. Abadi).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.07.033
Please cite this article in press as: Abdelfattah, M. A. O.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.07.033

2
M. A. O. Abdelfattah et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
Cl
Cl
N
N
N
CN
N
N
O
N
N
H
N
N
N
H3C
NH
3, FAUC 113
2, L-745870
1, PD168077
CH3
N
S
OH
Rotigotine
Chart 1. Some selective D4 receptors ligands.
electronic and steric impact of this part of the compounds on the
affinity and selectivity to D4 receptors.
O
N
N
H
+
N
H
AcOH, 0°C
Based on affinity and selectivity data obtained after testing the
affinity of the synthesized candidates towards the five dopaminer-
gic receptor subtypes, some of the synthesized derivatives would
have their thiophene ring replaced with other aryl and heteroaryl
moieties to demonstrate the effect of this particular part of the
structure on the affinity and selectivity towards the target protein,
and to configure out an interactive Structure Affinity Relationship
study. A molecular modeling study was done to justify the ob-
tained data in view of the residues conserved in the D4 binding
pocket.
H
N
H
R
N
NH
14a, b
R
Scheme 2. Synthesis of 3-[4-phenylpiperazin-1-ylmethyl]-1H-indole derivatives.
Examining the binding affinity data of the thienylmethylphenylpi-
perazin derivatives shows that these candidates lack the appropriate
affinity to D1-like family members with Ki values >10 lM, a com-
mon feature for the majority of ligands bearing this scaffold. All
the ten thienylmethylphenylpiperazin ligands belonging to this
series, 5a–5j, showed high to moderate affinity towards D4 receptor
subtype with Ki values ranging from 3.9 to 214 nM and selectivity
towards D4 subtypes over D2 and D3 with selectivity indices as high
for certain candidate, 5f, as >1351 makingit one of the most selective
D4 ligands reported so far.
Regarding the length of the spacer linking the arene moiety to
the phenylpiperazin one, it was meant to be designed as methelene
linker as ligands bearing such a feature are highly selective to D4
receptor subtypes over D2 and D3 ones due to the fact that these
short ligands bearing only one carbon as a spacer between the aryl
and the phenylpiperazin moieties cannot stretch that far into the
hydrophobic pocket at the transmembrane helix 2 (TM2)/TM3
interface.24
The synthesis of the arylmethylphenylpiperazin derivatives is
depicted in Schemes 1 and 2.19–22
The final target compounds were screened for their binding
affinity towards human-cloned dopamine receptor subtypes D1,
D2, D3, D4, and D5 utilizing our general protocol.23 Ki affinity bind-
ing data is shown in Table 1. All compounds have shown functional
activity ranging from partial agonists to full antagonist towards D4
receptor subtypes in the fluorescent calcium assay.23
Cl
OH
S
S
4
a
or
Herein, the effects of two major factors on the affinity and selec-
tivity towards D4 receptor subtypes can be possibly studied,
namely the nature of the arene moiety in terms of size and electro-
static potential, the nature and the position of the substituent on
the phenylpiperazin scaffold.
Ar
N
Cl
OH
N
N
6
8
N
Cl
R
c
5a- j
7a, b
9a, b
Starting with the effect of the nature of the substituent of the
phenylpiperazin scaffold on the affinity, it was found that ligands
bearing ortho oxygenated substituents have shown better affinity
towards D4 receptors rather than those bearing halogenated sub-
stituents at this area of the structure. Compound 5e having 2-OEt
showed the best D4 binding affinity among this series followed
by 5f (2-OH), 5d (2,3-Cl), 5c (2-Cl), 5b (2-F) with Ki values of 3.9,
7.4, 49.9, 52, 57 nM respectively. This affinity pattern of the newly
synthesized ligands may be rationalized in view of the results of re-
cent mutagenesis studies that have confirmed that this part of the
compound structure is supposed to interact with His 6.55 residue
in the binding pocket of D4 receptors24–26 and accordingly the nat-
ure of the substituent at this area could affect such an interaction as
shown by the binding data of our synthesized ligands, where the
11a, b
13a, b
Cl
b
or
S
10
12
S
Br
Scheme 1. Reagents: (a) SOCl2, CH2Cl2 (b) 37% HCHO, HCl gas, CH2Cl2 (c)
corresponding phenylpiperazin, TEA, MeCN.
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M. A. O. Abdelfattah et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
3
Table 1
Binding affinity data of the synthesized compounds to cloned human Dopamine receptor subtypes
N
N
R1
N
X
N
R1
X
Formula 2
Formula 1
Compound
Structure
X
Ki-Values [nM] average SEM
Formula
R1
D1
D2
D3
D4
D5
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
7a
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
1
1
2
2
S
S
S
S
S
S
S
S
H
2-F
2-Cl
2,3-Cl
2-OEt
2-OH
4-F
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
2541
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
—
>10,000
>10,000
2179 569
1545 75
162 42
>10,000
>10,000
>10,000
1593 123
2167 58
1648 126
1899 97
427 14
44.5 0.5
112 13
>10,000
>10,000
>10,000
62 4.1
221 31
65 13
57 15
>10,000
>10,000
>10,000
1743
>10,000
>10,000
2059 484
3523
52 13.5
49.9 5.9
3.9 0.3
7.4 1.8
105 10
214 4,5
78 4.6
152 12.2
0.7 0.1
4.4 0.8
4-Cl
S
S
3,4-Cl
4-OH
2-OEt
2,3-Cl
2-OEt
2,3-Cl
2-OEt
2,3-Cl
2-OEt
2,3-Cl
2-OEt
2,3-Cl
1534
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
—
HC@N
HC@N
HC@CH
HC@CH
S
255
2
42
1
7b
9a
327 6.5
41 2.5
264
351
219
6
4
6
59
92
1
3
2
31
0.7
5
9b
11a
11b
13a
13b
14a
14b
3
45.1
52.5
42.7
2
5
2
4.5 0.2
S
383 25
217
22.5
3
1
1
HC@CH
HC@CH
NH
NH
FAUC 113
5
242 5.5
473 18
502 13
3200 58
41 0.5
103 12
11 0.5
0.03
0
123
7
6.2 0.1
3.1 0.3
5000 121
At least two independent experiments were carried out in triplicate each.
electron donating oxygenated substituent would ensure an elec-
tron rich aromatic system that is able to provide higher dispersion
forces compared to that provided with a system bearing the elec-
tron withdrawing halogenated substituents thus leading to better
Van der Waals interaction with the imidazole ring of His 6.55.27,28
Regarding the position of the substituent of the phenylpiperazin
scaffold on the affinity, compounds bearing an ortho positioned
substituent on the phenylpiperazin scaffold have exhibited much
better affinity to D4 than their para substituted congeners, for
example, 5c versus 5h and 5f versus 5g. This ortho substituent
would affect the degree of non co-planarity between the phenyl
and the piperazin rings, a feature that seems crucial for the affinity
aspects to the target receptor. This is obvious when comparing the
dihedral angles of compounds 5c and 5f to their para substituted
analogues, 5h and 5j, respectively; a dihedral angle of about 60°
seems optimal for activity. This is confirmed by that the smaller
in size fluorine atom in the ortho position of compound 5b did
not greatly affect the dihedral angle and hence activity has not
been reduced so much in its para analogue 5g, Figure 1 in Supple-
mentary data.
From receptor subtype selectivity perspective, compound 5f has
shown to be highly selective towards D4 receptors over D2 with
selectivity index D2/D4 of >1351. Compounds 5a and 5b showed
to be more than 100 folds more selective to D4 receptors over
D2 with D2/D4 of 152 and 175, respectively, while other deriva-
tives showed also appreciable selectivity with D2/D4 values rang-
ing from 14 to 95.
As for D4 over D3 selectivity, compound 5f again showed to be
>1351 folds more selective to D4 over D3. Compounds 5a, 5b, 5e,
5g, 5h also showed appreciable selectivity towards D4 with D3/
D4 values ranging from 25 to 95, while compounds 5c, 5j showed
lower degree of selectivity to D4 receptor subtype with D3/D4 val-
ues of 8 and 1.5, respectively. Interestingly, compounds 5d and 5i
bearing a dichlorinated phenylpiperazin skeleton have shown to be
with better affinity on D3 rather than D4 with Ki values of 44.5,
62.3 nM, respectively, on D3 versus 49.9, and 78 nM, respectively,
on D4 receptors showing to be the first ligands of this class to vio-
late the common selectivity pattern and pointing out that the nat-
ure of the substituents on the phenylpiperazin scaffold may control
also ligand subtype selectivity.
In an attempt to rationalize the selectivity pattern of the syn-
thesized compounds among this series towards D4 receptor, we
have docked all the synthesized compounds to the D4 homology
model developed before29 and also to the recently co-crystallized
D3 receptor model with the antagonist eticlopride (PDB ID: 3PBL,
Deposition number: 2010-10-20). The docking poses showed ionic
salt bridge interaction with Asp 3.32 in D3 (Asp-110) and D4 (Asp-
115).
Figure 1 shows the 3D structures of the highest affinitive D4 li-
gands from each series overlaid on each other while docked into
the binding pocket of D4 receptor model. The 2D interactions
resulting from docking these highest affinitive D4 ligands to the
D4 receptor model are shown in Figure 2 in the Supplementary
data.
Figure 3 in Supplementary data illustrates the docking of com-
pounds 5d and 5i that showed better D3 affinity rather than D4 to
D3 receptor model.
Viewing the binding pockets of the D3 and D4 models could
show that amino acid residues 2.61 and 3.28 are resembling Val-
86 and Phe-106 in D3 while Phe-91 and Leu-111 in D4, respec-
tively, and thus might manipulate the ligands’ selectivity towards
either subtype and come in accordance with the results of the pre-
vious mutagenesis studies.24 Furthermore, we have observed that
two other amino acid residues contributing to the binding pocket
of the receptor subtypes were found to be different among them.
The first one is the EL2 residue Arg-186 in D4 that faces Ser-182
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4
M. A. O. Abdelfattah et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
Figure 1. 3D structures of compounds 5e (green), 7a (pink), 9a (purple), 11a (turquoise), 13a (orange), and 14a (gray) overlaid on each other inside the binding pocket of D4
receptor model. Amino acid residues and ligands’ Hydrogen atoms were removed for clarity.
in D3 receptor subtypes. The second one is the residue 5.38 that
resembles Phe-188 in D3 subtype, while faces Tyr-192 in D4 recep-
tors. Examining the docking poses of D4 receptor model, Figure 2 in
Supplementary data, could show that the unique D4 Tyr-192 is fac-
ing the phenylpiperazin unit of the docked ligands. The chemical
nature of this amino acid enables it to afford hydrogen bond inter-
action with the 2-OH group of compound 5f providing a possible
explanation for its superior selectivity towards D4 receptor sub-
types. It is also important to note that this selectivity was dramat-
ically reduced when shifting the hydroxyl function to the para
position as in compound 5j.
Comparing the selectivity data of compound 5f to that of 5b, 5c
and 5e would reveal decrease in selectivity towards the D4 recep-
tors over the other two subtypes. This might emphasis the contri-
bution of the Tyr-192 residue in controlling the subtype receptor
selectivity of the synthesized candidates, where this specific resi-
due faces Phe-188 in D3 and Phe-189 in D2 subtypes. These phen-
ylalanine residues in D2 and D3 receptors would resemble a sort of
incompatibility with the 2-OH group of compound 5f while afford
better hydrophobic interaction with the more lipophillic 2-F, 2-Cl
and the 2-OEt groups of compounds 5b, 5c, and 5e, respectively,
explaining the better affinity of these compounds to the other
two receptor subtypes relative to compound 5f itself.
Viewing the docking poses could also show that the Phe-91 res-
idue is conserved in the binding pocket of D4 receptor and faces
the also conserved and the less bulky Val-86 in D3 binding pocket.
This may provide a possible explanation why the relatively more
bulky dihalogenated bearing compounds 5d and 5i have shown
the best affinity towards D3 (with a relative larger pocket than
D4 subtypes) among the thienylmethylphenyl-piperazin series.
Moving to the effect of the heteroarene moiety on the binding
affinity and selectivity to D4 receptors, we have replaced the thio-
phene ring of compound 5e that showed the best affinity to the tar-
get protein among this series and compound 5d that showed better
affinity to D3 rather than D4 receptor subtypes with benzene, ben-
zothiophene, naphthalene, pyridine, and indole, so that factors like
ring size and ring electron density could be tested and thus pictur-
ing the second round of our optimization plan.
binding affinity of compound 5e have been very much developed
using pyridine ring in compound 7a that showed Ki value of
0.7 nM. Compound 14a having the indole ring as the heteroarene
moiety was much more superior with Ki as low as 0.03 nM show-
ing to be about 100 folds more affinitive to D4 than compounds 5e
and the reference compound 3, FAUC 113. These findings could
support the assumption that a specific negative electrostatic po-
tential of the ring at this area of the compound structure does
really matter rather than ring size, where the best D4 affinity
was obtained by the compounds bearing arenes with the highest
negative electrostatic potential, namely compounds 7a and 14a
having pyridine and indole arenes, respectively.
Interestingly all the docked compounds to D4 receptors model
have afforded a first to report arene–cation interaction through
their arene moiety with the unique Arg-186 in EL2 of the binding
pocket of the D4 receptors, Figure 2 in Supplementary data. Such
an interaction could be strengthen via increasing the negative elec-
trostatic potential at this area of the compound skeleton explaining
the high affinity and selectivity of compounds 7a and 14a towards
D4 subtypes.
Neither one of the 5d five analogues showed to bind preferen-
tially to D3 over D4 like compound 5d itself; however they showed
considerably good affinity to D3 with Ki values ranging from 41 to
123 nM.
Acknowledgments
The authors are grateful to the Alexander von Humboldt foun-
dation, Bonn for providing a fellowship to A.H.A. and his scholar
M.A.O.A. in Jena University, throughout which a part of this work
had been accomplished.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.07.
033.
Relative to 5e, compounds 11a and 13a having benzothiophene
and benzene had Ki values of 4.5 and 3 nM, respectively, that is al-
most similar to that of 5e (3.9 nM). Compound 9a with naphtha-
lene ring showed little better affinity with Ki value of 2 nM. The
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Please cite this article in press as: Abdelfattah, M. A. O.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.07.033