Identification of a new selective dopamine D4 receptor ligand

Article abstract of DOI:10.1016/j.bmc.2014.04.026

The dopamine D₄ receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D₄ ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD₄ receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D₄ receptor. Compound 27 (K _iD₄ = 0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D₄ receptor. Compound 28 (K_iD₄ = 3.9 nM) while not as potent, was more discriminatory for the D₄ receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT_1AR and 5HT_2BR, have binding affinity constants better than 100 nM (K_i <100 nM). Compound 28 is a potentially useful D₄-selective ligand for probing disease treatments involving the D₄ receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.

Full text of DOI:10.1016/j.bmc.2014.04.026

Bioorganic & Medicinal Chemistry 22 (2014) 3105–3114
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Identification of a new selective dopamine D4 receptor ligand
Dinithia Sampson a, , Xue Y. Zhu a, , Suresh V. K. Eyunni a, Jagan R. Etukala a, Edward Ofori a,
Barbara Bricker a, Nazarius S. Lamango 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:
Received 17 February 2014
Revised 5 April 2014
Accepted 14 April 2014
Available online 20 April 2014
The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addic-
tion to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions.
Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selec-
tive and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led
to further exploration of the piperazine moiety to identify new agents that are selective at the D4 recep-
tor. Compound 27 (KiD4 = 0.84 nM) was the most potent of the compounds tested. However, it only had
moderate selectivity for the D4 receptor. Compound 28 (KiD4 = 3.9 nM) while not as potent, was more dis-
criminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the
other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and
5HT2BR, have binding affinity constants better than 100 nM (Ki <100 nM). Compound 28 is a potentially
useful D4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting
smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus,
further optimization, functional characterization and evaluation in animal models may be warranted.
Published by Elsevier Ltd.
Keywords:
D4 ligand
D4 selective ligand
Aryl piperazine
Phenyl piperazine
Benzothiazole
Benzofuran
Benzoxazole
1. Introduction
and methamphetamine3,4 but also morphine-induced withdrawal
signs induced by naloxone.5 More recently, there was a report that
Targeting dopamine receptors for drug development has been
of interest for decades because of their potential utility in many
well-known pathological conditions.1 Initially, dopamine receptors
were classified as D1-like and D2-like for many years until it
became evident that the D1-like receptors consisted of D1 and D5
subtypes and the D2-like receptors consisted of D2, D3 and D4 sub-
types. By far, the D2-like receptors have been studied more because
of their association with clinically relevant neuropsychiatric condi-
tions, such as schizophrenia, mood disorders, Parkinson’s disease
and others. Each of these subtypes is now separately associated
with certain pathophysiological conditions. For example, several
D2 agonists and partial agonists have shown beneficial effects in
counteracting Parkinson’s disease, attention-deficit hyperactivity
disorder and certain mood disorders2 while D2 antagonism is asso-
ciated with antipsychotic properties.
the D4 receptor antagonist, L-745,870 (Chart 1) but not PD 168,077,
a selective D4 receptor agonist, attenuated nicotine-induced rein-
statement of nicotine seeking behavior.6 Thus, it would appear that
the pharmacological blockade of DAD4 may serve as a new and
potentially effective treatment against relapse to tobacco smoking.
On the other hand, PD 168,077 has been shown to induce penile
erection in rats when administered in vivo, and L-745,870 was able
to block this action, and thus, confirming the D4 receptor mediated
mechanism by which penile erection occured.7 This potential could
place D4 agonists in a strong position to replace the current PDE5
antagonists with a plethora of side-effects.8 In addition, D4-recep-
tor agonists may be useful in reversing cognitive deficits in
schizophrenia.9 These demonstrated therapeutic potentials have
encouraged the search for new D4 selective ligands in our
laboratories.
Since its cloning, the D4 receptor has attracted considerable
interest. For example, early reports indicated that D4 antagonists
attenuate not only the discriminative-stimulus effects of cocaine
We have previously carried out several SAR studies that sought
to identify structural entities that demonstrate DA receptor sub-
type selectivity.10–12 A frequent observation in such studies was
the fact that unlike the piperidine analogs of haloperidol, the piper-
azine analogs demonstrated selective and significant affinities to
the D4 receptor subtype. Chart 1 displays common D4 selective
ligands with the piperazine pharmacophore. The purpose of the
⇑
Corresponding author. Tel.: +1 850 599 3834; fax: +1 850 599 3934.
E-mail address: seth.ablordeppey@famu.edu (S.Y. Ablordeppey).
Equal contribution to this manuscript.
http://dx.doi.org/10.1016/j.bmc.2014.04.026
0968-0896/Published by Elsevier Ltd.

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D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
O
N
N
Cl
N
H
N
N
N
Cl
N
N
H
N
N
NC
PD168077
L-745870
N
FAUC 113
O
C
F
(CH2)3
N
N
Cl
Compound 1
Chart 1. Known D4 selective ligands with a piperazine pharmacophore
current study was to further explore the piperazine ring as a phar-
macophore in a search for new entities that are selective to the D4
receptor subtype using compound 1 (Chart 1), the piperazine ana-
log of haloperidol as the lead.
2-(2-chloroalkyl)benzo[d]oxazole, 41. Compound 41 was used to
alkylate 4-chlorophenyl-1-piperazine to yield the desired target
compounds 19–22.
The synthesis of benzofuran moiety in analogs 23–26 (Chart 4),
followed a literature procedure.16 2-Iodophenol was reacted with
an appropriate alkyl-1-yn-1-ol to form the corresponding benzofu-
ran alkanol, which was subjected to a tosylation reaction and the
resulting product was used to alkylate an appropriate aryl pipera-
zine or a related analog to form the target compounds as shown in
Scheme 4.
Finally, the synthesis of compound 28 (Chart 4) followed the
synthetic procedure previously utilized in obtaining compound
27 (Chart 4) as shown in Scheme 5.15 Briefly, 2-aminobenzenethiol
(46) was reacted with 4-chlorobutanoyl chloride (47) to form
2-(3-chloropropyl)-benzo[d]thiazole, 48, which was then used to
alkylate 2-(piperazin-1-yl)pyrimidine to form the desired target
compound, 28.
2. Chemistry
The syntheses of compounds 1–7 (Chart 2) have previously
been reported using routine N-alkylation reactions.9 Compound
8, the cyclic analog of 1, was synthesized as depicted in Scheme 1
below. The commercially available 4-chloro-1-(4-fluorophenyl)-
butan-1-one (29) was converted to 4-chloro-1-(4-fluorophenyl)-
2-methylenebutan-1-one (30) by refluxing in acetic anhydride in
the presence of hexamethylenetriamine.10,13 Compound 30 was
cyclized by heating in concentrated sulfuric acid to produce 2-(2-
chloroethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one (31) which
was protected by reaction with ethylene glycol to form the 1,3-
dioxolane, 32. Alkylating 4-(4-chlorophenyl)piperazine with 32
and deprotecting the dioxolane resulted in the formation of the
desired target compound 8 (Scheme 1).
3. Results and discussion
Compound 9 was similarly obtained using the desfluoro starting
material 4-chloro-1-(phenyl)butan-1-one. To obtain compound 10,
the indanone 31 was deoxygenated (32) under Clemmensen reac-
tion conditions14 and then used to alkylate 4-(4-chloro-
phenyl)piperazine (Scheme 1).
Compounds 11–14 and 16a–c (Chart 3) were previously synthe-
sized as a part of a drug design effort to obtain novel antipsychotic
drugs.9 In general, an appropriately substituted phenol or benzene-
thiol (34) was alkylated using 3-chloropropan-1-ol (35) and the
resulting alcohol (36) was either tosylated or mesylated and then
utilized in alkylating the heteroaryl piperazine (A–C) in Scheme 2.
The synthesis of compounds 15–16 followed the same procedure
reported in Scheme 2.
Cigarette smoking is associated with major diseases including
cardiovascular problems, stroke and cancers of several organs. In
fact, according to the CDC website, cigarette smoking harms nearly
every organ of the body and affects a person’s overall health.17
Quitting smoking cuts down on all risks including, cardiovascular
risks, stroke, and cancers of the lung, mouth, throat, esophagus
and bladder.18 Unfortunately, smoking cessation is difficult and
often requires therapeutic interventions. And yet there have been
articles suggesting significant risks associated with some of the
current pharmacological interventions.19 Thus, a search to find
new agents that could help those addicted to cigarette smoking
to quit the habit is an urgent and important public health need.
Similarly, the discovery of the selective D4 agonist, PD 168,077
as having the capability of reversing cognitive deficits in schizo-
phrenia9 and inducing penile erection7 and hence the potential to
treat erectile dysfunction is very interesting and could provide an
alternative treatment option in place of the PDE5 antagonists with
several known side-effects.8
The syntheses of compounds 17–18 (Chart 4) were also previ-
ously reported.15 To obtain the benzo[d]oxazole analogs, 19–22
(Chart 4, Scheme 3), 2-aminophenol was reacted with chloroalka-
noyl alkyl halide (39) to form the amide intermediate (40) which
was then cyclized using polyphosphoric acid (PPA) to obtain
X
(CH2)3
N
N
Cl
O
O
(CH2)3
N
Cl
7
F
F
1. X = C=O
2. X = S=O
3. X = CH2
4. X = S
(CH2)2
8. R = F
9. R = H
N
N
Cl
R
5. X = O
O
(CH2)3
N
N
Cl
(CH2)2
N
N
Cl
F
10
6
H
Chart 2. 4-Chlorophenyl piperazine analogs.

D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
3107
O
O
O
(ii)
Cl
Cl
Cl
(i)
R
R
R
(iv)
29
31
30
(iii)
X
O
(v)
O
(CH2)2
N
N
Cl
Cl
OR
(vi)
R
Cl
R
32
8. R = F, X = CO; 9. R = H, X = CO
10. R = F, X = CH2
R
33
(v)
Scheme 1. Synthesis of 4-chlorophenylpiperazine analogs, 8–10. Reagents and conditions: (i) HMTA, Ac2O, reflux; (ii) concd H2SO4, 60 °C; (iii) (a) ethylene glycol, TsOH,
reflux, 48 h; (b) NaBH4, MeOH; (iv) Zn/HgCl2, concd HCl, toluene; (v) KI, K2CO3, DME, 90 °C, 4-(4-chlorophenyl)piperazine, 12 h; (vi) TsOH, MeOH, rt.
N
N
X
(CH2)3
N
N
CH3
X
(CH2)3
N
N
F
F
15a; X = O; 15b; X = S, 15c; X = CH2,
11. X = CH2; 12. X = S
N
N
X
(CH2)3
N
N
O
(CH2)3
N
N
N
F
Y
13. Y = F; 14. Y = CF3
16a. X = O; 16b. X = S; 16c. X = CH2
Chart 3. Heteroaryl piperazine analogs.
X
X
XH
i
OH
ii
OTs
Cl
N
OH
+
37
36
R
R
R
35
iii
34; X = O or S
X
N
N
N
N Ar
Ar =
CH3
N
R
A
C
B
X = O or S; R = F or CF3 (11 - 16)
Scheme 2. Synthesis of heteroaryl piperazine analogs, 11–16. Reagents and conditions: (i) KI, K2CO3, iPrOH or DME, reflux; (ii) MsCl/TsCl, Et3N, DCM, rt; (iii) KI, K2CO3, DME,
90 °C, heteroaryl piperazine, 12 h.
N
S
N
O
N
N
N
N
(CH2)n
Cl
(CH2)n
Cl
19. n = 5 20. n = 4
21. n = 3 22. n = 2
17. n = 4; 18. n = 3
N
N
(CH2)n
Cl
N
N
N
(CH2)3
25
Cl
O
O
O
N
23. n = 2 24. n = 3
N
N
N
N
(CH2)3
26
(CH2)n
N
Cl
S
27. n = 4; 28. n = 3
Chart 4. Benzothiazole, benzoxazole and benzofuran analogs.
H
N
O
N
(CH2)n Cl
(ii)
NH2
OH
(i)
Cl
HN
N
(CH2)n Cl
+
Cl
n
+
O
Cl
O
40
41
(iii)
42
OH
39
38
N
(CH2)n
N
N
Cl
O
19 - 22, n =2 - 5
Scheme 3. Synthesis of benzoxazole derivatives, 19–22. Reagents and conditions: (i) EtOAc, TEA, reflux; (ii) PPA, 110 °C; (iii) CH3CN, K2CO3, KI, reflux.

3108
D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
I
i
ii
iii
OH
+
(CH2)n OH
(CH2)n NR2
n
O
O
OH
44
45
23-26
43
Scheme 4. Synthesis of benzofuran analogs, 23–26. Reagents and conditions: (i) An appropriate alkyl-1-yn-1-ol, Cu2O, pyridine, 100 °C, 15 h (ii) tosylCl, NEt3, CH2Cl2, rt,
overnight; (iii) NHR2 [aryl piperazine or related analog], ACN, NEt3, 60 °C, reflux.
O
NH2
N
S
N
N
N
S
(ii)
N
(i)
Cl
N
N
(CH2)3
+
Cl
(CH2)3 Cl
SH
N
N
28
47
48
HN
46
Scheme 5. Synthesis of benzothiazole analog, 28. Reagents and conditions: (i) Toluene, rt; (ii) KI, K2CO3, CH3CN, reflux.
Our laboratory’s attention has been drawn to these DAD4 recep-
tor-mediated pathologies and that has spurred us to mine our dat-
abases for new pharmacophores for the D4 receptor. Previous
publications from our lab have identified compounds 1–7 as hav-
ing low affinities for the D2 receptor while exhibiting selectivity
for the D4 receptor among D2-like receptors. We have now
screened these compounds at the D1-like receptors (Table 1) and
the results further demonstrate that their selectivity extends
beyond the D2-like receptors and hence we selected compound 1
as the lead agent to conduct a structure–activity relationship
(SAR) study that has led to the identification of potent and selective
D4 ligands. Replacing the carbonyl moiety in compound 1 with a
sulfoxide (2), methylene (3), sulfur (4) or oxygen (5) group/atom
resulted in increasing potency at the D4 receptor with Ki values
from 17.5 to 6.9 nM, respectively while binding at other DA recep-
tors showed no observable trends. The sulfoxide analog resulted in
the lowest affinity binding at the rest of the DA receptors while its
reduced counterpart, the sulfide (4) had moderate binding except
at the D1 receptor where its affinity binding Ki was 52 nM.
Overall, these compounds have demonstrated better selectivity
toward the D4 receptor when compared to compound 1. In partic-
ular, compound 5, the oxygen analog, not only had the best binding
at the D4 receptor, but demonstrated the highest selectivity among
compounds 1–5. Further probing of the oxygen analog revealed
that removing the para fluoro atom (6) has little or no contribution
to binding to the D2-like receptors while replacement of N-4 in the
piperazine ring with CH (7) resulted in a very significant increase
in potency for the D2 receptor with only minimal changes else-
where. Compound 8 was designed and synthesized to explore the
effect of restricting the carbonyl group in an indanone ring, on
binding affinity and selectivity. Indeed, this transformation
resulted in one of the highest selectivities toward the D4 receptor;
the ratios for the D2/D4 and D3/D4 being 253 and 406, respectively.
Synthesis of 9, an analog of 8 but without the fluorine atom
resulted in a significant decrease in binding at all the DA subtypes
including the D4 suggesting the fluorine may have some important
interaction at the binding sites for these indanones. Deoxygenation
of the carbonyl to form compound 10 however, produced only
minimal changes.
The next evaluations focused on the replacement of the 4-chlo-
rophenyl moiety. Our previous work indicated that pyridine and
pyrimidine rings impacted binding to CNS receptors.9–12 Hence,
we first explored replacing the 4-chlorophenyl moiety with the
pyridine ring in compounds 3–5 to obtain compounds 11–13
(Chart 2) and the binding affinities are reported in Table 2. Com-
pounds 11–13 bind with very high affinities at D4 versus D1–D3
receptors, and therefore demonstrate decreased selectivity for
the D4 receptor. Compound 14, an analog of 13 with the fluorine
atom replaced with a trifluoromethyl group, displayed significantly
lower binding affinities for all DA receptors suggesting either a ste-
ric limitation or deleterious electron withdrawing effect or both.
Replacement of the pyridine ring with 5-methyl substituted pyri-
dine for the trio (11–13) to form compounds 15a–c were also eval-
uated. Interestingly, compound 15a with the oxygen linker
resulted in the most potent analog for the D4 receptor (Ki = 1.1 nM)
among the 17 compounds evaluated thus far. In addition, it also
displayed the highest selectivity for the D4 receptor when com-
pared with the D2 receptor. Not surprisingly, compounds 15b and
15c, the sulfur and carbon analogs, respectively, have reduced
binding for the D4 receptor but retain similar affinities for the
D1–D3 receptors.
Finally in this series, compounds 16a–c, the pyrimidine analogs
of 11–13 were synthesized and evaluated. Once again the oxygen
analog 16a displayed the highest potency and selectivity for the
D4R among the three analogs. The carbon analog (16c) had a
similar binding profile at the DA subtypes as 16a although its
Table 1
Evaluation of binding affinities of 4-chlorophenyl analogs (Chart 2) at the dopamine receptor subtypes
Compd
Ki (pKi) SEM values in nM at the dopamine receptor subtypes
D1
D2
D3
D4
D5
D2/D4
D3/D4
1
2
3
4
5
6
7
8
9
ND
MT
589 56
52
135
ND
126
641 (6.19 0.06)
1701 (6.41 0.07)
837 92
253.3 38.9
635 (6.2 0.05)
284 21
211 22
390 34
447 (6.35 0.07)
41.0 4.0
1543 (5.81 0.08)
>10,000
403.9 66
1340 (5.87 0.06)
261 23
422 41
885 65
726 (6.1 0.1)
696 50.0
2477 (5.6 0.1)
4534 (5.34 0.08)
2772 271
17.5 2.0
13 (7.89 0.05)
7.8 0.4
8.7 0.5
6.9 0.3
5.6 (8.26 0.03)
9.5 0.3
6.1 (8.21 0.05)
36.0 (7.45 0.04)
13.0 1.0
ND
MT
14.5
48.8
36.4
24.3
56.5
79.8
4.3
253
>277
109
23.1
103
33.5
48.5
128
130
73.3
406
126
213
1758 212
2808 325
2684 223
ND
867 49
MT
3
8
9
MT
MT
10
1417 138
MT = missed primary assay threshold of 50% inhibition; ND = not determined.

D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
3109
Table 2
Evaluation of the binding affinities of heteroaryl piperazine analogs (Chart 3) at the DAR subtypes
Compd
Ki (pKi) SEM values in nM at the dopamine receptor subtypes
D1
D2
D3
D4
D5
D2/D4
D3/D4
11
12
13
14
15a
15b
15c
16a
16b
16c
238 24.0
265 24.0
180 14.0
2344 (5.63 0.09)
260 (6.58 0.07)
222 (6.65 0.07)
521 (6.28 0.08)
259 12.0
124 10.0
183 21.0
186 16.0
1092 (5.96 0.09)
1046 (5.98 0.07)
1106 (6 0.1)
1861 (5.7 0.1)
636 66.0
86 4.0
160 16.0
229 20.0
355 (6.45 0.05)
187 (6.7 0.1)
170 (6.8 0.1)
156 (6.8 0.1)
778 63.0
3.5 0.2
5.7 0.3
1.8 0.1
12 (7.9 0.1)
1.1 (8.96 0.08)
20.0 (7.71 0.06)
23.0 (7.64 0.06)
4.2 0.1
1451 133
3223 295
2392 252
>10,000
2576 (5.6 0.1)
2159 (5.7 0.1)
3264 (5.5 0.1)
MT
35.4
32.1
103
91.0
951
55.3
80.9
151
20.1
43.4
24.6
28.1
127
29.6
170
8.5
6.8
185
3.2
495 33.0
134 7.0
424 25.0
269 17.0
68.0 10.0
262 17.0
21.0 1.0
6.2 0.3
1370 114
3812 409
42.3
MT = missed primary assay threshold of 50% inhibition; ND = not determined.
selectivity for the D4R is much lower. Meanwhile, the sulfur analog
16b again demonstrated a 5-fold lower affinity for the D4R com-
pared to 16a. These evaluations have clearly demonstrated that
the oxygen analogs have the highest potencies for the D4R within
each cohort evaluated. Comparing the pyridine and pyrimidine
analogs in this series, the pyridine analogs overall, demonstrated
moderate enhancement in binding affinity at the D4R than the
pyrimidine analogs. In addition, among the twenty compounds
evaluated, none has a better binding affinity for the D5 receptor
than compound 7 with a Ki of 867 nM. In other words, the com-
pounds have little or no affinity for the D5R.
The last group of compounds evaluated is 17–28 (Chart 4),
which may be considered as the hetero-bicyclic analogs of the
compounds in Charts 2 and 3, with binding affinities reported in
Table 3. Compound 17 and 18 are benzothiazole analogs which
were previously synthesized and evaluated for binding to the D2-
like receptors.15 In this paper, their binding affinities to the D1-like
receptors were evaluated and the results are reported. The results
suggest that a chain length of 4 (17) produced a more potent agent
at the D4R than a chain length of 3 (18). The selectivities of both
compounds for the D4R were unremarkable.
(Ki = 33 nM) resulting in loss of selectivity. Further comparison of
this benzothiazole, 20 with the benzoxazole, 17 shows over 7-fold
differential, suggesting the benzothiazole ring with a 4-methylene
chain is preferred at the D4R. There is however no preference at the
D3 receptor since they (17 & 20) have similar binding affinities.
Compounds 21 and 22, benzoxazoles with a chain length of 3
and 2, respectively, resulted in compounds with only moderate
to very weak binding affinities at all the DA receptors.
We also synthesized and evaluated compounds obtained by
replacement of the benzoxazole with a benzofuran, (Chart 4),
23–26, of which 24 may be considered as a restricted analog of
the straight chain ether analog in Chart 2. The results indicated
that while somewhat selective for the D4 receptor, the 2 carbon
chain analog (23) and the 3-chain analog (24) have weaker binding
affinities for the D4 receptor. Replacement of the piperazine ring
with its bridged counterpart (25) and with a homopiperazine
(26) did not improve potency or selectivity.
Returning to the benzothiazoles, we further explored replace-
ment of the 4-chlorophenyl moiety with 2-(piperazin-1-yl)
pyrimidine to obtain the 4-chain (27) and 3-chain (28) analogs.
Compound 27 was the most potent D4 ligand in this study
(Ki = 0.84 nM) as previously reported15 albeit with diminished
selectivity, while 28 has high potency (Ki = 3.9 nM) and is by far
the most selective analog at the D4 receptor when compared with
other dopamine subtypes. Taking their binding constants at face
value, compound 28 is as potent but more selective than FAUC
113, a previously reported D4 ligand (Chart 1).20 In addition, while
not as potent as L-745,860,21 compound 28 is also more selective
Next, we synthesized and evaluated the benzoxazole analogs,
19–22, by systematically modifying the chain length from 5 to 2,
respectively. A chain length of five atoms (19) produced a weak
binding affinity at the D4R (Ki = 240 nM) while 20, with a chain
length of 4 atoms produced an 8-fold increase in binding to the
D4 receptor (Ki = 30.6 nM), thus suggesting a chain length of 4 is
preferred. Compound 20 however, has similar affinity for the D3R
Table 3
Evaluation of the binding affinities of benzothiazole, benzoxazole and benzofuran analogs (Chart 4) at the DAR subtypes
Compd
Ki (pKi) SEM values in nM at the dopamine receptor subtypes
D1
D2
D3
D4
D5
D2/D4
D3/D4
17
18
19
20
21
22
23
24
25
26
27
28
1897 364
1273 123
7939 592
MT
1172 76
MT
MT
1408 242
MT
274 24
MT
MT
ND
ND
219 12.0
2321 314
3108 1071
MT
3962 501
MT
MT
1979 291
MT
2507 208
26.5 4.5
MT
3200 58
960
31 4.0
214 47
119 25
4.0 0.0
31 40
ND
54.8
74.9
13.0
>327
27.3
>7.1
>35.5-
25.1
>4.2-
13.5
31.5
7.8
6.9
0.5
1.1
1.5
0.6
>35.5
29.0
0.3
>10,000
>10,000
MT
>10,000
MT
MT
MT
MT
1522 191
MT
240 36.8
30.6 6.3
145 18
1409 227
282.9
78.9 5.7
2397 294
185 11
0.84 0.09
3.9 (8.41 0.04)
3.1 0.3
33
6
180 31
850 126
MT
2290 423
670.7 118.4
1462 133
100 (7 0.06)
MT
7.9
119
>2564
MT
ND
ND
>2564
FAC 113a
L-745870b
5000 121
2300
0.43
MT = missed primary assay threshold of 50% inhibition; ND = not determined.
a
Ref. 20.
Ref. 21.
b

3110
D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
for the D4 receptor among the D2-like receptors. To determine the
extent of compound 28’s selectivity, we screened its binding affin-
ities at several other CNS receptors and the results are reported in
Table 4.
Screening experiments involving a total of 18 other receptors
indicated that apart from the 5HT1A and 5HT2B receptors, where
binding affinities were below 100 nM (Ki <100 nM), compound
28 exhibited significantly poorer affinities for the remainder of
the assayed receptors. The above results strongly suggest that
compound 28 can be a potentially useful D4-selective ligand for
probing D4R related pathophysiological conditions including
smoking cessation, erectile dysfunction and reversal of cognitive
deficits in schizophrenia depending on the intrinsic activity.
d 7.82 (dd, J = 9.0, 5.7 Hz, 2H), 7.13 (t, J = 9.0 Hz, 2H), 5.99 (s, 1H),
5.73 (s, 1H), 3.72 (t, J = 6.6 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H).
Compound 30 (1.2 g, mmol) was dissolved in concd H2SO4
(4 mL) and heated at 60 °C for 1 h. After cooling to rt, the mixture
was diluted with EtOAc (200 mL) and washed with sat’d NaHCO3
(2 ꢀ 200 mL). The organic layer was dried over Na2SO4, and
filtered. The filtrate was concentrated under vacuum followed by
column chromatography on silica gel to afford 2-(2-chloro-
ethyl)-5-fluoro-indan-1-one, 31 in quantitative yield. 1H NMR
(CDCl3):
d 7.76 (dd, J = 8.4, 5.4 Hz, 1H), 7.05–7.14 (m, 2H),
3.80–3.86 (m, 1H), 3.68–3.78 (m, 1H), 3.42 (dd, J = 17.1, 7.8 Hz,
1H), 2.90–2.98 (m, 1H), 2.83 (dd, J = 17.1, 4.2 Hz, 1H), 2.38–2.49
(m, 1H), 1.86–1.98 (m, 1H).
3.1. Conclusions
4.1.2. 20-(2-Chloroethyl)-50-fluoro-20,30-
dihydrospiro[[1,3]dioxolane-2,10-indene], 33
This study was initiated to identify selective DAD4 receptor
ligands. The results confirm the piperazine ring as a reliable phar-
macophore impacting potency and selectivity for the D4 receptor.
Of the 25 piperazine derivatives evaluated, all displayed higher
potencies at the D4 than at the D2 receptors. Compound 27
(Ki = 0.84 nM) has the highest potency at the D4 receptor but dis-
plays only moderate selectivity compared to the other DA sub-
types. The most significant finding however is the identification
of a novel benzothiazole alkyl piperazine, compound 28, with a
binding affinity constant (Ki) of 3.9 nM and no significant binding
affinity to any of the other DA receptor subtypes (less than 50%
inhibition of the appropriate radioligand at each of the other DA
subtypes). In addition, compound 28 has only weak to moderate
affinities for eighteen other CNS receptors. These results warrant
a more elaborate pharmacological profiling, including functional
characterization, which is the focus of our current ongoing studies.
A solution of 2-(2-chloro-ethyl)-5-fluoro-indan-1-one (5 g,
23.5 mmol), ethylene glycol (5 mL), TsOH (100 mg) in toluene
(50 mL) was refluxed under N2 for 48 h. Water was removed by
azeotropic distillation and the reaction was monitored by 1H
NMR. The reaction was quenched by addition of Et3N (1 mL),
diluted with EtOAc (250 mL), washed with sat NaHCO3, (25 mL),
H2O (25 mL). The organic layer was dried over Na2SO4, and filtered.
The filtrate was concentrated in under vacuum to dryness yielding
a mixture of 2-(2-chloro-ethyl)-5-fluoro-indan-1-one and its ethyl-
ene acetal in a ratio of 1/4. 2-(2-chloroethyl)-5-fluoro-indan-1-one
was removed by reducing to its 2-(2-chloro-ethyl)-5-fluoro-indan-
1-ol with NaBH4 in MeOH, followed by column chromatography on
silica gel which afforded 20-(2-chloroethyl)-50-fluoro-20,30-dihydro-
spiro[[1,3]dioxolane-2,10-indene] 33 (4.5 g, 75%). 1H NMR (CDCl3):
d 7.24–7.28 (m, 1H), 6.89–6.96 (m, 2H), 4.22–4.28 (m, 1H), 4.07–
4.16 (m, 3H), 3.70–3.74 (m, 1H), 3.62–3.68 (m, 1H), 3.55–3.61
(m, 1H), 3.07 (dd, J = 14.7, 6.6 Hz, 1H), 2.71–2.75 (m, 1H), 2.60–
2.68 (m, 1H), 2.11–2.20 (m, 1H), 1.91–2.00 (m, 1H).
4. Experimental
4.1.3. 2-(2-(4-(4-Chlorophenyl)piperazin-1-yl)ethyl)-5-fluoro-
indan-1-one hydrochloride, 8
Melting points were determined on a Gallenkamp (UK) appara-
tus and are uncorrected. All NMR spectra were obtained on a Var-
ian 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
performed with Davisil grade 634 silica gel. Starting materials
were obtained from Sigma–Aldrich and were used without further
purification.
A mixture of 33 (1.2 g, 4.67 mmol), 1-(4-chlorophenyl)pipera-
zine dihydrochloride (1.3 g, 5.6 mmol), KI (100 mg), K2CO3 (1.2 g,
8.75 mmol) in DME (10 mL) was heated to reflux under N2 for
12 h. The mixture was directly purified through column chroma-
tography on silica gel to afford 2-{2-[4-(4-chloro-phenyl)-pipera-
zin-1-yl]-ethyl}-5-fluoro-indan-1-one
ethylene
acetal.
The
product was dissolved in wet MeOH and TsOH was added with
stirring at rt. After stirring at rt for 12 h, the solution was diluted
with EtOAc (450 mL) and washed with saturated NaHCO3
(40 mL). The organic layer was dried over Na2SO4, filtered and
the filtrate was concentrated in vacuo to dryness and column chro-
matographed on silica gel to give 2-{2-[4-(4-chloro-phenyl)-pip-
erazin-1-yl]-ethyl}-5-fluoro-indan-1-one, 8. The product was
converted to the hydrochloride salt and further crystallization
from MeOH–Et2O afforded the HCl salt (450 mg, yield 28%), mp
202–203 °C. 1H NMR (DMSO-d6): d 11.15 (br s, 1H), 7.72 (dd,
J = 8.7, 4.5 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.24–7.28 (m, 3H),
7.00 (d, J = 9.0 Hz, 2H), 3.77–3.80 (m, 2H), 3.53–3.56 (m, 2H),
3.28–3.36 (m, 2H), 3.12–3.22 (m, 4H), 2.81–2.90 (m, 2H),
4.1. Synthetic procedure
4.1.1. Synthesis of 2-(2-chloroethyl)-5-fluoro-indan-1-one, 31
A
mixture of 4-chloro-1-(4-fluorophenyl)-butan-1-one, 29
(10 g, 50 mmol), hexamethylenetriamine (10.5 g, 75 mmol) in
Ac2O (25 mL) was refluxed under N2 for 16 h. After cooling to rt,
the mixture was diluted with CHCl3 (500 mL) and then washed
with HCl solution (10%, 2 ꢀ 300 mL), H2O (300 mL), and sat
NaHCO3 (300 mL). The organic layer was dried over Na2SO4, and fil-
tered. The filtrate was concentrated in vacuo, followed by column
chromatography on silica gel to afford 4-chloro-1-(4-fluoro-phe-
nyl)-2-methylene-butan-1-one, 30 (2.8 g, 26.4%). 1H NMR (CDCl3):
Table 4
Binding affinity at other relevant CNS receptors, Ki in nM (pKi) SEM
Compd
28
5HT1A
5HT2A
5HT2B
5HT2C
5HT3
MT
5HT6
MT
5HT7
H1
40.0 (7.39 0.04)
283 (6.55 0.03)
47.0 (7.33 0.05)
M1
280 (6.55 0.04)
342 (6.47 0.06)
Sigma 1
730 (6.14 0.06)
Sigma 2
Compd
28
a1A
a2A
a2C
M3
MT
DAT
MT
NET
SERT
MT
259 (6.59 0.08)
844 (6.07 0.04)
126 (6.9 0.04)
MT
2773 (5.56 0.06)
350 (6.46 0.05)
162 (6.79 0.08)
MT = missed primary assay threshold of 50% inhibition.

D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
3111
2.22–2.78 (m, 1H), 1.84–1.96 (m, 2H). Calcd for C21H23Cl2FN2O: C
61.62, H 5.66, N 6.84. Found: C 61.38, H 5.58, N 6.77.
3.25–3.39 (m, 2H), 3.11–3.21 (m, 2H), 2.92–3.00 (m, 2H), 2.80–
2.87 (m, 1H), 2.72–2.77 (m, 1H), 2.24 (s, 3H), 2.16–2.22 (m, 1H),
1.84–1.93 (m, 1H). Calcd for C28H31ClN2O4S.0.8H2O: C 62.11, H
6.07, N 5.17. Found: C 62.09, H 6.06, N 5.08.
4.1.4. 2-(2-Chloroethyl)-indan-1-one
A mixture of 4-chloro-1-phenyl-butan-1-one (10 g, 54 mmol),
hexamethylene triamine (10.5 g, 75 mmol) in Ac2O (25 mL) was
refluxed under N2 for 18 h. After cooling to rt, the mixture was
diluted with CHCl3 (500 mL) and then washed with HCl solution
(10%, 2 ꢀ 300 mL), H2O (300 mL), and saturated aq NaHCO3
(300 mL). The organic layer was dried over anhydrous Na2SO4, fil-
tered and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography on silica gel to afford 4-
chloro-2-methylene-1-phenyl-butan-1-one (2.8 g, 26%). 1H NMR
(CDCl3): d 7.75–7.78 (m, 2H), 7.52–7.56 (m, 1H), 7.42–7.47 (m,
2H), 6.01 (s, 1H), 5.78 (s, 1H), 3.73 (t, J = 6.6 Hz, 2H), 2.95 (t,
J = 6.6 Hz, 2H). The 4-chloro-2-methylene-1-phenyl-butan-1-one
(1.2 g, 6.15 mmol) was dissolved in concd H2SO4 (4 mL) and heated
at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with
EtOAc (200 mL), washed with saturated aq NaHCO3 (2 ꢀ 200 mL)
and dried over Na2SO4. The solution was filtered, solvent was
removed in vacuo and the residue was purified by column chroma-
tography on silica gel to afford 2-(2-chloro-ethyl)-indan-1-one in
quantitative yield. 1H NMR (CDCl3): d 7.75 (d, J = 7.5 Hz, 1H), 7.60
(t, J = 7.2 Hz, 1H), 7.45–7.48 (m, 1H,), 7.38 (t, J = 7.2 Hz, 1H),
3.75–3.86 (m, 1H), 3.68–3.74 (m, 1H), 3.39–3.47 (m, 1H), 2.89–
2.94 (m, 1H), 2.80–2.88 (m, 1H), 2.38–2.47 (m, 1H), 1.88–1.96
(m, 1H).
4.1.6. 2-(2-Chloroethyl)-5-fluoroindane, 32
Amalgamated zinc is prepared by stirring a mixture of zinc
(1.2 g), HgCl2 (120 mg) in H2O (5 mL) with concd HCl (0.1 mL) at
rt. After stirring for 5 min, the mixture was decanted, followed
by the addition of H2O (1 mL), concd HCl (1.75 mL), toluene
(10 mL), and 2-(2-chloroethyl)-5-fluoro-indan-1-one, 31 (2.0 g,
9.43 mmol). The mixture was refluxed with stirring for 12 h,
allowed to cool to rt and the solid was filtered off. The collected fil-
trate was diluted with EtOAc (200 mL), separated and the organic
layer was washed with H2O (50 mL) and saturated aq NaHCO3
(50 mL). The organic layer was dried over Na2SO4, filtered and
the filtrate was concentrated under vacuum. The resulting residue
was purified by column chromatography on silica gel to afford 32
(1.68 g, 90%). 1H NMR (CDCl3): d 7.09 (dd, J = 7.8, 4.8 Hz, 1H),
6.81–6.88 (m, 2H), 3.60 (t, J = 7.2 Hz, 2H), 3.00–3.08 (m, 2H),
2.68–2.73 (m, 1H), 2.54–2.63 (m, 2H), 1.94–2.02 (m, 2H).
4.1.7. 1-(4-Chlorophenyl)-4-(2-(5-fluoro-2,3-dihydro-1H-inden-
2-yl)ethyl)piperazine dihydrochloride, 10
A mixture of 32 (0.8 g, 4.0 mmol), 1-(4-chlorophenyl)piperazine
dihydrochloride (1 g, 4.3 mmol), KI (150 mg), K2CO3 (1.2 g,
8.7 mmol) in DME (10 mL) was heated to reflux under N2 for
12 h. The mixture was directly purified through column chroma-
tography on silica gel to afford 1-(4-chloro-phenyl)-4-[2-(5-flu-
oro-indan-2-yl)-ethyl]-piperazine, 9. The product was converted
to the hydrochloride salt immediately and then recrystallized from
MeOH–Et2O (0.78 g, 45%), mp 194–196 °C. 1H NMR (DMSO-d6):
11.00 (br s, 1H), 7.26 (d, J = 9.0 Hz, 2H), 7.17 (dd, J = 5.7, 8.1 Hz,
1H), 6.99 (m, 3H), 6.90 (dt, J = 2.4, 8.4 Hz, 1H), 3.77 (d,
J = 11.1 Hz, 2H), 3.53 (d, J = 11.1 Hz, 2H), 3.07–3.19 (m, 6H), 2.96–
3.05 (m, 4H), 2.45–2.60 (m,1H), 1.88–1.96 (m, 2H). Calcd for C21-
H26Cl3FN2: C 58.41, H 6.07, N 6.49. Found: C 58.56, H 6.01, N 6.49.
4.1.5. 2-{2-[4-(4-Chloro-phenyl)-piperazin-1-yl]-ethyl}-indan-
1-one tosylate, 9
A solution of 2-(2-chloro-ethyl)-indan-1-one (5 g, 25.6 mmol),
ethylene glycol (5 mL), p-toluene sulfonic acid (TsOH, 100 mg) in
toluene (50 mL) was refluxed under N2 for 48 h and water was
removed by azeotropic distillation. The reaction was monitored
by 1H NMR until a conversion of 80% was achieved. The reaction
was quenched by the addition of Et3N (1 mL), diluted with EtOAc
(250 mL), washed with saturated aq NaHCO3, (25 mL) and H2O
(25 mL). The organic layer was dried over Na2SO4, filtered and
the filtrate was concentrated in vacuo to dryness to afford a mix-
ture of 2-(2-chloro-ethyl)-indan-1-one and its ethylene acetal in
a ratio of 1/4. 2-(2-Chloroethyl)-indan-1-one was removed by
reducing to its 2-(2-chloro-ethyl)-indan-1-ol with NaBH4 in MeOH,
followed by column chromatography on silica gel to afford 2-(2-
chloro-ethyl)-indan-1-one ethylene acetal (4.4 g, 72%). 1H NMR
(CDCl3): d 7.20–7.32 (m, 4H), 4.28–4.31 (m, 1H), 4.08–4.19 (m,
3H), 3.65–3.74 (m, 1H), 3.52–3.63 (m, 1H), 3.04–3.15 (m, 1H),
2.62–2.74 (m, 2H), 2.12–2.24 (m, 1H), 1.92–2.05 (m, 1H). A mixture
of 2-(2-chloroethyl)indan-1-one ethylene acetal (1.0 g, 4.18 mmol),
1-(4-chlorophenyl)-piperazine dihydrochloride (1.4 g, 5.19 mmol),
KI (100 mg), K2CO3 (1.2 g, 8.75 mmol) in DME (10 mL) was heated
to reflux under N2 for 12 h. The mixture was allowed to cool to rt
and then directly purified through column chromatography on silica
gel to afford an oily residue. Without characterization, the product
was dissolved in MeOH and p-toluene sulfonic acid (800 mg) was
added with stirring at rt. After stirring for 12 h, the solution was
diluted with EtOAc (450 mL) and washed with sat NaHCO3
(40 mL). The organic layer was dried over Na2SO4, filtered and the
filtrate was concentrated in vacuo to dryness. The resulting residue
was purified by column chromatography on silica gel to
afford 2-{2-[4-(4-chlorophenyl)-piperazin-1-yl]-ethyl}indan-1-one.
The product was converted to p-toluenesulfonate and crystallized
in MeOH–Et2O to afford the p-toluenesulfonate salt, 9 (610 mg,
28%). Mp 215–216 °C; 1H NMR (DMSO-d6): 9.57 (br s, 1H), 7.71
(d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H),
7.47 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 8.1 Hz,
2H), 7.01 (d, J = 9.0 Hz, 2H), 3.80–3.85 (m, 2H), 3.58–3.62 (m, 2H),
4.1.8. 3-(4-Fluorophenoxy)propan-1-ol, 36a
A mixture of 4-fluorophenol (1.12g, 10 mmol), 3-chloropropa-
nol (1.4 g, 15 mmol), KI (50 mg), K2CO3 (2.76 g, 20 mmol) in PrOH
i
was refluxed under N2 for 1h. The mixture was diluted with EtOAc
(200 mL), washed with H2O (50 mL) and then brine (50 mL). The
organic layer was dried with Na2SO4, and filtered. The filtrate
was concentrated in vacuo, followed by distillation in vacuo to give
the intermediate, 3-(4-fluorophenoxy)propan-1-ol, 36a (1.53 g,
90%). 1H NMR (CDCl3): d 6.96 (t, J = 8.4 Hz, 2H), 6,84 (dd, J = 9.0,
4.5 Hz, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.84–3.87 (m, 2H), 1.99–2.07
(m, 2H).
4.1.9. 3-(4-Fluorophenoxy)propyl methanesulfonate, 37a
To a solution of 36a (1.3 g, 7.6 mmol), Et3N (3 mL) in CH2Cl2
(10 mL) was added at rt MsCl (0.8 mL, 10.3 mmol). The mixture
was stirred at rt for 12 h, solvent was removed and the residue
was purified through column chromatography on silica gel, to yield
3-(4-fluorophenoxy)propyl methanesulfonate, 37a (1.79 g, 95%).
1H NMR (CDCl3): d 6.97 (t, J = 8.1 Hz, 2H), 6.83 (dd, J = 9.0, 4.5 Hz,
2H), 4.44 (t, J = 6.0 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H), 2.18–2.23 (m,
2H).
4.1.10. 3-((4-Fluorophenyl)thio)propan-1-ol, 36b
A mixture of 4-fluorobenzenthiol (1.55 g, 12.1 mmol), 3-chloro-
propanol (2.26 g, 27.65 mmol), KI (100 mg), K2CO3 (3.3 g,
i
23.9 mmol) in PrOH (10 mL) was refluxed under N2 for 1h. The
mixture was diluted with EtOAc (200 mL), and washed with water
(50 mL), brine (50 mL). The organic layer was dried with Na2SO4,

3112
D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
and filtered. The filtrate was concentrated in vacuo, and followed
by distillation in vacuo to give product 3-(4-fluorophenylthio)pro-
pan-1-ol, 36b (1.62 g, 72%). 1H NMR (CDCl3): d 7.35 (dd, J = 8.4,
5.4 Hz, 2H), 6.99 (t, J = 8.4 Hz, 2H), 3.76 (t, J = 6.0 Hz, 2H), 2.98 (t,
J = 7.2 Hz, 2H), 1.80–1.89 (m, 2H).
4.1.16. 1-(4-(4-Fluorophenyl)butyl)-4-(5-methylpyridin-2-
yl)piperazine, 15c
Yield 22%, mp 74 °C. 1H NMR (CDCl3) d 8.01 (d, J = 2.7 Hz, 1H,),
7.29 (dd, J = 8.7, 2.7 Hz, 1H), 7.14–7.09 (m, 2H), 6.98–6.92 (m,
2H), 6.58 (d, J = 8.7 Hz, 1H), 3.50–3.46 (m, 4H), 2.63–2.52 (m,
6H), 2.42–2.37 (m, 2H), 2.18 (s, 3H), 1.68–1.50 (m, 4H). 13C NMR
(CDCl3): d 162.78, 159.56, 158.11, 147.67, 138.39, 137.97, 137.93,
129.72, 129.62, 122.37, 115.12, 114.84, 106.99, 58.59, 53.09,
45.65, 34.98, 29.51, 26.34, 17.35. Calcd for C20H26FN3: C 73.36, H
8.00, N 12.83. Found: C 73.79, H 8.28, N 12.47.
4.1.11. 3-(4-Fluorophenylthio)propyl-4-
methylbenzenesulfonate, 37b
To
a solution of 3-(4-fluorophenyl-thio)-propan-1-ol (1 g,
5.4 mmol), Et3N (2 mL)in CH2Cl2 (10 mL) was added at rt TsCl
(1.54 g, 8.1 mmol). The mixture was stirred at room temperature
for 12 h, and then followed by directly purification through column
chromatography on silica gel, and provided 3-(4-fluorophenyl-
thio)propyl 4-methylbenzenesulfonate (1.72 g, 94%). 1H NMR
(CDCl3): d 7.77 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.30
(dd, J = 5.4, 8.4 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 4.13 (t, J = 8.0 Hz,
2H), 2.86 (t, J = 7.2 Hz, 2H), 1.85–1.92 (m, 2H).
4.1.17. General Procedure for the synthesis of n-chloro-N-(2-
hydroxy-phenyl)alkylamide, 40, (n = 2–5)
For n = 2, a solution of 2-aminophenol (1.0 g, 9.16 mmol), 3-
chloropropionylchloride, (1.39 g, 11 mmol, 1.2 equiv) and Et3N
(1.12 g, 11 mmol, 1.2 equiv) in EtOAc (25 mL) was heated to reflux
for 6–10 h. After allowing to cool to rt, EtOAc (100 mL) was added
and the solution was washed once with 10% HCl (100 mL). The
aqueous layer was extracted with EtOAc (3 ꢀ 100 mL) and the
combined organic layers was dried over anhydrous Na2SO4 and
concentrated by rotary evaporation under reduced pressure. The
pure product, 3-chloro-N-(2-hydroxyphenyl)propanamide, 40
was obtained as a colorless solid by column chromatography using
EtOAc/hexane (3:7) as eluent.
4.1.12. 3-(4-Fluorophenylthio)propyl methanesulfonate, 37c
To
a solution of 3-(4-fluorophenylthio)propan-1-ol (1.2 g,
6.45 mmol), Et3N (3 mL) in CH2Cl2 (10 mL) was added at rt MsCl
(1 mL, 12.7 mmol). The mixture was stirred at room temperature
for 12 h, and then followed by directly purification through column
chromatography on silica gel, and provided 3-(4-fluorophenyl-
thio)propyl methanesulfonate (1.60 g, 94%). 1H NMR (CDCl3): d
7.37 (dd, J = 9.0, 4.8 Hz, 2H), 7.00 (t, J = 9.0 Hz, 2H), 4.30 (t,
J = 8.0 Hz, 2H), 3.00 (s, 3H), 2.78 (t, J = 7.2 Hz, 2H), 1.99–2.04 (m,
2H).
4.1.18. General procedure for the synthesis of (n-
chloroalkyl)benzoxazole, 41, (n = 2–5)
A mixture of 3-chloro-N-(2-hydroxyphenyl)-propanamide (1 g,
5.01 mmol) and polyphosphoric acid (PPA, 3 g) was heated with
magnetic stirring at 130 °C for 3–4 h. The reaction mixture was
poured into ice-water (50 mL), neutralized with saturated aq
NH3, and extracted with EtOAc (2 ꢀ 50 mL). The combined extract
was washed with H2O, brine, dried (Na2SO4), and concentrated to
give the crude product which was purified by column chromatog-
raphy using EtOAc/hexane (1:9) to give 2-(2-chloroethyl)benzox-
azole as a pale yellow oily liquid.
4.1.13. General procedure of alkylation of arylpiperazines, 15a–
c
A mixture of aryl piperazines (0.4 mmol, 1 equiv) and K2CO3
(4 mmol, 4 equiv) was stirred and refluxed for 20 min in CH3CN
(10 mL). To the mixture, a solution of substituted tosylsulfonates/
mesylates/chlorides (0.53 mmol, 1.3 equiv) in CH3CN (5 mL) was
added drop wise. The reaction mixture was refluxed overnight,
diluted with EtOAc (100 mL), filtered and washed with brine. The
organic layer was collected, dried (Na2SO4), filtered, and the sol-
vent was evaporated. The residue obtained was chromatographed
on a silica gel column using hexane and EtOAc combinations as
eluent. The final compounds were obtained in moderate yields,
converted to HCl salts where necessary and re-crystallized using
appropriate solvents.
4.1.19. General procedure for the synthesis of 2-{2-[4-(4-chloro-
phenyl)-piperazin-1-yl]-ethyl}-benzoxazole
A mixture of 2-(2-chloroethyl)benzoxazole, (100 mg, 0.55 mmol),
4-chlorophenyl-piperazine, (108 mg, 0.55 mmol), and K2CO3 (433
mg, 3.30 mmol) in CH3CN (3 mL) was heated at reflux for 12–24 h.
After cooling to rt, the solvent was removed under vacuum, H2O
(10 mL) was added and the solution was extracted with EtOAc
(3 ꢀ 50 mL). The pooled organic layer was washed with brine, dried
over Na2SO4 and concentrated by rotary evaporation at reduced
pressure. The residue was purified by column chromatography
using EtOAc/hexane (9:1) as eluent to yield the pure product
4.1.14. 1-(3-(4-Fluorophenoxy)propyl)-4-(5-methylpyridin-2-
yl)piperazine, 15a
Yield 30%, mp 79.6 °C. 1H NMR (CDCl3): d 8.02 (s, 1H), 7.32 (dd,
J = 8.7, 2.4 Hz, 1H,), 6.99–6.93 (m, 2H), 6.85–6.81 (m, 2H), 6.59 (d,
J = 8.7 Hz, 1H,), 4.00 (t, J = 6.6 Hz, 2H,), 3.52–3.48 (m, 4H), 2.61–
2.55 (m, 6H), 2.19 (s, 3H), 2.05–1.96 (m, 2H). 13C NMR (CDCl3): d
158.74, 158.03, 155.59, 155.07, 155.04, 147.67, 138.41, 122.45,
115.90, 115.60, 115.46, 115.35, 107.03, 66.75, 55.23, 53.04, 45.60,
26.65, 17.34. Calcd for C19H24FN3O: C 69.28, H 7.34, N 12.76.
Found: C 69.47, H 7.30, N 12.50.
(2-{2-[4-(4-chlorophenyl)piperazin-1-yl]-ethyl}benzoxazole) as
colorless solid. The other benzoxazoles were similarly prepared.
a
4.1.20. 2-(5-(4-(4-Chlorophenyl)piperazin-1-
yl)pentyl)benzo[d]oxazole, 19
Yield 45%, mp 110–112 °C. 1H NMR (CDCl3): d 7.68–7.65 (m,
1H), 7.50–7.46 (m, 1H), 7.31–7.28 (m, 2H), 7.19 (d, J = 9.3 Hz,
2H), 6.82 (d, J = 9.3 Hz, 2H), 3.17–3.13 (m, 4H), 2.95 (t, J = 7.5 Hz,
2H), 2.59–2.56 (m, 4H), 2.40 (t, J = 7.5 Hz, 2H), 1.98–1.91 (m, 2H),
1.66–1.58 (m, 4H). Calcd for C22H26ClN3O: C 68.83, H 6.83, N
10.95. Found: C 69.12, H 6.86, N 10.72.
4.1.15. 1-(3-((4-Fluorophenyl)thio)propyl)-4-(5-methylpyridin-
2-yl)piperazine, 15b
Yield 62%, mp 85.5 °C. 1H NMR (CDCl3): d 8.00 (d, J = 2.4 Hz,
1H,), 7.37–7.29 (m, 3H), 7.01–6.96 (m, 2H), 6.58 (d, J = 8.7 Hz,
1H), 3.48–3.45 (m, 4H), 2.92 (t, J = 7.5 Hz, 2H), 2.54–2.46 (m, 6H),
2.18 (s, 3H), 1.86–1.77 (m, 2H). 13C NMR (CDCl3): d 163.32,
160.06, 158.04, 147.65, 138.40, 132.20, 132.09, 122.41, 116.14,
115.85, 107.01, 105.00, 57.12, 53.01, 45.62, 32.86, 26.39, 17.34.
Calcd for C19H24FN3S: C 66.05, H 7.00, N 12.16. Found: C 66.06, H
7.03, N 12.13.
4.1.21. 2-(4-(4-(4-Chlorophenyl)piperazin-1-
yl)butyl)benzo[d]oxazole, 20
Yield 70%, mp 127–129 °C. 1H NMR (CDCl3): d 7.68–7.65 (m,
1H), 7.49–7.46 (m, 1H), 7.31–7.28 (m, 2H), 7.19 (d, J = 9.3 Hz,
2H), 6.82 (d, J = 9.0 Hz, 2H), 3.14 (t, J = 4.8 Hz, 4H), 2.98 (t,
J = 7.5 Hz, 2H), 2.58 (t, J = 4.8 Hz, 4H), 2.45 (t, J = 7.5 Hz, 2H),

D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
3113
1.98–1.93 (m, 2H), 1.72–1.62 (m, 2H). Calcd for C21H24ClN3O 0.18
H2O: C 67.60, H 6.48, N 11.26. Found: C 67.69, H 6.61, N 10.98.
26.32, 24.88. Calcd for C21H23ClN2Oꢁ0.3H2O: C 70.01, H 6.43, N
7.78. Found: C 69.9, H 6.41, N 7.42.
4.1.22. 2-(3-(4-(4-Chlorophenyl)piperazin-1-
yl)propyl)benzo[d]oxazole, 21
4.1.28. 2-(3-(Benzofuran-2-yl)propyl)-5-(4-chlorophenyl)-2,5-
diazabicyclo[2.2.1]heptane, 25
Yield 37%, mp 98–99 °C. 1H NMR (CDCl3): d 7.68–7.65 (m, 1H),
7.49–7.46 (m, 1H), 7.30–7.28 (m, 2H), 7.18 (d, J = 9.3 Hz, 2H),
6.80 (d, J = 9.0 Hz, 2H), 3.09 (t, J = 5.1 Hz, 4H), 3.01 (t, J = 7.8 Hz,
2H), 2.59 (t, J = 5.1 Hz, 4H), 2.53 (t, J = 6.9 Hz, 2H), 2.14–2.09 (m,
2H). Calcd for C20H22ClN3O: C 67.50, H 6.23, N 11.81. Found: C
67.28, H 6.35, N 11.56.
Yield 70%, mp 88.1–89.5 °C. 1H NMR (CDCl3): d 7.46 (dd, J = 5.4,
4.5 Hz,1H), 7.19 (m, 1H), 7.17 (m, 1H), 7.13 (d, J = 9.6 Hz, 2H), 6.45
(d, J = 12.0 Hz, 2H), 6.35 (s, 1H), 4.18 (br s, 1H), 3.57 (br s, 1H), 3.35
(dd, J = 4.5, 3.3 Hz, 1H,), 3.22 (d, J = 9 Hz, 1H), 2.99 (dd, J = 4.5,
4.5 Hz, 1H), 2.78 (t, J = 9.0 Hz, 2H), 2.55 (m, 4H), 1.94 (t, J = 9 Hz,
2H), 1.84 (t, J = 9 Hz, 2H). 13C NMR (CDCl3): d 158.9, 154.2, 145.7,
128.9, 123.3, 122.2, 120.9, 120.05, 113.8, 110.6, 102.1, 61.7, 57.7,
56.9, 52.05, 36.3, 27.1, 26.01. Calcd for C22H23ClN2O: C 72.02, H
6.32, N 7.64. Found: C 71.75, H 6.38, N 7.51.
4.1.23. 2-(2-(4-(4-Chlorophenyl)piperazin-1-
yl)ethyl)benzo[d]oxazole, 22
Yield 58%, mp 110–112 °C. 1H NMR (CDCl3): d 7.69–7.66 (m,
1H), 7.52–7.47 (m, 1H), 7.32–7.30 (m, 2H), 7.19 (d, J = 9.3 Hz,
2H), 6.83 (d, J = 9.0 Hz, 2H), 3.18–3.14 (m, 6H), 3.01 (t, J = 6.9 Hz,
2H), 2.70 (t, J = 5.1 Hz, 4H). Cacld for C19H20ClN3O: C 66.76, H
5.90, N 12.29. Found: C 67.06, N 5.97, H 11.90.
4.1.29. 1-(3-(Benzofuran-2-yl)propyl)-4-(4-chlorophenyl)-1,4-
diazepane dihydrochloride, 26
Yield 89%, mp 138.1–139.9 °C. 1H NMR (CDCl3): d 7.46 (dd,
J = 6.0, 4.8 Hz, 1H), 7.39 (dd, J = 6.0Hz, 3.3 Hz, 1H), 7.14–7.22 (m,
2H), 7.12 (d, J = 7.2 Hz, 2H), 6.57 (d, J = 6.0 Hz, 2H), 6.35 (s, 1H),
3.53 (t, J = 6.0 Hz, 2H), 3.44 (t, J = 9.0 Hz, 2H), 2.73–2.81 (m, 4H),
2.66 (t, J = 6.0 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.91–2.00 (m, 4H).
Calcd for C22H27Cl3N2Oꢁ0.5H2O: C 63.77, H 6.32, N 6.76. Found: C
63.78, H 6.35, N 6.61.
4.1.24. General method for tosylated alkyl benzofurans
The method reported in Bakunova et al.,16 was followed to con-
struct the benzofuran moiety. A mixture of 2-iodophenol (3 g,
1 equiv), alkyl-1-yn-1-ol (1.1 equiv), and copper(I) oxide (1.36 g,
0.7 equiv) in dry pyridine (15 mL) was stirred at 100–120 °C over-
night. The mixture was allowed to cool to rt, diluted with EtOAc
(50 mL), filtered through celite and concentrated. The residue
was dissolved in EtOAc (100 mL), washed with 2 M HCl (50 mL)
and brine (100 mL), dried over Na2SO4, and concentrated. The res-
idue was, then, dissolved in CH2Cl2 (10 mL) and TsCl (1.1 equiv)
and Et3N (1.4 equiv) were added at rt while stirring overnight.
The solution was diluted with EtOAc (50 mL), washed with H2O
(3 ꢀ 50 mL) and brine (50 mL). The pooled organic solvent was
dried (Na2SO4), concentrated under reduced pressure and purified
using column chromatography with hexane/EtOAc (7:3) as the
eluent.
4.1.30. 2-(3-Chloropropyl)benzo[d]thiazole, 48
A mixture of 2-aminobenzenethiol (10 g, 80 mmol) and 4-chlo-
robutyl chloride (14 g, 99 mmol) in toluene (100 mL) was stirred
for 48 h at rt. The mixture was diluted with EtOAc (300 mL) and
washed with saturated aq NaHCO3 (2 ꢀ 100 mL). The organic layer
was dried with Na2SO4, and filtered. The filtrate was concentrated
in vacuo, followed by chromatography on silica gel to afford 2-(3-
chloropropyl)benzo[d]thiazole (13.5 g, 80%) as an oil. 1H NMR
(CDCl3): d 7.98 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.47 (t,
J = 8.4 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H), 3.69 (t, J = 6.6 Hz, 2H), 3.30
(t, J = 7.5 Hz, 2H), 2.34–2.42 (m, 2H).
4.1.25. General procedure for benzofuran coupling
4.1.31. 2-(3-(4-(Pyrimidin-2-yl)piperazin-1-
yl)propyl)benzo[d]thiazole trihydrobromide, 28
To a stirred solution of CH3CN (10 mL) and Et3N (2 equiv), the
appropriate haloalkylbenzofuran (1 equiv) and an arylcycloalkyl-
amine (1.1 equiv) were added and refluxed overnight. The solution
was allowed to cool to rt, diluted with EtOAc (50 mL) and washed
with H2O and brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified using column chroma-
tography with hexane/EtOAc (6:4) as the eluent to afford an
orange-yellow solid.
A mixture of 2-(3-chloropropyl)benzothiazole (1.5 g, 7.08 mmol),
2-(piperazin-1-yl)pyrimidine dihydrochloride (1.6 g, 6.7 mmol), KI
(200 mg), K2CO3 (1.2 g, 8.7 mmol) in DME (10 mL) was heated to
reflux under N2 for 12 h. The mixture was diluted with EtOAc
(400 mL) and washed with brine (50 mL). The organic layer was
dried over Na2SO4, and filtered. The filtrate was concentrated in
vacuo to dryness and the residue was column chromatographed
on silica gel to afford 2-[3-(4-pyrimidin-2-yl-piperazin-1-yl)
propyl]benzothiazole, 28. The product was converted into the HBr
salt, and recrystallized from MeOH–Et2O (865 mg, 21%), mp
>260 °C. 1H NMR (DMSO-d6): d 12.08 (br s, 2H), 10.13 (br s, 1H),
8.45 (d, J = 4.5 Hz, 2H), 8.07 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.1 Hz,
1H), 7.48 (dt, J = 1.5, 8.1 Hz, 1H), 7.40 (dt, J = 1.5, 8.1 Hz, 1H), 6.78
(t, J = 4.5 Hz, 1H), 4.68 (d, J = 14.1 Hz, 2H), 3.63 (d, J = 14.1 Hz, 2H),
3.35–3.44 (m, 2H), 3.20–3.31 (m, 4H), 3.04–3.14 (m, 2H),
2.25–2.35 (m, 2H). Calcd for C18H24Br3N5S: C 37.13, H 4.16,
N 12.03. Found: C 37.22, H 4.11, N 12.01.
4.1.26. 1-(2-(Benzofuran-2-yl)ethyl)-4-(4-
chlorophenyl)piperazine, 23
Yield 93%, mp 166.6–168.2 °C. 1H NMR (CDCl3): d 7.49 (dd,
J = 4.5, 4.5 Hz, 1H), 7.42 (d, J = 12.0 Hz, 1H), 7.24 (m, 4H), 6.87 (d,
J = 9.0 Hz, 2H), 6.46 (s, 1H), 3.19 (t, J = 15 Hz, 4H), 3.03 (t,
J = 9.0 Hz, 2H), 3.85 (t, J = 9.0 Hz, 2H), 2.70 (t, J = 15 Hz, 4H). 13C
NMR (CDCl3): d 157.4, 154.3, 149.98, 128.98, 124.3, 123.2, 122.2,
120.2, 117.3, 110.07, 102.3, 56.1, 52.8, 49.3, 26.2. Calcd for C20H21-
ClN2O: C 70.48, H 6.21, N 8.22. Found: C 70.63, H 6.30, N 8.25.
4.1.27. 1-(3-(Benzofuran-2-yl)propyl)-4-(4-
chlorophenyl)piperazine, 24
4.2. Receptor binding studies
Yield 90%, mp 84.8–85.9 °C. 1H NMR (CDCl3): d 7.49 (dd, J = 6.0,
6.0 Hz, 1H), 7.41 (d, J = 12.0 Hz, 1H), 7.19 (m, 4H), 6.84 (d,
J = 9.0 Hz, 2H), 6.41 (s, 1H), 3.15 (t, J = 15 Hz, 4H), 2.83 (t,
J = 9.0 Hz, 2H), 2.62 (t, J = 12.0 Hz, 2H), 2.49 (t, J = 9 Hz, 4H), 1.97
(m, 2H). 13C NMR (CDCl3): d 158.5, 154.5, 149.98, 128.94, 124.25,
123.21, 122.47, 120.24, 117.22, 110.75, 102.1, 57.66, 53.05, 49.11,
Binding affinities (Ki, nM) reported in Tables 1–4 were con-
ducted by the National Institute of Mental Health Psychoactive
Drug Screening Program (NIMH-PDSP) unless otherwise stated.
Details of the methods and the radioligands used for the binding
assays at each receptor were previously reported.22

3114
D. Sampson et al. / Bioorg. Med. Chem. 22 (2014) 3105–3114
Pomeranz, H. Neurology 2002, 59, 293; (d) Habek, M.; Petravic, D. Clin.
Acknowledgements
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This work was supported by NIH Grant #5SC1GM088451-01-04
and a Title III Grantto Florida A&M University. Thework was also sup-
ported in part by RCMI Grant #5 G12 MD007582-30 and the Pharma-
ceutical Research Center NIH/NCRR Grant #1C06-RR12512-01.
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