Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents

Article abstract of DOI:10.1016/j.bmc.2011.12.019

Using haloperidol as a scaffold, new agents were designed to investigate the structural contributions of various groups to binding at CNS receptors associated with atypical antipsychotic pharmacology. It is clear that each pharmacophoric group, the butyrophenone, the piperidine and the 4-chlorophenyl moieties contributes to changes in binding to the receptors of interest. This strategy has resulted in the identification of several new agents, compounds 16, 18, 19, 23, 24 and 25, with binding profiles which satisfy our stated criteria for agents to act as potential atypical antipsychotics. This research demonstrates that haloperidol can serve as a useful lead in the identification and design of new agents that target multiple receptors associated with antipsychotic pharmacology.

Full text of DOI:10.1016/j.bmc.2011.12.019

Bioorganic & Medicinal Chemistry 20 (2012) 1291–1297
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Multi-receptor drug design: Haloperidol as a scaffold for the design
and synthesis of atypical antipsychotic agents
Kwakye Peprah a, Xue Y. Zhu a, Suresh V.K. Eyunni a, Vincent Setola b, Bryan L. Roth b,
Seth Y. Ablordeppey a,
⇑
a Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA
b Department of Pharmacology, Medicinal Chemistry and Psychiatry, University of North Carolina at Chapel Hill, School of Medicine, NC 27599, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Using haloperidol as a scaffold, new agents were designed to investigate the structural contributions of
various groups to binding at CNS receptors associated with atypical antipsychotic pharmacology. It is
clear that each pharmacophoric group, the butyrophenone, the piperidine and the 4-chlorophenyl moie-
ties contributes to changes in binding to the receptors of interest. This strategy has resulted in the iden-
tification of several new agents, compounds 16, 18, 19, 23, 24 and 25, with binding profiles which satisfy
our stated criteria for agents to act as potential atypical antipsychotics. This research demonstrates that
haloperidol can serve as a useful lead in the identification and design of new agents that target multiple
receptors associated with antipsychotic pharmacology.
Received 22 October 2011
Revised 6 December 2011
Accepted 13 December 2011
Available online 22 December 2011
Keywords:
Haloperidol
CNS receptor ligands
Antipsychotics
Published by Elsevier Ltd.
Atypical antipsychotics
Dopaminergic and serotonergic agents
1. Introduction
(Fig. 1) may also contribute to haloperidol’s EPS problems.6 These
theories have inspired us to begin a search for drugs that could
Until recently, haloperidol (1) has been a drug of choice in the
treatment of schizophrenia and has represented the typical anti-
psychotic drugs as a mainstay of treatment from the 1960s until
this decade.1 While its therapeutic effectiveness has been attrib-
uted to potent dopamine (DA) D2 receptor binding affinity
(D2 Ki = 0.89 nM), haloperidol also binds with low to high affinity
at several other central nervous system (CNS) receptors, including
not be transformed in vivo to produce the harmful metabolites.7
Our laboratory has been interested in the potential of haloperidol
as a lead to obtain novel entities without EPS but which display
multi-receptor binding profiles similar to those of atypical antipsy-
chotic agents. Towards this end, we have designed and synthesized
new agents based on the haloperidol pharmacophore which could
not be transformed into the toxic quaternary metabolites, but which
possess atypical antipsychotic binding profiles.7–10 In furtherance of
this interest, the current study explores the effect of the replace-
ment of both butyrophenone and piperidine moieties in haloperidol
with bioisosteres that could not be bio-transformed into toxic
metabolites, that is, BCPP+ and FBPA respectively.
In previous studies, we have proposed a set of binding criteria
that would lead to new agents without the known side effects
observed with the atypical antipsychotic agents in use.9 These in-
clude: compounds should bind with moderate affinity at the D2
receptor (30 nM < Ki < 150 nM), as avid affinity to this receptor
may lead to induction of acute EPS; and a weak or no binding affinity
to 5HT2C and histamine H1 receptors, as both receptors are reported
to be associated with weight gain and subsequently type II diabetes,
often observed with some of the atypical antipsychotics.
other DA subtypes, serotonin (5-HT) receptors and alpha (a)
adrenoceptors (Tables 1 and 4). Thus, haloperidol can serve as a
scaffold for the design of new agents that target multiple receptors
associated with antipsychotic pharmacology.
The dwindling interest in haloperidol and other typical antipsy-
chotics is partially related to the induction of severe short- and long-
term debilitating movement disorders including Parkinsonism-like
symptoms, sometimes referred to as extrapyramidal syndrome
(EPS) and tardive dyskinesia (TD).2,3 Several theories have been
proposed to explain haloperidol’s long-term side effects including
metabolic transformation of the piperidine moiety to quaternary
pyridinium (BCPP+) species which have similar but weaker poten-
tial as 1-methyl-4-phenyl pyridinium (MPP+) to destroy D2 recep-
tors in the substantia nigra of the brain.4,5 More recently, Kim and
others have shown that N-dealkylation of the butyrophenone
moiety to produce 3-(4-fluorobenzoyl) propionic acid (FBPA)
2. Chemistry
Alkylating agent, 1-fluoro-4-(4-iodobutyl)benzene (2) was
⇑
Corresponding author. Tel.: +1 850 599 3867; fax: +1 850 599 3934.
E-mail address: seth.ablordeppey@famu.edu (S.Y. Ablordeppey).
prepared using a literature procedure with modification11 by
0968-0896/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmc.2011.12.019

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K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1291–1297
Table 1
Binding of phenyl piperidine analogs at dopamine and serotonin receptors of interest
X
N
Y
Cl
F
Compounds
X
Binding (Ki SEM) data of phenyl piperazine analogs at selected receptors (nM)
#
Y
D2
D3
240
4.6
D4
5HT1A
5HT2A
5HT2C
17
4700
MP
>10000
MP
>10000
>10000
>10000
Cloza
130
0.89
24
8.8 9.5
5.3 0.3
185 13
54
10
140
3600
8.9
120
Hal, 1a
C@O
CH2
S
O
S
COH
COH
COH
COH
CH
5
6
7
8
9
10
2
666 39
49.0 1.7
182 22
130 14
696 50
243 35
1.5 0.1
247.8 4.3
2.4 0.1
658 50
317 29
302 23
72
7
74.0
6
93 10
112 17
39
9.5 0.3
35
3
454 92
169 15
613 216
O
S@O
CH
CH
41
998 68
4
121
9
1
222 17
MP = Missed primary assay threshold of 50% inhibition, Cloz, Clozapine; Hal, Haloperidol.
a
The binding data of these compounds were previously reported in Refs. 7,9,10
Table 2
Binding of phenyl piperazine analogs at dopamine and serotonin receptors of interest
Z
X
N
N
A
Compounds
A
Binding (Ki SEM) data of phenyl piperazine analogs at selected receptors (nM)
#
X
Z
D2
D3
*D4
5HT1A
5HT2A
5HT2C
11a
12
13
14
15
16
17
18
F
F
F
F
F
F
H
H
C@O
CH2
S
S
O
O
O
O
4-Cl
4-Cl
4-Cl
4-CF3
4-Cl
H
254 39
284 21
211 22
4753 593
390 34
37*
404 66
261 23
422 41
544 58
885 65
207*
17.5 2.0
7.8
8.7
89
6.9
7.4
5.6
4.5
90.9 21.0
110 16
3552 943
MP
MP
MP
MP
MP
MP
MP
112
7
81
53
5
3
166 12
1080 389
1129 114
60
80
6
4
24.0*
154*
25.0*
57.6 2.8
19.8 1.0
46.0 4.2
4-Cl
H
447*
726*
119*
79.3 13.7
a
The synthesis and DA binding data of compound 11 were previously reported in Ref. 9,10; MP = Missed primary assay threshold of 50% inhibition.
The SEM of the binding data of compounds with asterisk are less than 20%.
*
Table 3
Binding data for aryl piperazine analogs at dopamine and serotonin receptors of interest
Ar
X
N
N
F
Compounds
X
Binding (Ki SEM) data of aryl piperazine analogs at selected receptors (nM)
Compd #
Ar
D2
D3
D4
6.5 0.8
5HT1A
30.5
5HT2A
5HT2C
19
20
21
22
23
24
25
C@O
CH2
S
O
CH2
S
2-Pyrimidine
2-Pyrimidine
2-Pyrimidine
2-Pyrimidine
2-Pyridine
98.0 15.0
269 17
424 25
636 66
124 10
183 21
186 16
244.1 106.0
262 17
5
22.0 4.0
41.0 2.0
27.0 2.0
23.0 1.0
50.0 3.0
26.0 1.0
18.0 1.0
4132 1081
MP
8829 2674
>10000
MP
8097 495
8277 497
6.2 0.3
21.0 1.0
4.2 0.1
3.5 0.2
5.7 0.3
1.8 0.1
8.6 0.7
93.1 29.0
23.0 3.0
1.1 0.1
6.2 0.5
3.6 0.2
68.0 10.0
778 63
86.0 4.0
160 16
2-Pyridine
2-Pyridine
O
229 20
MP = Missed primary assay threshold of 50% inhibition.
coupling 4-fluorophenyl magnesium bromide with 1,4-dibromo-
butane in the presence of Li2CuO4, and followed by halide
exchange in acetone under reflux (Scheme 1). Coupling of 2 with
selected amines in DME using K2CO3 as base provided ligands 5,
12, 20, 23 (Tables 1–3). 3-(4-fluorophenoxy)propan-1-ol, 3a was
obtained by refluxing 4-fluorophenol, 3-chloropropanol, K2CO3,
and KI in iPrOH Scheme 2. Mesylation was carried out at room tem-
perature employing Et3N as a base to afford 3-(4-fluorophen-
oxy)propyl methane sulfonate, 4a Scheme 2. Methane sulfonates,
4b and 4c were similarly synthesized. Alkylation of selected
amines in the presence of K2CO3 and KI in DME, with methane
sulfonates (4a, 4b and 4c) resulted in the formation of compounds
6–9, 13–18, 21–23 and 24–26 (Tables 1–3). The syntheses of these
compounds are shown in Scheme 3. Sulfoxide 10 was obtained by
oxidation of 9 with m-CPBA in MeOH as shown in Scheme 4.
3. Results and discussion
The first strategy was to conduct preliminary SAR studies on
haloperidol to observe how changes in the various segments of

K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1291–1297
1293
Table 4
Binding profile of selected synthetic compounds and their comparison with standard agents
Receptors
Binding (Ki SEM) data of compounds at selected receptors (nM)
19 23 24
98.0 15.3 124 10 183 21
16
18
25
186 16
Cloz*
Hal*
D2
D4
37.0 0.9
7.4 0.9
24.0 0.9
57.6 2.8
MP
ND
62.9 12.7
ND
119 0.9
4.5 0.9
25.0 0.9
46.0 4.2
MP
130
54
140
8.9
17
ND
1.8
ND
1.8
0.89
10
3600
120
4700
ND
440
ND
1600
6.5 0.8
30.5 5.0
22.0 4.0
4132 1081
ND
912 152
80.0 9.6
MP
3.5 0.2
1.1 0.1
50.0 3.0
MP
90.0 4.0
167 24
308.2 24.4
MP
5.7 0.3
6.2 0.5
26.0 1.0
8097 495
291 36
212 30
45.1 8.5
MP
1.8 0.1
3.6 0.2
18.0 1.0
8277 497
208 33
262 23
194.5 8.5
MP
5HT1A
5HT2A
5HT2C
5HT7
H1
ND
67.9 9.7
ND
Alpha 2C
M1
MP
MP
*
Cloz, Clozapine; Hal, Haloperidol; ND = Not determined; MP = Missed primary assay threshold of 50% inhibition.
Cl
O
Cl
OH
Ketone reductase
N+
N+
F
BCPP+ (HPP+)
F
+
RHPP
CYP3A4
CYP3A4
CYP3A4
MAO-A
O
OH
OH
OH
Ketone reductase
CYP3A4
OH
Cl
Cl
N
N
F
F
Reduced Haloperidol
[Haloperidol Metabolite II]
Haloperidol 1
CYP3A4
O
CYP3A4
Cl
HN
CO2H
FBPA (Haloperidol metabolite III]
F
4-(4-chlorophenyl)-4-hydroxypiperidine
[Haloperidol Metabolite I]
Figure 1. Metabolic transformation of haloperidol.
MgBr
I
a,b
Br
+
Br
F
F
2
Scheme 1. Reagents and conditions: (a) Li2CuO4, THF, N2, ꢀ10 °C, 2 h; (b) KI, acetone, 60 °C, 24 h.
the structure affect binding at DA and 5HT receptor subtypes of
interest. The structure was delineated in 3 segments, the butyro-
phenone moiety, the piperidine and the 4-chlorophenyl moiety as
depicted below.
resulted in a 27-fold decrease in binding to the D2 receptor com-
pared to haloperidol (Table 1). Replacement of the carbonyl group
with sulfur 6 (D2 Ki = 8.8 nM) and oxygen 7 (D2 Ki = 5.3 nM)
resulted in more moderate decreases in affinity at the D2 receptor.
Overall, with the piperidinol in place, the carbonyl appears to be an
important group for binding to D2 receptors but is not a necessary
group since it can be replaced by a methylene group, sulfur, or oxy-
gen to display potent binding at the D2 receptor. The trend in bind-
ing at the D2 receptor is an increase from the methylene group to
sulfur and then to oxygen. Binding to the D3 receptor for the three
compounds shows little or no observable pattern although the
sulfur analog displayed the highest potency among them. At the
D4 receptor, the sulfur analog displayed over 24-fold decrease in
binding while the oxygen analog displayed over 4-fold increase
in binding compared to the methylene analog. A significant obser-
vation relates to the binding of two of the compounds to 5HT
receptor subtypes. Compound 7, the oxygen analog, displayed a
49-fold increase in binding (Ki = 74.0 nM) at the 5HT1A receptor
Butyrophenone
Piperidine
OH
O
F
C CH2CH2CH2
N
Cl
Chlorophenyl
The butyrophenone moiety was the focus of the first modifica-
tions and these modifications are referenced to haloperidol. Reduc-
tion of the carbonyl to a methylene group 5 (D2 Ki = 24.0 nM)

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K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1291–1297
XH
X
OH
X
OMs
b
a
Y
Y
Y
X = O, S
Y = H, F
3a Y = F, X = O
3b Y = F, X = S
3c Y = H, X = O
4a Y = F, X = O
4b Y = F, X = S
4c Y = H, X = O
i
Scheme 2. Reagents and conditions: (a) KI, K2CO3, PrOH, 80 °C,12 h; (b) MsCl, Et3N, CH2Cl2, 5 °C to rt.
while retaining the 4-chloro atom 17 did not result in an increase
2
X
4a
4b
4c
a
N
Y Ar
in binding but instead led to significant decreases except for the
5HT1A receptor where binding increased by a factor of 3 (5HT1A,
Ki = 19.8 nM). When both halides were removed to obtain com-
pound 18, binding improved at all receptors of interest compared
to 17 but was mixed compared to compound 16.
+
HN
Y
Ar
Y
5 - 26
Y = N, CH, CHOH
Ar =
N
We also investigated replacements of the 4-chlorophenyl ring
with heteroaromatic rings associated with increased binding at
5HT receptors. Replacement of the 4-chlorophenyl group in com-
pound 11 with the 2-pyrimidinyl group to obtain compound 19,
led to improvement in binding affinity at all the receptors investi-
gated. Reduction of the carbonyl group to a methylene group 20
did not improve binding at the D2-like and the 5HT2A receptors
but did improve binding affinity at the 5HT1A receptor (19
(Ki = 30.5 nM); 20 (Ki = 8.6 nM)). Replacement of the carbonyl
group with sulfur 21 or oxygen 22 did not result in any significant
modifications of binding affinity at the receptors investigated.
Replacing the 2-pyrimidinyl group in compounds 20, 21 and 22
with a 2-pyridinyl moiety to form 23, 24 and 25 respectively were
also evaluated. Compound 23 binds with increased affinity at the
D2-like receptors and also shows either an increased potency or
no changes at the serotonin receptor subtypes investigated. In fact,
compound 23 has the highest binding affinity (Ki = 1.1 nM) at the
5HT1A receptor in this investigation. Compounds 24 and 25, the
sulfur and oxygen analogs also showed significant D4 potency
Cl
CF3
N
N
Scheme 3. Reagents and conditions: (a) KI, K2CO3, DME, 90 °C 12 h.
while compound 6 bound with a moderate increase in affinity
(Ki = 317.0 nM) compared to haloperidol. At the 5HT2A receptor,
the methylene substituent had a moderate binding affinity while
the sulfur (Ki = 72.0 nM) and oxygen (Ki = 93.0 nM) analogs
displayed increased binding over haloperidol.
The next SAR focus was on the piperidine moiety. Removal of
the alcohol function from compounds 6 and 7 to form 8 and 9
respectively resulted in significant decreases in binding to the D2
receptor as observed in previous reports.7 However, there was an
increase in binding for the sulfur analog 8 (Ki = 39.0 nM) and a
more moderate decrease in binding at the D4 receptor for the oxy-
gen analog 9 (Ki = 9.5 nM). At both the 5HT1A and 5HT2A receptors,
the absence of the alcohol group did not result in much change in
binding. It is interesting to note that oxidizing the sulfur analog 8
to form the sulfoxide 10 which appears to mimic the carbonyl moi-
ety structurally, resulted in diminished binding at all the receptors
examined except at the 5HT1A receptor and thus suggests that the
sulfoxide may not serve as a bioisostere of the carbonyl group. The
next evaluation, replacement of the piperidine with a piperazine
resulted in analogs 11–18. Compound 11, the piperazine analog
of haloperidol, produced a substantial decrease in affinity to the
D2 receptor from 0.89 to 253.5 nM. Binding affinity decreased or
changed minimally at essentially all the other receptors evaluated.
Reduction of the carbonyl to a methylene group to form compound
12 did not modify binding significantly at these receptors. Like-
wise, replacement of the carbonyl with sulfur 13 and oxygen 15
did not result in significant changes in binding at dopamine and
serotonin receptors of interest. In the eastern hemisphere, replace-
ment of the 4-chloro atom on the phenyl ring with the bigger and
more powerful electron withdrawing CF3 group 14 led to a dra-
matic decrease in binding affinity at all the receptor subtypes
investigated. This may suggest there is a steric obstruction to bind-
ing at these receptors. The contributions of the two halogens in the
western and eastern hemispheres were also evaluated using com-
pound 15 as the template. Compound 16, with the chloro atom
removed, binds at the D2 receptor with 37 nM affinity, this being
an over 10-fold increase in binding. Removal of the 40-fluoro atom
and selectivity and high affinity binding to 5HT1A and 5HT2A
.
A review of how the current compounds under investigation
have satisfied our criteria9 for obtaining new antipsychotic agents
with moderate D2 binding and high affinity binding (Ki < 50 nM) to
5HT1A and 5HT2A receptors shows several compounds including 16,
18, 19, 23, 24, and 25 meet the stated criteria and were therefore
slated for further evaluation.
These compounds were thus screened for their binding affini-
ties at 5HT7, a2c and M1 to assess their capacity to improve cogni-
tive properties. They showed only moderate binding affinity at the
5HT7 receptor, and similar affinity at the a2C receptor. The 5-HT7
receptor abounds in the hippocampus, which is involved in learn-
ing and memory.12 Studies have shown that 5-HT7 receptor antag-
onists and 5-HT7 receptor gene knockout have the potential to
impair some cognitive functions in mice.13 The adrenergic a2c
receptor has also been implicated as potentially relevant to cogni-
tive function.14 Evaluation at M1 receptors showed the compounds
to have little or no affinity at the muscarinic M1 receptor (Table 4).
The blockade of this cholinergic receptor has been associated with
cognitive deficits, which may be particularly severe in susceptible
individuals such as the elderly.15 The propensity of the compounds
to induce metabolic side-effects such as weight gain was investi-
gated by evaluating their binding affinities at H1 and 5HT2C recep-
tors. The results are recorded in Table 4. All the 6 compounds
O
S
a
S
N
Cl
N
Cl
F
F
10
9
Scheme 4. Reagents and condition: (a) m-CPBA, MeOH, rt, 4 h.

K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1291–1297
1295
evaluated bind with only moderate affinity at the H1 receptor and
have little or no binding to the 5HT2C receptor. Histamine H1 recep-
tor blockade has been implicated in weight gain associated with
atypical antipsychotic therapy16,17 and so has the 5HT2C recep-
tor.18,19 This suggests that these compounds would have attenu-
ated capacity to induce weight gain.
Overall, the SAR of haloperidol indicates the butyrophenone, the
piperidine and the 4-chlorophenyl moieties each play a role in its
multi-receptor binding profile. Six compounds (16, 18, 19, 23, 24
and 25) have been identified as meeting the general criteria we have
proposed as sufficient to be considered for further evaluation. Based
on further screening results, there is sufficient data to engender
evaluation of these compounds in vivo in order to understand the
pharmacology imposed on them as a result of the binding profiles
observed. These in vivo evaluations are currently underway.
4.1.5. 3-(4-Fluorophenoxy)propyl methanesulfonate (4a)
Yield 95%. 1H NMR (CDCl3): d 6.97 (2H, t, J = 8.1 Hz), 6.83 (2H,
dd, J = 4.5, 9.0 Hz), 4.44 (2H, t, J = 6.0 Hz), 4.05 (2H, t, J = 6.0 Hz),
2.21 (2H, m).
4.1.6. 3-((4-Fluorophenyl)thio)propyl methanesulfonate (4b)
Yield 94%. 1H NMR1H NMR (CDCl3): d 7.37 (2H, dd, J = 9.0,
4.8 Hz), 7.00 (2H, t, J = 9.0 Hz), 4.30 (2H, t, J = 8.0 Hz), 3.00 (3H, s),
2.78 (2H, t, J = 7.2 Hz), 2.02 (2H, m).
4.1.7. 3-Phenoxypropyl methanesulfonate (4c)
Yield 92%. 1H NMR (CDCl3): d 7.30 (2H, m), 6.97 (1H, m), 6.90
(2H, m), 4.43 (2H, t, J = 6.3 Hz), 4.08 (2H, t, J = 6.0 Hz), 2.97 (3H,
s), 2.21 (2H, m).
4.1.8. General procedure for coupling iodides with amines
A
mixture of 1-fluoro-4-(4-iodobutyl)benzene (2) (1.58 g,
4. Experimental
5.7 mmol), 4-(40-chlorophenyl) piperidin-4-ol (1.0 g, 4.7 mmol),
and K2CO3 (1.96 g, 17 mmol) in DME (25 mL) was refluxed under
N2 for 12 h with stirring. The mixture was diluted with EtOAc
(500 mL) and washed with water (300 mL). The organic phase was
collected, dried with sodium sulfate, and filtered. The filtrate was
concentrated by evaporation under reduced pressure, followed by
purification using column chromatography with hexane:EtOAc
(1:4) as eluent to afford 4-(40-chlorophenyl)-1-(40-(4-fluoro-
phenyl)butyl)piperidin-4-ol (5) (0.83 g) as an off-white solid after
crystallization in EtOAc/Et2O; yield 48.5%, mp 140–141 °C. 1H
NMR (CDCl3): d 7.26 (2H, m), 7.15 (2H, d, J = 4.5 Hz), 6.95 (2H, m),
6.87 (2H, m), 3.98 (2H, t, J = 6.6 Hz), 3.06 (2H, d, J = 5.7 Hz), 2.54
(2H, t, J = 6.9 Hz), 1.98 (4H, m), 1.80 (4H, m). Calcd for C21H25
ClFNOꢁ0.2 H2O: C 69.01, H 6.89, N 3.83; Found: C 68.82, H 6.86, N
3.82.
Melting points were determined on a Gallenkamp (UK) appara-
tus and are uncorrected. NMR spectra were obtained on a Varian
300 MHz Mercury Spectrometer. Elemental analyses were carried
out by Atlantic Microlab, Inc., Norcross, GA, and are within 0.4%
of theory unless otherwise noted. Flash chromatography was per-
formed with Davisil grade 634 silica gel. N,N-Dimethylformamide
was distilled from CaSO4 and stored over 4 Å molecular sieves.
4-Chloro-40-fluorobutyrophenone was obtained from Sigma–Al-
drich, but was purified by distillation under reduced pressure to
a colorless liquid prior to use. Other starting materials were used
without further purification.
4.1. 1-Fluoro-4-(4-iodobutyl)benzene (2)
This iodide was prepared following a literature procedure.20 The
bromide was first obtained, followed by halide exchange to obtain
the iodide. Yield 82.1% 1H NMR (CDCl3): d 7.13 (2H, m), 6.98 (2H,
m), 3.20 (2H, t, J = 6.6 Hz), 2.62 (2H, t, J = 7.8 Hz), 1.84 (2H, m),
1.73 (3H, m).
4.1.9. 1-(4-Chlorophenyl)-4-(4-(4-fluorophenyl)butyl)piperazine
(12)
Using 2 and 1-(4-chlorophenyl) piperazine, produced com-
pound 12: yield 52.2%, mp 89–90 °C. 1H NMR (CDCl3): d 7.19 (2H,
m), 7.13 (2H, m), 6.95 (2H, m), 6.84 (2H, m), 3.14 (4H, m), 2.56
(6H, m), 2.39 (2H, t, J = 7.5 Hz), 1.59 (4H, m). Calcd for C20H24ClFN2:
C 69.97, H 6.97, N 8.08; Found: C 69.29, H 7.03, N 7.91.
4.1.1. General procedure for the synthesis of methanesulfonates
(4a, 4b, 4c)
A mixture of 4-fluorophenol (1.1 g, 10 mmol), 3-chloropropanol
(1.4 g, 15 mmol), KI (50 mg), K2CO3 (2.8 g, 20 mmol) in PrOH was
i
4.1.10. 2-(4-(4-(4-Fluorophenyl)butyl)piperazin-1-yl)pyrimidine
(20)
Using 2 and 2-(piperazin-1-yl)pyrimidine, produced compound
20; yield 51.7%, mp 54–55 °C. 1H NMR (CDCl3): d 8.31 (2H, m), 7.12
(2H, m), 6.95 (2H, m), 6.47 (1H, m), 3.82 (4H, m), 2.61 (2H, t,
J = 6.9 Hz), 2.48 (4H, m), 2.38 (2H, m), 1.62 (4H, m). Calcd for
refluxed under N2 for 1 h. The mixture was diluted with EtOAc
(200 mL), and washed with water (50 mL), brine (50 mL). The or-
ganic layer was dried with Na2SO4, and filtered. The filtrate was
concentrated in vacuo, and followed by distillation in vacuo to give
the desired product 3-(4-fluorophenoxy)propan-1-ol (3a). To a
solution of 3a (1.3 g, 7.6 mmol), Et3N (3 mL) in CH2Cl2 (10 mL)
was added at room temperature MsCl (0.8 mL, 10.3 mmol). The
mixture was stirred at room temperature for 12 h, followed by di-
rect purification through column chromatography on silica gel, to
provide 3-(4-fluorophenoxy)propyl methanesulfonate (4a).
C18H23FN4: C 68.76, H 7.37, N 17.82; Found: C 68.47, H 7.45, N
17.64.
4.1.11. 1-(4-(4-Fluorophenyl)butyl)-4-(pyridin-2-yl)piperazine (23)
Using 2 and 1-(pyridin-2-yl)piperazine, produced compound
23; yield 44%, mp 58–59 °C. 1H NMR (CDCl3): d 8.19 (1H, m),
7.47 (1H, m), 7.13 (2H, m), 6.96 (2H, m), 6.62 (2H, m), 3.54 (4H,
t, J = 4.8 Hz), 2.61 (2H, t, J = 7.2 Hz), 2.53 (4H, t, J = 5.1 Hz), 2.39
(2H, t, J = 7.8 Hz), 1.60 (2H, m). Calcd for C19H24FN3ꢁ0.1H2O: C
72.40, H 7.67, N 13.33; Found: C 72.39, H 7.81, N 13.14.
4.1.2. 3-(4-Fluorophenoxy)propan-1-ol (3a)
Yield 90%. 1H NMR (CDCl3): d 6.96 (2H, t, J = 8.4 Hz), 6,84 (2H, dd,
J = 4.5, 9.0 Hz), 4.09 (2H, t, J = 6.0 Hz), 3.85 (2H, m), 2.03 (2H, m).
4.1.3. 3-(4-Fluorophenylthio)propan-1-ol (3b)
Yield 72%. 1H NMR (CDCl3): d 7.35 (2H, dd, J = 5.4, 8.4 Hz), 6.99
(2H, t, J = 8.4 Hz), 3.76 (2H, t, J = 6.0 Hz), 2.98 (2H, t, J = 7.2 Hz), 1.85
(2H, m).
4.1.12. General procedure for the coupling reaction of methane
sulfonates with amines
A mixture of 3-(4-fluorophenylthio)propyl methanesulfonate
(4b) (1.0 g, 3.79 mmol), 4-(4-chloro-phenyl)-piperidin-4-ol (0.8 g,
3.79 mmol), KI (120 mg), K2CO3 (1.2 g, 8.7 mmol) in DME (10 mL)
was heated to reflux under N2 for 12 h. The cooled mixture was then
diluted with EtOAc (400 mL) and washed with H2O (200 mL). The
4.1.4. 3-Phenoxy-propan-1-ol (3c)
Yield 75%. 1H NMR (CDCl3): d 7.29 (2H, m), 6.93 (3H, m), 4.13
(2H, t, J = 6.0 Hz), 3.88 (2H, m), 2.06 (2H, m), 1.90 (1H, br s).

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K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1291–1297
organic layers were pooled, dried with Na2SO4, and filtered. The fil-
trate was concentrated in vacuo, then followed by purification
through column chromatography on silica gel, to afford 4-(4-chloro-
phenyl)-1-(3-((4-fluorophenyl)thio)propyl)piperidin-4-ol (6); yield
74%, mp 121–122 °C. 1H NMR (CDCl3): d 7.43 (2H, d, J = 8.4 Hz), 7.35
(2H, dd, J = 4.8, 8.7 Hz), 7.31 (2H, d, J = 8.4 Hz), 6.99 (2H, t, J = 8.4 Hz),
2.92 (2H, t, J = 7.5 Hz), 2.75 (2H, m), 2.51 (2H, t, J = 7.8 Hz), 2.41 (2H,
m), 2.08 (2H, m), 1.82 (2H, m), 1.70 (2H, m). Calcd for C20H23ClFNOS:
C 63.23, H 6.10, N 3.69; Found: C 63.08, H 6.12, N 3.71.
t, J = 6.3 Hz), 3.17 (2H, t, J = 5.1 Hz), 2.60 (6H, m), 2.00 (2H, m).
Calcd for C19H22ClFN2O: C 65.42, H 6.36, N 8.03; Found: C 65.22,
H 6.40, N 8.01.
4.1.19. 1-(3-(4-Fluorophenoxy)propyl)-4-phenylpiperazine (16)
Using 4a and 1-phenylpiperazine, produced 16; yield 48.9%, mp
63.1–64.9 °C. 1H NMR (CDCl3): d 7.26 (m, 2H), 6.95 (m, 4H), 6.84
(3H, m), 4.0 (2H, t, J = 6.3 Hz), 3.22 (4H, m), 2.61 (6H, m), 2.00
(2H, m). Calcd for C19H23FN2O: C 72.58, H 7.37, N 8.91; Found: C
72.59, H 7.37, N 8.73.
4.1.13. 4-(4-Chloro-phenyl)-1-[3-(4-fluoro-phenoxy)-propyl]-pi
peridin-4-ol (7)
4.1.20. 1-(4-Chlorophenyl)-4-(3-phenoxypropyl)piperazine HCl
(17)
Using 3-(4-fluorophenoxy)propyl methanesulfonate (4a) and 4-
(4-chlorophenyl) piperidin-4-ol, produced compound 7; yield
Using 3-phenoxypropyl methanesulfonate 4c and 1-(4-chloro-
phenyl)piperazine produced 17 which was converted into the
HCl salt, followed by re-crystallization from MeOH using EtOAc;
yield of 39%, mp 208–209 °C. 1H NMR (DMSO-d6): d 11.07 (1H, br
s), 7.28 (4H, m), 7.02 (2H, d, J = 9.0 Hz), 6.92 (3H, m), 4.04 (2H, t,
J = 6.0 Hz), 3.79 (2H, m), 3.58 (2H, m), 3.27 (2H, m), 3.14 (4H, m),
2.21 (2H, m). Calcd for C19H24Cl2N2O: C 62.13, H 6.59, N 7.63;
Found: C 62.29, H 6.67, N 7.60.
43.8%, mp 140.0–141.4 °C. 1H NMR (CDCl3):
d 7.45 (2H, d,
J = 9.0 Hz), 7.32 (2H, d, J = 9.0 Hz), 6.96 (2H, t, J = 9.0 Hz), 6.84
(2H, dd, J = 4.5, 9.0 Hz), 4.00 (2H, t, J = 6.0 Hz), 2.85 (2H, m), 2.61
(2H, t, J = 7.5 Hz), 2.49 (2H, t, J = 9.0 Hz), 2.13 (2H, m), 2.10 (2H,
m), 1.74 (2H, m). Calcd for C20H23ClFNO2: C 66.02, H 6.37, N
3.85; Found: C 66.01, H 6.34, N 3.86
4.1.14. 4-(4-Chlorophenyl)-1-(3-((4-fluorophenyl)thio)propyl)pi
peridine hydrochloride (8)
4.1.21. 1-(3-Phenoxypropyl)-4-phenylpiperazine (18)
Using 4b and 4-(4-chlorophenyl)-piperidine produced the free
base of 9 which was converted into the HCl salt; yield 82%, mp
172–173 °C. 1H NMR (DMSO-d6): d 10.37 (1H, br s), 7.45 (2H, dd,
J = 5.1, 8.7 Hz), 7.38 (2H, d, J = 9.0 Hz), 7.22 (2H, t, J = 8.7 Hz), 7.18
(2H, d, J = 9.0 Hz), 3.49 (2H, m), 3.13 (2H, m), 3.20 (4H, m), 2.80
(1H, m), 1.96 (4H, m). Calcd for C20H24Cl2FNS: C 60.00, H 6.04, N
3.50; Found: C 60.32, H 5.99, N 3.54.
Using 4c and 1-phenylpiperazine produced 18 which was con-
verted into the HCl salt followed by re-crystallization from
MeOH/EtOAc; yield 48%, mp 195–196 °C. 1H NMR (DMSO-d6):
11.07 (1H, br s), 7.26 (4H, m), 6.96 (5H, m), 6.84 (1H, m), 4.05
(2H, t, J = 6.0 Hz), 3.80 (2H, m), 3.59 (2H, m), 3.28 (2H, m), 3.13
(4H, m), 2.22 (2H, m). Calcd for C19H25ClN2O: C 68.56, H 7.57, N
8.42; Found: C 68.30, H 7.56, N 8.26.
4.1.15. 4-(4-Chlorophenyl)-1-(3-(4-fluorophenoxy)propyl)piperi
dine (9)
4.1.22. 2-(4-(3-((4-Fluorophenyl)thio)propyl)piperazin-1-
yl)pyrimidine (21)
Using 4a and 4-(4-chlorophenyl) piperidine, produced com-
pound 8; yield 35.1%, mp 63–65 °C. 1H NMR (CDCl3): d 7.26 (2H,
d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 6.96 (2H, t, J = 9.0 Hz), 6.84
(2H, dd, J = 9.0, 4.5 Hz), 3.99 (2H, t, J = 6.6 Hz), 3.06 (2H, m), 2.54
(2H, t, J = 6.9 Hz); 2.06 (2H, m), 1.98 (2H, m), 1.77 (4H, m). Calcd
for C20H23ClFNO: C 69.09, H 6.66, N 4.03; Found: C 69.49, H 6.80,
N 4.04.
Using 4b and 2-(piperazin-1-yl)pyrimidine, produced 21; yield
87%. The free base was converted to the HCl salt; mp 150–151 °C.
1H NMR (DMSO-d6): d 8.42 (2H, d, J = 4.8 Hz), 7.44 (2H, dd, J = 5.4,
9.0 Hz), 7.19 (2H, t, J = 9.0 Hz), 6.75 (1H, d, J = 4.8 Hz), 4.66 (2H, d,
J = 12 Hz), 3.50 (2H, d, J = 12 Hz), 3.31 (2H, m), 3.18 (2H, m), 3.00
(4H, m), 1.95 (2H, m). Calcd for C17H22ClFN4S: C, 55.35; H, 6.01; N,
15.19; Found: C 55.35; H 5.86; N 15.19.
4.1.16. 1-(4-Chlorophenyl)-4-(3-((4-fluorophenyl)thio)propyl)pi
perazine (13)
4.1.23. 2-(4-(3-(4-Fluorophenoxy)propyl)piperazin-1-
yl)pyrimidine (22)
Using 4b and 1-(4-chlorophenyl) piperazine dihydrochloride,
produced 13; yield 70.3%, mp 85–86 °C. 1H NMR (CDCl3): d 7.36
(2H, dd, J = 5.1, 8.7 Hz), 7.21 (2H, d, J = 8.7 Hz), 7.01 (2H, t,
J = 8.7 Hz), 6.82 (2H, d, J = 8.7 Hz), 3.36 (4H, br s), 2.96 (4H, m),
2.90 (4H, m), 2.03 (2H, m). Calcd for C19H22ClFN2S: C 62.54, H
6.08, N 7.68; Found: C 62.21, H 5.96, N 7.61.
Using 4a and 2-(piperazin-1-yl)pyrimidine hydrochloride, pro-
duced 22; yield 54.8%, mp 82–83 °C. 1H NMR (CDCl3): d 8.34 (2H,
d, J = 4.5 Hz), 6.96 (2H, t, J = 8.4 Hz), 6.84 (2H, dd, J = 4.5, 9.0 Hz),
6.47 (1H, t, J = 4.5 Hz), 4.01 (2H, t, J = 6.0 Hz); 3.83 (4H, t,
J = 5.4 Hz), 2.55 (6H, m); 2.00 (2H, m). Calcd for C17H21FN4Oꢁ0.2H2O:
C 63.81, H 6.62, N 17.51; Found: C 64.03, H 6.65, N 17.63.
4.1.17. 1-(3-((4-Fluorophenyl)thio)propyl)-4-(4-(trifluoromethyl)
phenyl)piperazine HCl (14)
4.1.24. 1-(3-((4-Fluorophenyl)thio)propyl)-4-(pyridin-2-yl)piper
azine (24)
Using 4b and 1-(4-(trifluoromethyl)phenyl)piperazine pro-
duced the free base of 14 which was converted to the HCl salt
immediately, 14; yield 78%, mp 213–214 °C. 1H NMR (DMSO-d6):
d 10.44 (1H, br s), 7.55 (2H, d, J = 9.0 Hz), 7.45 (2H, dd, J = 5.1,
8.7 Hz), 7.20 (2H, t, J = 8.7 Hz), 7.11 (2H, d, J = 9.0 Hz), 3.97 (2H,
d, J = 12 Hz), 3.53 (2H, d, J = 12 Hz), 3.21 (4H, m), 3.10 (2H, m),
3.00 (2H, m), 1.96 (2H, m). Calcd for C20H23ClF4N2S: C 55.23, H
5.33, N 6.44; Found: C 55.04, H 5.29, N 6.44.
Using 4b and 1-(pyridin-2-yl)piperazine produced 24; yield
48.1%, mp 81–82 °C. 1H NMR (CDCl3): d 8.18 (1H, m), 7.46 (1H, m),
7.36 (2H, m), 7.00 (2H, m), 6.62 (2H, m), 3.523 (4H, t, J = 5.4 Hz),
2.94 (2H, t, J = 7.2 Hz), 2.51 (6H, m), 1.82 (2H, m). Calcd for
C18H22FN3S: C 65.23, H 6.69, N 12.68; Found: C 64.97, H 6.58, N 12.53.
4.1.25. 1-(3-(4-Fluorophenoxy)propyl)-4-(pyridin-2-yl)piperazine
(25)
Using 4a and 1-(pyridin-2-yl)piperazine, produced 25; yield
51.2%, mp 73–74 °C. 1H NMR (CDCl3): d 8.20 (1H, m), 7.47 (1H,
m); 6.95 (2H, m), 6.85 (2H, m), 6.63 (2H, m), 4.000 (2H, t,
J = 6.3 Hz), 3.55 (4H, t, J = 4.8 Hz), 2.58 (6H, m), 2.00 (2H, m). Calcd
for C18H22FN3O: C 68.55, H 7.03, N 13.32; Found: C 68.44, H 7.18, N
13.14.
4.1.18. 1-(4-Chlorophenyl)-4-(3-(4-fluorophenoxy)propyl)pipera
zine (15)
Using 4a and 1-(4-chlorophenyl) piperazine dihydrochloride,
produced 15; yield 75.9%, mp 97–98 °C. 1H NMR (CDCl3): d 7.20
(2H, d, J = 6.0 Hz), 6.96 (2H, t, J = 8.4 Hz), 6.83 (4H, m), 4.00 (2H,

K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1291–1297
1297
4.1.26. 1-(4-Chlorophenyl)-4-(3-((4-fluorophenyl)thio)propyl)-1,
4-diazepane (26)
1SC1GM088451-01, NIMH Psychoactive Drug Screening Program,
and a Title III Grant to Florida A&M University. This work was sup-
ported in part by the Pharmaceutical Research Center NIH/NCRR 1
C06-RR12512-01 Grant. The authors would like to thank Mrs Bar-
bara Bricker for her editorial assistance during the writing of this
manuscript.
Using 4b and 1-(4-chlorophenyl)-1,4-diazepane produced 26
which was converted to the HCl salt and recrystallized from
MeOH–Et2O; yield 69%, mp 172–173 °C. 1H NMR (DMSO-d6):
d 11.2 (1H, s), 7.63 (1H, s), 7.42 (2H, dd, J = 5.4, 9.0 Hz), 7.17 (4H,
m), 6.75 (2H, d, J = 9.0 Hz), 3.75 (2H, m), 3.41 (4H, m), 3.16 (2H, m),
3.08 (2H, m), 2.99 (2H, t, J = 7.2 Hz), 2.38 (2H, m), 2.10 (2H, m),
1.98 (2H, m). Calcd for C20H26Cl3FN2S: C 53.16, H 5.80, N 6.20;Found:
C 53.39, H 5.98, N 6.22.
References and notes
1. Wang, P. S.; Joyce, C. W.; Terri, T.; Pincus, H. A. Schizophr. Bullet. 2000, 26, 451.
2. Haro, J. M.; Salvador-Carulla, I. C. N. S. Drugs 2006, 20, 293.
3. Minzenberg, M. J.; Yoon, J. H.; Carter, C. S. In American Psychiatric Publishing
Textbook of Psychiatry; Hales, R. E., Yudofsky, S. C., Gabbard, G. O., Eds., fifth ed.;
American Psychiatric Publishing Inc.: Arlington VA., 2008; pp 407–456.
4. Fang, J.; Zuo, D.; Yu, P. H. Psychopharmacology 1995, 121, 373.
5. Rollema, H.; Skolnik, M.; D’Engelbronner, J.; Igarashi, K.; Usuki, E.; Castagnoli,
N., Jr. J. Pharmacol. Exp. Ther. 1994, 268, 380.
6. Kim, H. S.; Song, M.; Yumkham, S.; Choi, J. H.; Lee, T.; Kwon, J.; Lee, S. J.; Kim, J.
I.; Lee, K. W.; Han, P. L.; Shin, S. W.; Baik, J. H.; Kim, Y. S.; Ryu, S. H.; Suh, P. G. J.
Neurochem. 2006, 99, 458.
7. Lyles-Eggleston, M.; Altundas, R.; Xia, J.; Sikazwe, D. M. N.; Fan, P.; Yang, Q.; Li,
S.; Zhang, W.; Zhu, X.; Schmidt, A. W.; Vanase-Frawley, M.; Shrihkande, A.;
Villalobos, A.; Borne, R. F.; Ablordeppey, S. Y. J. Med. Chem. 2004, 47, 497.
8. Sikazwe, D. M. N.; Li, S.; Mardenborough, L.; Cody, V.; Roth, B. L.; Ablordeppey,
S. Y. Bioorg. Med. Chem. Lett. 2005, 14, 5739.
9. Ablordeppey, S. Y.; Altundas, R.; Bricker, B.; Zhu, X. Y.; Kumar, E. V. K. S.;
Jackson, T.; Khan, A.; Roth, B. L. Bioorg. Med. Chem. 2008, 16, 7291.
10. Sikazwe, D. M. N.; Nkansah, N. T.; Altundas, R.; Zhu, X. Y.; Setola, V.; Roth, B. L.;
Ablordeppey, S. Y. Bioorg. Med. Chem. 2009, 17, 1716.
11. Friedman, L.; Shani, A. J. Am. Chem. Soc. 1974, 96, 7101.
12. Gasbarri, A.; CIfariello, A.; Pompili, A.; Meneses, A. Behav. Brain. Res. 2008, 195,
164.
13. Sarkisyan, G.; Hedlund, P. B. Behav. Brain. Res. 2009, 202, 26.
14. Björklund, M.; Sirviö, J.; Riekkinen, M.; Sallinen, J.; Scheinin, M.; Riekkinen, P.,
Jr. Neuroscience 2000, 95, 481.
15. Terry, A. V., Jr.; Mahadik, S. P. J. Pharmacol. Exp. Ther. 2007, 320, 961.
16. Kim, S. F.; Huang, A. S.; Snowman, A. M.; Teuscher, C.; Snyder, S. H. PNAS 2007,
104, 3456.
4.1.27. 4-(4-Chlorophenyl)-1-(3-((4-fluorophenyl)sulfinyl)propyl)
piperidine HCl (10)
To a solution of 1-(3-(4-fluorophenylthio)propyl)-4-(4-chloro-
phenyl)piperidine (9) (200 mg, 0.549 mmol) in MeOH was added
with stirring m-CPBA (200 mg) at room temperature. After stirring
for 4 h at room temperature, the mixture was diluted with EtOAc
(200 mL) and washed with sat. NaHCO3 (30 mL) and brine (20 mL).
The organic layer was dried over Na2SO4, and filtered. The filtrate
was concentrated in vacuo and the residue subjected to column
chromatography on silica gel to afford 4-(4-chlorophenyl)-1-(3-
((4-fluorophenyl)sulfinyl)propyl)piperidine. The product was con-
verted to the HCl salt immediately and then recrystallized from
MeOH–Et2O to yield (178 mg, 78%), mp 196–197 °C. 1H NMR
(DMSO-d6): d 7.75 (2H, dd, J = 5.4, 9.0 Hz), 7.46 (2H, t, J = 9.0 Hz),
7.39 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 3.50 (2H, m), 3.13
(2H, m), 3.00 (2H, m), 2.85 (2H, m), 2.06 (1H, m), 1.94 (6H, m). Calcd
for C20H24Cl2FNOS: C 57.69, H 5.81, N 3.36; Found: C 57.54, H 5.84, N
3.40.
4.2. Receptor binding studies
17. Kroeze, W. K.; Hufeisen, S. J.; Popadak, B. A.; Renock, S. M.; Steinberg, S.;
Ernsberger, P.; Jayathilake, K.; Meltzer, Y. M.; Roth, B. L.
Neuropsychopharmacology 2003, 28, 519.
18. Reynolds, G. P.; Hill, M. J.; Kirk, S. L. J. Psychopharmacol. 2006, 20, 15.
19. Reynolds, G. P.; Zhang, Z. J.; Zhang, X. B. Lancet 2002, 359, 2086.
20. Petrov, V. A. J. Fluorine Chem. 2000, 117, 23.
Binding affinities reported in Tables 1–4 were conducted by the
National Institute of Mental Health Psychoactive Drug Screening
Program (NIMH–PDSP). Details of the methods and radioligands
used for the binding assays were previously reported.21
21. Shapiro, D. A.; Renock, S.; Arrington, E.; Chiodo, L. A.; Liu, L. X.; Sibley, D. R.;
Roth, B. L.; Mailman, R. Neuropsychopharmacology 2003, 28, 1400.
Acknowledgments
We gratefully acknowledge the financial support of the National
Institute of General Medical Studies (NIGMS) for MBRS Grant No.