Development of CNS multi-receptor ligands: Modification of known D2pharmacophores

Article abstract of DOI:10.1016/j.bmc.2016.06.011

Several known D₂pharmacophores have been explored as templates for identifying ligands with multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant receptors in the treatment of neuropsychiatric disease

Full text of DOI:10.1016/j.bmc.2016.06.011

Accepted Manuscript
Development of CNS Multi-Receptor Ligands: Modification of Known D2
Pharmacophores
Jagan R. Etukala, Xue Y. Zhu, Suresh V.K. Eyunni, Edem K. Onyameh, Edward
Ofori, Barbara Bricker, X.P. Huang, Hye J. Kang, Bryan L. Roth, Seth Y.
Ablordeppey
PII:
S0968-0896(16)30434-5
DOI:
http://dx.doi.org/10.1016/j.bmc.2016.06.011
BMC 13067
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 April 2016
27 May 2016
3 June 2016
Please cite this article as: Etukala, J.R., Zhu, X.Y., Eyunni, S.V.K., Onyameh, E.K., Ofori, E., Bricker, B., Huang,
X.P., Kang, H.J., Roth, B.L., Ablordeppey, S.Y., Development of CNS Multi-Receptor Ligands: Modification of
Known D2 Pharmacophores, Bioorganic & Medicinal Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bmc.
2016.06.011
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Development of CNS Multi-Receptor Ligands: Modification of Known D2 Pharmacophores
Jagan R. Etukala,a Xue Y. Zhu,a Suresh V. K. Eyunni,a Edem K. Onyameh,a Edward Ofori,a Barbara
Bricker,a X. P. Huang,b Hye J. Kang,b Bryan L. Roth,b Seth Y. Ablordeppey a,*
aDivision of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and
Pharmaceutical Sciences, Tallahassee, FL 32307, USA
bDepartment of Pharmacology, Medicinal Chemistry and Psychiatry, University of North Carolina at
Chapel Hill, School of Medicine, NC 27599, USA
ABSTRACT
Several known D2 pharmacophores have been explored as templates for identifying ligands with
multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant
receptors in the treatment of neuropsychiatric diseases. This approach has resulted in the identification
of ligands that target multiple CNS receptors while avoiding others associated with deleterious effects.
In particular, compounds 11, 15 and 22 may have potential for further development as antipsychotic
agents as they favorably interact with the clinically relevant receptors including D2R, 5-HT1AR, and 5-
HT7R. We have also identified the pair of compounds 11 and 10 as high affinity D2R ligands with and
without SERT binding affinities, respectively. These differential binding profiles endow the pair with
the potential for evaluating SERT contributions to antipsychotic drug activity in animal behavioral
models. In addition, compound 11 has no significant affinity for 5-HT2CR and binds only moderately to
the H1R, suggesting it may not induce weight gain or sedation when used clinically. Taken together,
compound 11 displays an interesting pharmacological profile that necessitates the evaluation of its
functional and in vivo effects in animal models which are currently ongoing.
*Corresponding author.
Tel.: +1 850 599 3834; fax: +1 850 599 3934; E-mail: seth.ablordeppey@famu.edu (S.Y. Ablordeppey).
KEYWORDS: Multi-receptor targeting, Dopamine receptor ligands, Antipsychotic, Pharmacophore,
CNS receptor

1. Introduction
The dopamine D2 receptor (D2R) has long been considered the target for drug development in
schizophrenia and other neuropsychiatric diseases.1 More recently, however, several neuropsychiatric
illnesses are being viewed as multiple receptor pathological diseases, meaning that effective drugs
designed to treat these diseases must target several receptors simultaneously.2-6 This view is supported,
for example, by the fact that a neuropsychiatric disease like schizophrenia manifests at least three
different symptoms: positive, negative and cognitive symptoms. While blocking D2R has been
associated with treating the positive symptoms, the negative and cognitive symptoms remain
unresolved.7, 8 Several recent articles have indicated that the negative symptoms of schizophrenia may
be ameliorated by activating the serotonin 5-HT1A receptor (5-HT1AR)9-13 while the cognitive symptoms
may be treated by agents that activate the 5-HT1AR and antagonize the 5-HT7 receptor (5-HT7R).14-18
Taken together, we hypothesize that a drug that interacts appropriately with these receptors should have
improved therapeutic outcomes over several currently marketed drugs for treating schizophrenia.
Indeed, one of the most recent drugs introduced on the market, lurasidone, targets multiple receptors
including D2, 5-HT2A, 5-HT7 and 5-HT1A, and has found clinical utility not only in treating the positive
symptoms of schizophrenia but also in producing improvement in cognitive symptoms, and is even
prescribed for bipolar depression.19, 20
Our laboratory has been involved in multi-receptor targeting as possible treatment options for CNS
diseases over the years.2, 21, 22 In this article, we explored different modifications to pharmacophoric
groups (Figure 1) present in ligands that have high affinity for CNS receptors or elaborated structurally
similar functionalities to such pharmacophores. The working hypothesis was that by modifying the
arylalkyl groups attached to the amino groups in the pharmacophores shown in Figure 1, it was possible
to broaden the affinity of a target compound to other CNS receptors including the D2R, 5-HT1AR, 5-
HT7R and SERT. In view of the role of the D2R as a primary target for drug development against
neuropsychiatric diseases including schizophrenia and bipolar depression, it was of interest to first
obtain agents that had moderate to high affinity to the D2R (10≥Ki≤250 nM) before introducing
structural features that lead to binding at the other receptors of interest. We also intended to identify
compounds that while binding to these receptors will simultaneously have low or little affinities at 5-
HT2BR, 5-HT2CR and histamine H-1 receptors as these have been associated with known side effects
including valvular heart disease,23-25 weight gain26-28 and sedation.26-28

Figure 1. Structures of standard drugs and the pharmacophoric groups (R = R1 = H) used in obtaining
the target compounds.
2. Chemistry
The pharmacophoric groups (R = R1 = H) in 1, 3, 4 and 5 were commercially available from
Sigma/Aldrich. Pharmacophore 6 was previously synthesized.29-31 To synthesize the target compounds 7
– 22, different alkylating agents were required as depicted in Figure 2. Alkylating groups 28 – 29 were
obtained by reacting 5-chloropentanoyl chloride or 4-chlorobutanoyl chloride with 2-aminobenzenethiol
as previously reported,21, 32 while 30 was synthesized from 2-amino-4-chlorobenzenethiol and 5-
chloropentanoyl chloride using the same procedure.
Figure 2. Alkylating agents 28-33.

Scheme 1. Synthesis of target compounds 7, 8, 12, 16, 18, 19, and 21. Reagents and conditions: (i)
K2CO3, KI, CH3CN/DME, reflux, 12-15 h.
We also previously reported the synthesis of alkylating agent 3121, 32 while 32 was obtained by following
a literature procedure.33-37 Briefly, 4-(1H-indol-3-yl)butanoic acid was reduced by lithium aluminum
chloride and the resulting primary alcohol converted to the iodide (32) using triphenylphosphine (Ph3P)
and iodine in CH2Cl2. The benzoxazole alkylating agent 33 was synthesized following the literature
procedure we reported earlier.38 6-Chlorohexanoyl chloride or 5-chloropentanoyl chloride were each
reacted with 2-aminophenol in the presence of triethylamine (Et3N) and heated to reflux to provide the
amide intermediate which underwent cyclization with polyphosphoric acid (PPA) to produce the
resulting alkylating agent 33 in good yield.

Scheme 2. Synthesis of target compounds 9, 13, 17 and 22. Reagents and conditions: (i) K2CO3, KI,
CH3CN/DME, reflux, 12-15 h.
Scheme 3. Synthesis of target compounds 10, 14 and 20. Reagents and conditions: (i) K2CO3, CH3CN,
reflux, 12-15 h.

Scheme 4. Synthesis of target compounds 11 and 15. Reagents and conditions: (i) K2CO3, CH3CN,
reflux, 12-15 h.
3. Results and Discussion
The pharmacophoric groups in spiperone (1), the chloro analog of benperidol (3), haloperidol (5) and the
tropane analog of haloperidol (6) in Figure 1 constituted the group of starting fragments selected
because of their association with high affinity binding to the D2 receptor.29-31 The flunarizine
pharmacophore (4) was also included for evaluation as flunarizine has been shown to demonstrate
multiple CNS actions.39 We have hypothesized that by attaching various aryl alkyl groups to these
pharmacophores, it is possible to obtain compounds which can bind to the D2R and other clinically
relevant receptors including 5-HT1AR and 5-HT7R. In particular, it was of interest to attach aryl
(benzothiazole-, benzoxazole- and indole-) alkyl groups in view of their observed effects on binding
affinity to CNS receptors.21, 32, 38
Figure 3. Structures of target compounds in group 1.

Table 1
Binding affinity (Ki nM/ pKi ± SE) of group 1 compounds at selected DA and 5-HT receptorsa
Compound
7
Ki nM/ pKi ± SE
5-HT1A
D2
D3
D4
5-HT2A
5-HT7
24.0/
7.62±0.04
32.0/
7.49±0.06
132.0/
6.88±0.04
195/
6.71±0.07
>10,000/
N/A
626.0/
6.2±0.1
18.0/
7.74±0.08
499.0/
6.3±0.07
1,512.0/
5.8±0.1
102.0/
6.99±0.06
1,123.0/
5.8±0.1
1,598.0/
5.8±0.1
8
25.0/
7.59±0.07
18.0/
7.75±0.04
162.0/
6.79±0.05
103.0/
6.99±0.04
3,720.0/
5.43±0.04
518.0/
6.29±0.05
9
10
10.0/
7.99±0.04
21.0/
7.68±0.05
118.0/
6.93±0.04
382/
6.42±0.07
MTA
N/A
1511/
5.8±0.1
22.0/
7.65±0.06
31.0/
7.5±0.1
1.6/
8.81±0.05
376.0/
6.42 ± 0.07
982.0/
6.01±0.07
>10,000/
N/A
11
0.16±0.02b 0.32±0.04c
1.4±0.5c
17.2±3.8d
1.1±0.07e
110±17f
Spiperone
aMTA = Missed 50% threshold inhibition. N/A = Not available. Data points without SE have errors below
20% of the mean. bRef.40; cRef.41; dRef.42; eRef.43; fRef.44.
The first group of compounds (Figure 3), 7-11, were obtained by the alkylation of 1-phenyl-1,3,8-
triazaspiro[4.5]decan-4-one (2) with the appropriate arylalkyl group (Schemes 1-4), and their binding
affinity constants are reported in Table 1. Compound 7 showed potent binding to the D2R but only
moderate to weak binding affinities to the 5-HT receptors evaluated. Introduction of a chloro group onto
the benzothiazole ring (8) to explore the effect of an electron withdrawing group on the ring electron
density did not produce any significant changes in binding affinity. Similarly, insertion of a carbonyl
moiety (9) had no significant effect. Furthermore, replacement of the benzothiazole with either
benzoxazole (10) or indole (11) moieties failed to extend significant increase in affinity to the 5-HT
receptors. Based on their overall binding profile at these receptors, group 1 compounds could, in general,
be classified as showing selectivity to the D2 and D3 receptors (Ki range 10 - 32 nM) while binding to the
D4R is mixed, with 11 showing the highest binding affinity (Ki = 1.6 nM) and compound 8 the lowest (Ki
= 1512 nM). Compounds 8 and 9 bind with moderate affinity to the 5-HT1AR (Ki = 102 and 103 nM,
respectively) and combined with their high affinity to the D2R, could serve as useful agents for further
exploration.
5-Chloro-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one, the pharmacophore of 3, was next selected
for alkylation and resulted in compounds 12– 15. These along with compounds 16 and 17 constitute
group 2 analogs (Figure 4, Schemes 1-4). Synthesis and subsequent screening produced the binding
affinity data reported in Table 2. Compound 12 has about 9-fold lower affinity to the D2R (Ki = 215 nM)
compared to the corresponding analog in group 1 (compound 7) suggesting that the triazaspiro[4.5]decan-

4-one (pharmacophore 2) has a better affinity for the D2R than pharmacophore 3. Indeed, compounds 13-
15 which utilize pharmacophore 3 display lower binding affinity compared to the corresponding analogs
in group 1. In addition, the binding of the group 2 compounds had only moderate to poor binding to the
selected 5-HT receptors.
Figure 4. Structures of target compounds in group 2.
Table 2
Binding affinity (Ki nM/ pKi ± SE ) of group 2 compounds at DA and 5-HT receptorsa
Compound
Ki nM/ pKi ± SE
D2
D3
163.0/
D4
5-HT1A
5-HT2A
5-HT7
215.0/
671.0/
1162.5/
N/A
>10,000/
N/A
286.0/
6.54±0.06
12
6.67±0.05 6.79±0.06 6.17±0.06
217.0/
64.0/
1,710.0/
252.0/
1,564.0/
127.0/
13
6.66±0.04 7.2±0.04
5.77±0.07
6.6±0.04
5.81±0.04
6.9±0.05
95.0/
109.0/
841.0/
611/
3,392.0/
313.0/
14
7.02±0.06 6.96±0.06 6.08±0.05
6.21±0.05
5.47±0.05
6.5±0.06
134.0/
6.87±0.07 7.3±0.1
53.0/
16.0/
7.79±0.06
MTA
N/A
MTA
N/A
111.0/
6.95±0.08
15
195.0/
6.71±0.07 7.5±0.1
33.0/
68.0/
7.17±0.05
MTA
N/A
519.0/
6.28±0.05
778.0/
6.1±0.1
16
17
159.0/
6.8±0.07
233.0/
6.6±0.1
1,217.0/
5.91±0.05
MTA
N/A
1,082.0/
5.97±0.07
562.0/
6.3±0.1
0.027b
0.29±0.02c 0.066b
N/A
1.2d
N/A
Benperidol*
aMTA = Missed 50% inhibition threshold, N/A = Not applicable or not available; bRef.45;
cRef.46; d Ref.47 , *Only Ki values provided.
We also evaluated two piperazine analogs utilizing the 1-(bis(4-fluorophenyl)methyl)-piperazine,
pharmacophore from 4. Alkylating this group with the previous benzothiazole-alkyl groups produced
compounds 16 and 17 which bind to the D2R with moderate affinities (Ki = 195.0 and 159.0 nM,
respectively). Like the other group 2 analogs, D2R binding affinity was lower along with weak affinity
to the 5-HT receptors evaluated. Overall, the group 2 analogs have D2R binding affinity constants below

250 nM, varying moderate to high binding affinities at the D3 (Ki = 33 - 233 nM) and D4 (Ki = 16 –
1710 nM) receptors and relatively poor binding to the 5-HT receptors.
Figure 5. Structures of target compounds in group 3.
Table 3
Binding affinity (Ki nM/ pKi ± SE) of group 3 compounds at DA and 5-HT receptorsa
Compound
Ki nM/ pKi ± SE
5-HT1A
D2
D3
D4
5-HT2A
5-HT7
763.0/
6.12±0.05 7.55±0.09
201.0/
6.7±0.08
438±28
44.0/
28.0/
163.0/
6.79±0.04
140.0/
6.85±0.06
229±49
432.0/
6.36±0.09
508.0/
6.29±0.09
10.0/
7.98±0.28
5.3 ±0.99
34.0/
7.47±0.04
771.0/
6.11±0.08
3,153±368/
274.0/
6.60±0.06
MTA
N/A
3600/
5.44±0.03
27.7±8.0
168.0/
189.0/
6.72±0.08
983.0/
N/A
18
19
6.78±0.04
4,255.0/
5.37±0.06
5,970±1189/ MTA
>10,000/
N/A
MTA
N/A
120.0/
6.91±0.02
30.9±6.0
291.0/
6.54±0.06
942±200
13.0/
20b
21
1,009/
6.0±0.07
80.0/
7.1±0.08
1100/
7.35±0.03 7.89±0.6
180.0/ 16.0/
6.74±0.07 7.79±0.07
0.89/ 2.5/
9.05±0.30 8.61±0.05
Analog 6*,b 1.6±0.14
5.1±3.0
22
Haldol 5*
5.95±0.13
ND
aMTA = Missed 50% threshold inhibition. ND = Not Determined. N/A = Not applicable. Data points
without SE have errors below 20% of the mean. *Previously reported in2, 48 b = Only Ki values
provided.
Compounds in Group 3 (Figure 5) are obtained by alkylating 4-chlorophenyl piperidinol or tropanol
pharmacophores from 5 and 6. We have previously shown that these pharmacophores can be manipulated
to control their CNS receptor binding profiles.29-31 Using the previously synthesized benzothiazole- or
benzoxazole- linked alkyl groups, 4-chlorophenyl piperidinol was targeted for alkylation to produce
compounds 18 – 20 (Schemes 1-3). These compounds were synthesized and screened at the same
receptors as before and the results are reported in Table 3. Apart from compound 19 with moderate
binding affinity (Ki = 201 nM) none of the other four analogs meets the D2 binding criterion. Other than
compound 18 which binds with relatively high affinities at the 5-HT1AR and 5-HT7R (Ki = 34.0 and 189.0
nM, respectively), there were no significant improvements in binding at the 5-HT receptors. Finally, the
tropane analogs 21 and 22 were synthesized and similarly screened. Compound 21 binds with high affinity
at the D2R and D3R (Ki = 44.0 and 13 nM, respectively) but binds poorly to the D4R and 5-HT receptors.
Compound 22 on the other hand binds with moderate affinity to the D2R (Ki = 180.0 nM) and with even

higher affinity at the 5-HT7R (Ki = 80.0 nM). Overall, the group 3 analogs have high to moderate binding
to the D2R and variable binding affinities to the 5-HT receptors evaluated.
In view of the fact that D2R ligands with favorable interactions at 5-HT1AR, 5-HT2AR, 5-HT7R and the
serotonin transporter (SERT) have potential utility as effective agents for schizophrenia and bipolar
depression for example, compounds 7 – 11, 14 -15, 21 and 22 were selected for further evaluation at other
receptors associated with improved pharmacological profile and the results are recorded in Table 4. The
binding affinities of these compounds at other receptors associated with the undesirable side effects (5-
HT2B, 5-HT2C and H1 receptors) are also reported.
Table 4
Binding affinity (Ki nM/ pKi ± SE) of selected compounds at CNS receptorsa and their clog P valuesb
Ki nM/ pKi ± SE
Receptor
7
8
9
10
11
14
15
21
22
24/
18/
25/
10/
22/
95/
134/
44/
180/
D2R
7.62±0.04 7.74± 0.08 7.59±0.07 7.99±0.04 8.86±0.06 7.02±0.06 8.57±0.07 7.35±0.03
6.74±0.07
MTA
195/
102/
103/
382/
376/
611/
MTA
MTA
51/
274/
5HT1AR
5HT2AR
5HT2BR
5HT2CR
5HT7R
SERT
6.71±0.07 6.99±0.06 6.99±0.04 6.42±0.07 6.4± 0.1
6.21±0.05
3392/
6.60±0.06
>10K/
MTA
>10K/
122/
1123/
5.8±0.1
36/
3720/
5.43±0.04
1578/
MTA
905/
982/
7.65±0.06 5.47±0.05
202/ 515/
342/
758/
6.91±0.06 7.44±0.08 5.8±0.1
6.04±0.08 6.69±0.08 6.29±0.06 7.29±0.07 6.47±0.06
6.12±0.09
MTA
MTA
614/
MTA
MTA
MTA
>10K
10.0/
MTA
MTA
4623/
5.34±0.09
1009/
6.21±0.08
1598/
626/
518/
1511/
313/
6.5±0.06
386/
111/
80.0/
7.1±0.08
54.0/
8.33±0.05
1028/
6.2±0.1 5.8±0.1
6.29±0.05 5.82±0.09
6.95±0.08 6.0±0.07
25/
MTA
3056/
5.51±0.06 6.55±0.07
284/
MTA
180/
8.33±0.05 6.41±0.06 7.6±0.04
273/ 510/ 255/
6.74±0.08
187/
504/
263/
ND
535/
H1R
8.93±0.07 6.56±0.06
2.48 4.37
6.27±0.09 6.56±0.07 6.3±0.1
2.57 3.51 4.47
6.61±0.06 6.73±0.08
5.42 5.48
5.99±0.08
5.20
3.35
cLog P
aMTA = Missed 50% threshold inhibition. ND = Not Determined. bcLog P values were estimated using ChemDraw 12.0
We have hypothesized that compounds which simultaneously interact with the D2R and, for example,
either the 5-HT7R or SERT, have the potential to augment the effectiveness of primarily single receptor
agents used in the treatment of schizophrenia or bipolar depression. Evaluation of the data in Table 4
shows that compounds 8 (D2R and 5-HT1AR), 9 (D2R and 5-HT1AR), 11 (D2R and SERT), 15 (D2R and
SERT), and 22 (D2R, 5-HT7R and SERT) may have potential utility as hits in the development of agents
for the treatment of schizophrenia and bipolar depression, depending on their functional status. In
addition, while both compounds 11 and 10 bind with high affinities to D2R, 11 binds with high affinity to
SERT but 10 is without significant affinity to SERT. This differential binding profile endows the pair with
the potential for evaluating SERT contributions in animal behavioral studies. Furthermore, compound 11
has the desirable profile of no significant affinity for 5-HT2CR and only moderate binding to the H1R.

Since the compounds are designed to target CNS receptors, we also estimated some of the key
physicochemical characteristics including their clog P values using ChemDraw version 12 as reported in
Table 4. Apart from compounds 15, 21 and 22 all the other compounds have estimated clog P values
below 5.0. Compound 11, which displays the most interesting binding affinity profile, was further
compared with haloperidol and spiperone and the results indicate compound 11 (log P = 3.52; clog P =
3.51; tPSA = 47.61) compares favorably with haloperidol (log P = 3.49; clog P = 3.85; tPSA = 40.54) and
spiperone (log P = 2.78; clog P = 2.82; tPSA = 52.65) in terms of their lipophilicity (clog P/log P) and
topological polar surface area (tPSA) values. Overall, both the pharmacological and physicochemical
profiles of these compounds suggest further evaluation of their functional activities at the respective
receptors and in vivo animal testing to further ascertain their true potentials as leads for preclinical
examination.
4. CONCLUSION
By modifying the arylalkyl groups attached to various CNS pharmacophores, we have demonstrated that
receptor binding profiles of these agents can be obtained that could form the basis of identifying multi-
receptor targeting ligands. Several of the compounds have desirable multi-receptor binding profiles to
receptors of interest. In particular, compounds 11, 15 and 22 may have potential utility as leads for further
optimization to treat schizophrenia and bipolar disorders depending on their functional status. We have
also identified compounds 11 and 10 as high affinity D2R ligands with and without SERT binding
affinities, respectively, which suggests that they may have a great potential for evaluating SERT
contributions in animal behavioral studies. Compound 11 has no significant affinity for 5-HT2CR and
binds only moderately to the H1R suggesting little or no induction of sedation or weight gain. In addition,
compound 11’s physicochemical characteristics as calculated by ChemDraw, are consistent with drugs
that cross the BBB and elicit their pharmacological properties in the CNS.
5. METHODS
5.1. Reagents and general procedures
1
Melting points were determined on a Gallenkamp (UK) apparatus and are uncorrected. H 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 performed on Combi-Flash (Teledyne Isco) using RediSep normal phase silica
columns. N,N-dimethylformamide was distilled from CaSO4 and stored over 4Å molecular sieves.
Starting materials were obtained from either Sigma-Aldrich or VWR and were used without further
purification.
5.2. General procedure for the synthesis of alkylating agents (28-30)

To a solution of 2-aminothiophenol (5 g, 39.9 mmol) or 2-amino-4-chlorobenzenethiol in toluene (100
mL), 5-chlorobutanoyl chloride or 5-chloropentanoyl chloride (43.9 mmol) was added drop wise over a 15
min period during which an off-white precipitate was formed. After the reaction mixture was stirred at
room temperature (rt) overnight, water (100 mL) was added, the two layers were separated and the
aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extract was washed with
water (100 mL) and saturated NaCl solution (100 mL), dried over Na2SO4 and concentrated in vacuo. The
crude product was purified on Combiflash using EtOAc/Hexanes, to yield 2-(3-chloropropyl)benzo-
[d]thiazole 28 or 2-(4-chlorobutyl)benzo[d]thiazole 29 as an oily liquid or 5-chloro-2-(4-
chlorobutyl)benzo[d]thiazole (30) as a solid.
5.2.1. 2-(3-Chloropropyl)benzo[d]thiazole (28)
Oily liquid, Yield: 72%, 1H NMR (CD3OD): d 8.14 (d, 1H, J = 4.1 Hz), 8.02 (d, 1H, J = 4.1 Hz), 7.72-
7.59 (m, 2H), 3.64-3.57 (m, 2H), 3.38-3.28 (m, 2H), 1.95-1.86 (m, 2H).
5.2.2. 2-(4-Chlorobutyl)benzo[d]thiazole (29)
Oily liquid, Yield 56%, 1H NMR (CDCl3): d 7.98-7.95 (m, 1H), 7.85e7.82 (m, 1H), 7.48-7.42 (m, 1H),
7.37-7.32 (m, 1H), 3.60 (t, 2H, J = 7.5Hz), 3.15 (t, 2H, J = 7.5Hz), 2.09-1.97 (m, 2H), 1.95-1.90 (m, 2H).
5.2.3. 5-Chloro-2-(4-chlorobutyl)benzo[d]thiazole (30)
1
Solid, Yield: 89%, Mp: 110oC, H NMR (CDCl3): δ 7.95 (d, 1H, J = 2.1 Hz), 7.74 (d, 1H, J = 8.1 Hz),
7.35-7.32 (dd, 1H, J = 1.8, 6.6 Hz), 3.56 (t, 2H, J = 6.0 Hz), 3.15 (t, 2H, J = 7.5 Hz), 2.08-2.00 (m, 2H),
1.96-1.89 (m, 2H).
5.3. Procedure for the synthesis of 3-(4-iodobutyl)-1H-indole (32)
The synthesis of 3-(4-iodobutyl)-1H-indole followed literature procedures.36, 49 To a solution of indole-3-
butyric acid (2 gm, 9.8 mmol) dissolved in THF (30 mL) and cooled to 0oC was added portionwise
LiAlH4 (2.24 gm, 59.0 mmol, 6 eq) in THF. The mixture was allowed to warm to room temperature with
stirring for 18 hr. The reaction mixture was cooled to 0oC and a saturated solution of Na2SO4 (20 mL) was
added in a dropwise manner over the period of 30 min. The resulting white precipitate was filtered, the
filtrate was washed with EtOAc (2 x 100 mL), the pooled organic phase was washed with water (50 mL)
and saturated brine solution (50 mL), dried over anhydrous Na2SO4 and the solvent removed under
reduced pressure. The crude product 3-(4-hydroxybutyl)-1H-indole was obtained as a colorless solid and
used for the next step without further purification (1.70 g), Yield: 91%, Mp: 32-33oC. 1HNMR (300 MHz,
CDCl3): δ 7.95 (s, 1H), 7.60 (d, 1H, J = 7.8 Hz), 7.36-7.33 (m, 1H), 7.21-7.08 (m, 2H), 6.97 (s, 1H), 3.67
(t, 2H, J = 6.3 Hz), 2.79 (t, 2H, J = 7.5 Hz), 1.84-1.63 (m, 4H). To a stirred solution of triphenylphosphine
(4.46 g, 17.0 mmol) and imidazole (1.58 g, 17.0 mmol) in dichloromethane (DCM) (45 mL) cooled to

0oC, was added I2 (4.32 g, 17.0 mmol) and the reaction mixture was stirred at 0oC for 30 min. Thereafter, a
solution of 3-(4-hydroxybutyl)-1H-indole (2.30 g, 12.15 mmol) in DCM (5 mL) was added, the reaction
mixture was allowed to warm to rt with stirring for 12 hr, then filtered and the filtrate was washed with
hexane (2 x 100 mL). The combined organic solution was washed with water (100 mL) and saturated
brine (80 mL) before being dried over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the crude product was purified on CombiFlash using EtOAc/hexanes as eluent. The pure
product 3-(4-iodobutyl)-1H-indole was isolated as an oily liquid (2.40 g), Yield: 66%. 1HNMR (300 MHz,
CDCl3): δ 7.91 (s, 1H). 7.59 (d, 1H, J = 8.1Hz), 7.35 (d, 1H, J = 8.1 Hz), 7.22-7.17 (t, 1H, J = 6.9 Hz),
7.12 (m, 1H), 6.97 (d, 1H, J = 2.1 Hz), 3.22 (t, 2H, J = 6.9 Hz), 2.84 (t, 2H, J = 6.9 Hz), 1.96-1.76 (m,
4H).
5.4. General alkylation procedure for compounds (7-12)
The procedure previously reported by us was followed16. A mixture of 2-(3-chloropropyl)benzo[d]thiazole
(28) (1.3 mmol), or the appropriate alkylating agent (29 or 30), the appropriate amine (1.33 mmol), KI
(100 mg), K2CO3 (13.3 mmol), and CH3CN (15 mL) was heated to reflux for 12-24 h. The reaction
progress was monitored by TLC and at completion, the mixture was cooled to rt, solvent removed, the
resulting residue loaded onto a cartridge and purified by flash chromatography using EtOAc/hexane (9:1)
to give the pure desired products. The hydrochloride salts where necessary were prepared by dissolving
each pure compound in an appropriate solvent, adding excess ethereal HCl solution, removing solvent
under reduced pressure, and recrystallizing the residue from an appropriate solvent.
5.4.1. 8-(4-(benzo[d]thiazol-2-yl)butyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (7): Yield: 32.4%,
o
1
Mp: 184-185 C, H NMR (300 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.03-8.00 (m, 1H), 7.93-7.89 (m, 1H),
7.48-7.43 (m, 1H), 7.39-7.34 (m, 1H), 7.22-7.16 (t, 2H, J = 10.2 Hz), 6.81 (d, 2H, J = 7.8 Hz), 6.73-6.68
(t, 1H, J = 7.2 Hz), 4.54 (s, 2H), 3.16-3.11 (t, 2H, J = 7.8 Hz), 2.71-2.46 (m, 6 Hz), 2.39-2.34 (t, 2H, J =
7.2Hz), 1.90-1.80 (m, 2H), 1.60-1.51 (m, 4H). Calcd for: C24H28N4OS. 0.2 H2O: C 67.96, H 6.65, N
13.21; Found: C 67.95, H 6.70, N 12.94.
5.4.2.
8-(4-(5-chlorobenzo[d]thiazol-2-yl)butyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
(8):
Yield: 40%, Mp: 206-208oC, 1HNMR (300 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.08-8.05 (d, 1H, J = 9.0
Hz), 8.00 (d, 1H, J = 1.8 Hz), 7.46-7.42 (dd, 1H, J = 1.8, 8.4 Hz), 7.22-7.17 (dd, 2H, J = 1.2, 7.2 Hz),
6.83-6.81 (d, 1H, J = 8.1 Hz), 6.74-6.69 (t, 1H, J = 7.5 Hz), 4.55 (s, 2H), 3.29 (s, 2H), 3.18-3.13 (t, 2H, J
= 7.5 Hz), 2.71-2.62 (m, 4H), 2.39-2.34 (t, 2H, J = 7.5 Hz), 1.87-1.82 (m, 2H), 1.55-1.51 (m, 4H). Calcd
for C24H27ClN4OS.0.1 H2O: C 63.10, H 6.00, N 12.26; Found: C 62.85, H 6.06, N 12.17.
5.4.3. 8-(4-(benzo[d]oxazol-2-yl)butyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (10):

1
Yield 56.2%, Mp: 176-177 oC, H NMR (300 MHz, DMSO-d6): δ 8.57 (s, 1H), 7.67-7.61 (m, 2H), 7.33-
7.30 (m, 2H), 7.19 (t, 2H, J = 7.5 Hz), 6.81 (d, 1H, J = 7.8 Hz), 6.70 (t, 1H, J = 7.2 Hz), 4.54 (s, 2H),
2.96-2.94 (t, 2H, J = 7.8 Hz), 2.70-2.50 (m, 6H), 2.35 (t, 2H, J = 7.5 Hz), 1.87-1.78 (m, 2H), 1.60-1.50 (m,
4H). Calcd for: C24H28N4O2. 0.24 H2O: C 70.52, H 6.90, N 13.71; Found: C 70.52, H 6.85, N 13.68.
5.4.4. 8-(4-(1H-indol-3-yl)butyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (11): Yield: 48.9%, Mp:
o
1
208-210 C, H NMR (300 MHz, DMSO-d6): δ 10.79 (s, 1H), 9.03 (s, 1H), 7.52-6.80 (m, 10H), 4.61 (s,
2H), 3.70-3.17 (m, 4H), 2.80-2.62 (m, 6H), 2.00-1.50 (m, 6H). Calcd for: C25H30N4O. 0.3H2O: C 73.61,
H 7.56, N 13.73; Found: C 74.00, H 7.62, N 13.39.
5.4.5.
1-(1-(4-(benzo[d]thiazol-2-yl)butyl)piperidin-4-yl)-5-chloro-1H-benzo[d]imidazol-2(3H)-one
(12): Yield: 24.2%, Mp: 186-188 oC, 1H NMR (300 MHz, DMSO-d6): δ 11.00 (s, 1H), 8.04-8.01 (m, 1H),
7.9-7.90 (m, 1H), 7.49-7.46 (dd, 1H, J = 1.5, 5.7 Hz), 7.40-7.35 (m, 1H), 7.18 (d, 1H, J = 8.1 Hz), 6.99-
6.95 (dd, 2H, J = 2.1, 9.6 Hz), 4.14-4.00 (m, 1H), 3.12 (t, 2H, J = 7.2 Hz), 2.95 (d, 2H, J = 10.5 Hz), 2.35
(t, 2H, J = 7.5 Hz), 2.29-2.20 (m, 2H), 2.02-1.94 (m, 2H), 1.86-1.81 (m, 2H), 1.62-1.52 (m, 4H). Calcd
for: C23H25ClN4OS. 0.66 H2O: C 61.00, H 5.56, N 12.37; Found: C 60.99, H 5.57, N 11.99.
5.4.6.
1-(1-(4-(benzo[d]oxazol-2-yl)butyl)piperidin-4-yl)-5-chloro-1H-benzo[d]imidazol-2(3H)-one
1
(14): Yield: 34%, Mp: 189-191oC, HNMR (300 MHz, DMSO-d6): δ 7.67-7.63 (m, 2H), 7.35-7.30 (m,
2H), 7.18 (d, 1H, J = 8.1 Hz), 7.00-6.95 (m, 2H), 4.14-4.4.02 (m, 1H), 2.96 (t, 4H, J = 7.2 Hz), 2.34 (t,
2H, J = 6.9 Hz), 2.27-2.22 (m, 2H), 1.98 (t, 2H, J = 10.5 Hz), 1.80 (m, 2H), 1.61-1.49 (m, 4H). Calcd for:
C23H25ClN4O2. 0.5 H2O: C 63.66, H 5.81, N 12.91; Found: C 63.52, H 6.09, N 12.76.
5.4.7. 1-(1-(4-(1H-indol-3-yl)butyl)piperidin-4-yl)-5-chloro-1H-benzo[d]imidazol-2(3H)-one (15):
o
Yield: 40%, Mp: 95-97 C, 1HNMR (300 MHz, CDCl3): δ 9.16 (s, 1H), 7.99 (s, 1H), 7.62 (d, 1H, J = 7.5
Hz), 7.36 (d, 1H, J = 8.7 Hz), 7.22-7.07 (m, 4H), 7.02 (d, 2H, J = 8.7 Hz), 4.40-4.30 (m, 1H), 3.12 (d, 2H,
J = 11.7 Hz), 2.80 (t, 2H, J = 7.2 Hz), 2.48 (t, 4H, J = 6.9 Hz), 2.15 (t, 2H, J = 12.3 Hz), 1.83-1.68 (m,
6H). Calcd for: C24H27ClN4O. 0.18 EtOAc: C 65.69, H 6.20, N 12.77; Found: C 65.66, H 6.45, N 12.34.
5.4.8. 2-(4-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)butyl)benzo[d]thiazole dihydrochloride(16):
Yield: 54.4%, Hydroscopic, 1H NMR (300 MHz, CD3OD): δ 8.01-7.98 (m, 1H), 7.94-7.91 (m, 1H), 7.70-
7.60 (m, 4H), 7.58-7.53 (m, 1H), 7.49-7.44 (m, 1H), 7.13 (t, 4H, J = 8.7 Hz), 5.14-5.00 (m, 1H), 3.60-3.52
(m, 4H), 3.32-3.25 (m, 10H), 2.04-1.82 (m, 4H). Calcd for: C28H31Cl2F2N3S. 0.75H2O: C 59.62, H 5.81, N
7.45; Found: C 59.45, H 5.41, N 7.28.
5.4.9. 1-(benzo[d]thiazol-2-yl)-5-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)pentan-1-one
dihydrochloride (17): Yield: 63.7%, Hygroscopic, 1H NMR (300 MHz, CDCl3): δ 13.10 (s, 1H), 8.15 (d,
1H, J = 7.8 Hz), 7.98-7.92 (m, 5H), 7.60-7.50 (m, 2H), 7.20-7.10 (m, 4H), 5.16 (s, 1H), 4.34 (brs, 2H),

4.14-4.05 (m, 2H), 3.68-3.58 (m, 2H), 3.35 (brs, 2H), 3.21 (brs, 2H), 2.06-1.94 (brs, 6H). Calcd for:
C29H31Cl2F2N3OS.H2O: C 57.52, H 5.66, N 6.94; Found: C 57.63, H 5.60, N 6.66
5.4.10. 1-(3-(benzo[d]thiazol-2-yl)propyl)-4-(4-chlorophenyl)piperidin-4-ol hydrochloride (18):
Yield: 27%, Mp. 199-200 oC, 1H NMR (DMSO-d6): δ 10.89 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.95 (d, J =
7.8 Hz, 1H), 7.38-7.52 (m, 6H), 5.59 (s, 1H), 3.42-3.46 (m, 2H), 3.16-3.26 (m, 6H), 2.37-2.45 (m, 2H),
2.27-2.35 (m, 2H), 1.74-1.79 (m, 2H). Calcd for: C21H24Cl2N2OS: C 59.57, H 5.71, N 6.62; Found: C
59.54, H 5.71, N 6.62.
5.4.11. 1-(4-(benzo[d]thiazol-2-yl)butyl)-4-(4-chlorophenyl)piperidin-4-ol (19): Yield: 17.5%, Mp:
143-145 oC, 1H NMR (CDCl3): δ 7.79-7.94 (m, 1H), 7.86-7.83 (m, 1H), 7.48-7.42 (m, 3H), 7.38-7.29 (m,
3H), 3.16 (t, 2H, J = 7.8 Hz), 2.98-2.84 (m, 2H), 2.60-2.52 (m, 4H), 2.30-2.18 (m, 2H), 2.00-1.90 (m, 2H),
1.80-1.72 (m, 5H). Calcd for: C22H25ClN2OS: C 65.90, H 6.28, N 6.91; Found: C 65.56, H 6.17, N 6.91.
5.4.12. 1-(4-(benzo[d]oxazol-2-yl)butyl)-4-(4-chlorophenyl)piperidin-4-ol (20): Yield: 49.5%, Mp:
o
1
134-135 C, H NMR (CDCl3): δ 7.67-7.64 (m, 1H), 7.49-7.46 (m, 1H), 7.43 (d, 2H, J = 9.0 Hz), 7.32-
7.28 (m, 4H), 2.97 (t, 2H, J = 7.8 Hz), 2.80 (dd, 2H, J = 2.4, 8.7 Hz), 2.47 (t, 2H, J = 7.8 Hz), 2.37 (dd,
2H, J = 2.1, 9.6 Hz), 2.14-2.04 (m, 2H), 1.97-1.92 (m, 2H), 1.73-1.64 (m, 5H). Calcd for: C22H25ClN2O2:
C 68.65, H 6.55, N 7.28; Found: C 68.39, H 6.36, N 7.10.
5.5 General procedure for the synthesis of compounds 21 and 22: A mixture of alkylating agent (29 or
31) (2.5 mmol), 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol (680 mg, 2.85 mmol), K2CO3 (700 mg,
5.07 mmol) in DME (10 mL) was heated to reflux under N2 for 16 h. The mixture was diluted with EtOAc
(400 mL), washed with brine (50 mL) and the organic layer was dried over Na2SO4, and filtered. The
filtrate was concentrated in vacuo to dryness and column chromatographed on silica gel to afford the
desired product. The product was converted into the HCl salt, followed by crystallization from MeOH-
Et2O to afford the pure HCl salt.
5.5.1. Synthesis of 8-(4-(benzo[d]thiazol-2-yl)butyl)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol
hydrochloride (21): Yield 37%, Mp: 198-200 °C, 1H NMR (DMSO-d6): 10.92 (1H, brs), 8.04 (1H, d, J =
8.1 Hz), 7.92 (1H, d, J = 8.1 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.47 (1H, m), 7.40 (1H, m), 7.34 (2H, d, J =
8.4 Hz), 3.98 (2H, m), 3.15 (2H, m), 3.00 (2H, m), 2.63 (2H, m), 2.46 (4H, m), 2.08 (2H, m), 1.93 (6H,
m). Calcd for C24H28Cl2N2OS•0.4H2O: C 61.24, H 6.00, N 5.95; Found: C 61.29, H 6.05, N 5.85.
5.5.2.
1-(Benzo[d]thiazol-2-yl)-5-(3-(4-chlorophenyl)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-
1
pentan-1-one hydrochloride (22): Yield 43%, Mp: 202-204 °C, H NMR (DMSO-d6): 10.46 (1H, brs),
8.24 (2H, m), 7.73 (2H, d, J = 8.7 Hz), 7.64 (2H, m), 7.36 (2H, d, J = 9.0 Hz), 5.47 (1H, s), 4.30 (2H, m),

3.35 (4H, m), 3.14 (2H, m), 3.00 (2H, m), 2.57 (2H, m), 2.09 (2H, m), 1.88 (4H, m), 1.75 (2H, m). Calcd
for C25H28Cl2N2O2S•0.8H2O: C 59.36, H 5.58, N 5.54; Found: C 59.46, H 5.82, N 5.57.
5.5. Receptor binding studies
Binding affinities reported in Tables 1–4 were conducted by the National Institute of Mental Health
Psychoactive Drug Screening Program (NIMH-PDSP).5 Details of the methods and radioligands used
for the binding assays are available on the NIMH PDSP website at http://pdsp.med.unc.edu/UNC-
CH%20Protocol%20Book.pdf.
ACKNOWLEDGEMENTS
This work would not have been possible without the continuing financial support of the NIH/NIGMS
SCORE grant number 2SC1GM116724, NIMHD RCMI grant number G12 RR03020 and a Title III Grant
to Florida A&M University. The work was also supported in part by the Pharmaceutical Research Center
NIH/NCRR grant number 1C06RR12512. Ki determinations and receptor binding profiles were
generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program,
Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD,
PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH,
Bethesda MD, USA. Funding sources acknowledged had no involvement in the study design, data
collection and interpretation, or article preparation and submission of this manuscript.
REFERENCES
1.
2.
Seeman, P. CNS Neurosci. Ther. 2011, 17, 118.
Ablordeppey, S.Y.; Altundas, R.; Bricker, B.; Zhu, X.Y.; Kumar, E.V.; Jackson,
T.; Khan, A.; Roth, B.L. Bioorg. Med. Chem. 2008, 16, 7291.
Bolognesi, M.L. Curr. Med. Chem. 2013, 20, 1639.
Anighoro, A.; Bajorath, J.; Rastelli, G. J. Med. Chem. 2014, 57, 7874.
Besnard, J.; Ruda, G.F.; Setola, V.; Abecassis, K.; Rodriguiz, R.M.; Huang, X.P.;
Norval, S.; Sassano, M.F.; Shin, A.I.; Webster, L.A.; Simeons, F.R.; Stojanovski,
L.; Prat, A.; Seidah, N.G.; Constam, D.B.; Bickerton, G.R.; Read, K.D.; Wetsel,
W.C.; Gilbert, I.H.; Roth, B.L.; Hopkins, A.L. Nature 2012, 492, 215.
Zimmermann, G.R.; Lehar, J.; Keith, C.T. Drug Discov Today 2007, 12, 34.
Citrome, L. J. Clin. Psychiatry 2014, 75 Suppl 1, 21.
3.
4.
5.
6.
7.
8.
9.
10.
Walters, Y.; Agius, M. Psychiatr Danub 2014, 26 Suppl 1, 285.
Rollema, H.; Lu, Y.; Schmidt, A.W.; Zorn, S.H. Eur. J. Pharmacol. 1997, 338, R3.
Rollema, H.; Lu, Y.; Schmidt, A.W.; Sprouse, J.S.; Zorn, S.H. Biol. Psychiatry 2000,
48, 229.
11.
Sprouse, J.S.;
Reynolds, L.S.;
Braselton, J.P.;
Rollema, H.; Zorn, S.H.
Neuropsychopharmacology 1999, 21, 622.
12.
13.
Ichikawa, J.; Meltzer, H.Y. Brain Res. 2000, 858, 252.
Diaz-Mataix, L.; Scorza, M.C.; Bortolozzi, A.; Toth, M.; Celada, P.; Artigas, F. J.
Neurosci. 2005, 25, 10831.

14.
Bonaventure, P.; Aluisio, L.; Shoblock, J.; Boggs, J.D.; Fraser, I.C.; Lord, B.;
Lovenberg, T.W.; Galici, R. PLoS One 2011, 6, e20210.
15.
16.
Cifariello, A.; Pompili, A.; Gasbarri, A. Behav. Brain Res. 2008, 195, 171.
Abbas, A.I.; Hedlund, P.B.; Huang, X.P.; Tran, T.B.; Meltzer, H.Y.; Roth, B.L.
Psychopharmacology (Berl.) 2009, 205, 119.
17.
18.
Ishiyama, T.; Tokuda, K.; Ishibashi, T.; Ito, A.; Toma, S.; Ohno, Y. Eur. J.
Pharmacol. 2007, 572, 160.
Enomoto, T.; Ishibashi, T.; Tokuda, K.; Ishiyama, T.; Toma, S.; Ito, A. Behav.
Brain Res. 2008, 186, 197.
19.
20.
Loebel, A.; Citrome, L. BJPsych Bull 2015, 39, 237.
Franklin, R.;
Zorowitz, S.;
Corse, A.K.;
Widge, A.S.; Deckersbach, T.
Neuropsychiatr. Dis. Treat. 2015, 11, 2143.
21.
22.
23.
24.
Zhu, X.Y.; Etukala, J.R.; Eyunni, S.V.; Setola, V.; Roth, B.L.; Ablordeppey, S.Y.
Eur. J. Med. Chem. 2012, 53, 124.
Peprah, K.; Zhu, X.Y.; Eyunni, S.V.; Setola, V.; Roth, B.L.; Ablordeppey, S.Y.
Bioorg. Med. Chem. 2012, 20, 1291.
Rothman, R.B.; Baumann, M.H.; Savage, J.E.; Rauser, L.; McBride, A.; Hufeisen,
S.J.; Roth, B.L. Circulation 2000, 102, 2836.
Setola, V.; Hufeisen, S.J.; Grande-Allen, K.J.; Vesely, I.; Glennon, R.A.; Blough,
B.; Rothman, R.B.; Roth, B.L. Mol. Pharmacol. 2003, 63, 1223.
Setola, V.; Roth, B.L. Expert Opin. Drug Metab. Toxicol. 2005, 1, 377.
Kroeze, W.K.; Hufeisen, S.J.; Popadak, B.A.; Renock, S.M.; Steinberg, S.;
Ernsberger, P.; Jayathilake, K.; Meltzer, H.Y.; Roth, B.L. Neuropsychopharmacology
2003, 28, 519.
25.
26.
27.
28.
29.
30.
Opgen-Rhein, C.; Brandl, E.J.; Muller, D.J.; Neuhaus, A.H.; Tiwari, A.K.; Sander,
T.; Dettling, M. Pharmacogenomics 2010, 11, 773.
Matsui-Sakata, A.; Ohtani, H.; Sawada, Y. Drug Metab. Pharmacokinet. 2005, 20,
368.
Sikazwe, D.M.; Li, S.; Mardenborough, L.; Cody, V.; Roth, B.L.; Ablordeppey,
S.Y. Bioorg. Med. Chem. Lett. 2004, 14, 5739.
Lyles-Eggleston, M.; Altundas, R.; Xia, J.; Sikazwe, D.M.; 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.
Sikazwe, D.M.; Li, S.; Lyles-Eggleston, M.; Ablordeppey, S.Y. Bioorg. Med. Chem.
Lett. 2003, 13, 3779.
31.
32.
Peprah, K.; Zhu, X.Y.; Eyunni, S.V.; Etukala, J.R.; Setola, V.; Roth, B.L.;
Ablordeppey, S.Y. Bioorg. Med. Chem. 2012, 20, 1671.
33.
34.
35.
Oisaki, K.; Abe, J.; Kanai, M. Org. Biomol. Chem. 2013, 11, 4569.
Blair, L.M.; Sperry, J. Synlett 2013, 24, 1931.
López-Alvarado, P.; Steinhoff, J.; Miranda, S.; Avendaño, C.; Carlos Menéndez, J.
Tetrahedron 2009, 65, 1660.
36.
Mamolo, M.G.; Zampieri, D.; Zanette, C.; Florio, C.; Collina, S.; Urbano, M.;
Azzolina, O.; Vio, L. Eur. J. Med. Chem. 2008, 43, 2073.
37.
38.
Perregaard, J.; Moltzen, E.K.; Meier, E.; Sanchez, C. J. Med. Chem. 1995, 38, 1998.
Sampson, D.; Zhu, X.Y.; Eyunni, S.V.; Etukala, J.R.; Ofori, E.; Bricker, B.;
Lamango, N.S.; Setola, V.; Roth, B.L.; Ablordeppey, S.Y. Bioorg. Med. Chem. 2014,
22, 3105.
39.
Capella, D.; Laporte, J.R.; Castel, J.M.; Tristan, C.; Cos, A.; Morales-Olivas, F.J.
BMJ 1988, 297, 722.
40.
41.
Richelson, E.; Nelson, A. Eur. J. Pharmacol. 1984, 103, 197.
Tang, L.; Todd, R.D.; Heller, A.; O'Malley, K.L. J. Pharmacol. Exp. Ther. 1994, 268,
495.

42.
43.
44.
Sundaram, H.; Newman-Tancredi, A.; Strange, P.G. Biochem. Pharmacol. 1993, 45,
1003.
Branchek, T.; Adham, N.; Macchi, M.; Kao, H.T.; Hartig, P.R. Mol. Pharmacol.
1990, 38, 604.
Bard, J.A.; Zgombick, J.; Adham, N.; Vaysse, P.; Branchek, T.A.; Weinshank, R.L.
J. Biol. Chem. 1993, 268, 23422.
45.
46.
Seeman, P.; Tallerico, T. Mol. Psychiatry 1998, 3, 123.
Rangel-Barajas, C.; Malik, M.; Vangveravong, S.; Mach, R.H.; Luedtke, R.R.
Neuropharmacology 2014, 83, 18.
47.
48.
49.
Leysen, J.E.; Niemegeers, C.J.; Van Nueten, J.M.; Laduron, P.M. Mol. Pharmacol.
1982, 21, 301.
Schmidt, A.W.; Lebel, L.A.; Howard, H.R., Jr.; Zorn, S.H. Eur. J. Pharmacol. 2001,
425, 197.
Smith, S.M.; Takacs, J.M. J. Am. Chem. Soc. 2010, 132, 1740.

Development of CNS Multi-Receptor Ligands: Modification of Known D2 Pharmacophores
Jagan R. Etukala,a Xue Y. Zhu,a Suresh V. K. Eyunni,a Edem Onyameh,a Edward Ofori,a Barbara Bricker,a X. P.
Huang,b H. J. Kang, Bryan L. Roth,b Seth Y. Ablordeppey a,*
aDivision of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical
Sciences, Tallahassee, FL 32307, USA
bDepartment of Pharmacology, Medicinal Chemistry and Psychiatry, University of North Carolina at Chapel Hill,
School of Medicine, NC 27599, USA
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