Design and synthesis of dual 5-HT1Aand 5-HT7receptor ligands

Article abstract of DOI:10.1016/j.bmc.2016.05.053

5-HT_1Aand 5-HT₇receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT₇receptor ligand culminating in the identification of several dual 5-HT_1Aand 5-HT₇receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.

Full text of DOI:10.1016/j.bmc.2016.05.053

Accepted Manuscript
Design and Synthesis of Dual 5-HT1A and 5-HT7 Receptor Ligands
Edward Ofori, Xue Y. Zhu, Jagan R. Etukala, Kwakye Peprah, Kamansky R.
Jordan, Adia A. Adkins, Barbara A. Bricker, X.P. Huang, Hye J. Kang, Bryan
L. Roth, Seth Y. Ablordeppey
PII:
S0968-0896(16)30386-8
DOI:
http://dx.doi.org/10.1016/j.bmc.2016.05.053
BMC 13037
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 April 2016
17 May 2016
26 May 2016
Please cite this article as: Ofori, E., Zhu, X.Y., Etukala, J.R., Peprah, K., Jordan, K.R., Adkins, A.A., Bricker, B.A.,
Huang, X.P., Kang, H.J., Roth, B.L., Ablordeppey, S.Y., Design and Synthesis of Dual 5-HT1A and 5-HT7 Receptor
Ligands, Bioorganic & Medicinal Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bmc.2016.05.053
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Design and Synthesis of Dual 5-HT1A and 5-HT7 Receptor Ligands
Edward Ofori,a Xue Y. Zhu,a Jagan R. Etukala,a Kwakye Peprah,a Kamansky R. Jordan,a Adia A.
Adkins,a Barbara A. 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
5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major
role in the etiology of major central nervous system diseases such as depression, sleep disorders, and
schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have
carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the
identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone
derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low
nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate
affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may
serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat
diseases of CNS origin.
*Corresponding Author
Keywords: Dual receptor ligands, multi-receptor targeting, CNS ligands, serotonin receptors, 5-HT1A
receptor and 5-HT7 receptor ligands.

1. Introduction
It is now well established that targeting a single receptor is often inadequate in treating several diseases
including diseases originating from the central nervous system. Thus, drugs such as aripiprazole,
lurasidone and others derive their superior therapeutic outcomes from their ability to target multiple
receptors in the CNS.1-4
The neurotransmitters, dopamine (DA) and serotonin (5-HT), are of particular interest because of their
involvement in several neurological and psychiatric diseases such as schizophrenia, major depressive
disorder (MDD), depression, attention deficit and hyperactivity disorder (ADHD), and addiction.5-8
Recent research has indicated that the serotonin receptors (5-HTRs) in particular play significant roles in
CNS physiological activities, and dysregulation of these receptors often results in several diseases. For
example, the serotonin 1A receptor (5-HT1AR) which is found predominantly in the dorsal raphe nuclei,
hippocampus, and cortico-limbic regions, controls memory, cognition, and mood, functions which are
impaired in anxiety, depression and schizophrenia.9 Several lines of evidence now support the anti-
negative symptoms and cognitive enhancement effects of ligands which activate 5-HT1AR in
schizophrenia.6, 10 Similarly, the serotonin 7 receptor (5-HT7R), the most recent addition to the 5-HT
receptor subtypes,11-13 has been shown to mediate key functions such as sleep, mood, learning, memory,
and cognition.14-17 Interestingly, the 5-HT7R forms heterodimers with the 5-HT1AR in most brain
regions, producing a cross talk which has been implicated in depression and other CNS disorders. Both
receptors share over 40% sequence homology which may account for the cross reactivity seen among
ligands which interact at both receptors.18-20 It stands to reason therefore that agents with dual binding
affinities to both receptors may be beneficial as treatment options for depression and other cognitive
impairment disorders.
Our lab has been engaged in multiple receptor-targeting in order to extend the scope and utility of CNS
agents. The purpose of the current research was to investigate the 1,2,3,4-tetrahydroisoquinoline (THIQ)
moiety as a pharmacophore for the dual targeting of the 5-HT1A and 5-HT7 receptors so as to probe their
potential utility in CNS diseases. To that end, we have designed and synthesized several arylalkyl
substituted THIQs in order to identify new lead agents for further development.
2. Chemistry
In general, the compounds evaluated in this manuscript were obtained by refluxing or carrying out a
microwave-assisted reaction of THIQ with various alkylating agents in dimethoxyethane (DME) or
acetonitrile (CH3CN) in the presence of K2CO3 as a base and a catalytic amount of KI. The target

compounds were prepared by first N-alkylating potassium phthalimide with 1,4-dibromobutane to
produce alkyl bromide 1b which was separately reacted with THIQ, decahydroisoquinoline, and
isoindoline to afford compounds 1, 2 and 3 respectively (Scheme 1). A three-step reaction procedure
was used to synthesize compound 4 (Scheme 2). Commercially available 4-(1H-indol-3-yl)butanoic
acid, 2a was reduced using LAH in dry THF to produce the corresponding alcohol which was
subsequently converted to the iodo intermediate 2b via an Appel reaction.21, 22 The obtained alkylating
agent was then coupled to THIQ to afford 4. Deoxygenation of the previously reported indanone 3a23
under Clemmenson reduction conditions yielded 3b which was then used to alkylate THIQ and afforded
compound 5 as shown in Scheme 3. Chloride 4a, mesylate 4b, and tosylate 4c were synthesized by
literature procedures and subsequently used to alkylate THIQ to yield compounds 6, 7, and 8
respectively (Scheme 4) using the general alkylating conditions described in Scheme 1. Sulfoxide 9 was
prepared by oxidation of 8 using the previously reported meta peroxybenzoic acid (m-CPBA) mediated
oxidative conditions depicted in Scheme 5.23
Alkylating agents 6a, 6b, and 6e were obtained commercially and were used to synthesize compounds
10, 11, and 16 respectively whereas 6c and 6d were prepared following Friedel-Crafts acylation reaction
as reported24 and subsequently used to obtain compounds 12a and 14 respectively (Scheme 6). Finally,
using potassium ferrocyanide (K4[Fe(CN)6].3H2O) as the cyanide source, palladium catalyzed
cyanation25 of 12a afforded compound 12 (Scheme 6). Base-catalyzed hydrolysis of the cyano group26
in 12 afforded the corresponding amide 13 (Scheme 6). Demethylation of 14 with hydrobromic acid
afforded compound 15 (Scheme 6).
Scheme 1. Synthesis of isoindoline-1,3-dione analogs. Reagents and conditions: a) 1,4-dibromobutane,
DMF, 100 oC; b) K2CO3/KI, CH3CN, reflux, 12-24 h. I = THIQ; ii = decahydroisoquinoline; iii =
isoindoline.

Scheme 2. Synthesis of 3-substituted-1H-indole analog. Reagents and condition: a) LiAlH4 in dry THF,
rt ,12 h; b) I2/PPh3, imidazole; c) THIQ, K2CO3/KI, DME, reflux,12 h.
Scheme 3. Synthesis of 5-fluoro-2,3-dihydro-1H-indene analog. Reagents and conditions: a) Zn
Amalgam, Conc. HCl, toluene, reflux; b) THIQ, K2CO3/KI, DME, reflux, 12 h; c) ethereal HCl.
Scheme 4. Synthesis of 4-fluorobutyrophenone analogs. Reagents and conditions: a) THIQ, K2CO3/KI,
DME, MW; b) ethereal HCl.
Scheme 5. Synthesis of sulfoxide analog . Reagents and conditions: a) m-CPBA, MeOH, 0 oC to rt

Scheme 6. Synthesis of 4-subtituted-butyrophenone analogs. Reagents and conditions: a. THIQ,
o
o
K2CO3/KI, DME, 120 C, MW; (b) K4[Fe(CN)6].3H2O, Pd(OAc)2, KI , Na2CO3, N2, DMA, 120 C, 12
h; (c) KOH, t-butyl alcohol, reflux, 12 h; d) aq. HBr 48%, NaI, 110oC, MW.
3. Results and Discussion
The THIQ moiety has been the subject of several recent publications.27-33 In a campaign to synthesize
new drugs with selective affinity for the 5-HT7 receptor, we synthesized 2-(4-(3,4-dihydroisoquinolin-
2(1H)-yl)butyl)isoindoline-1,3-dione (1) and evaluated its affinity for key 5-HTR subtypes including the
5-HT7R. As shown in Table 1, compound 1 demonstrated a low nanomolar potency at the 5-HT7R and
little affinity to the other key 5-HTR subtypes including 5-HT1AR where it is over 50-fold less potent.
Replacement of the THIQ ring in 1 with decahydroisoquinoline to yield 2 resulted in close to a 40-fold
decrease in binding affinity to the 5-HT7R, with binding affinity at 5-HT1AR and 5-HT2AR remaining
essentially unchanged. Compound 2 however, displays selectivity towards the 5-HT2CR (Ki = 37 nM).
Further modification of 1 by replacing the tetrahydroisoquinoline ring with isoindoline ring to obtain 3
resulted in significant loss of activity at all receptor subtypes except the 5-HT2CR where there was
moderate affinity (Ki = 151 nM). Based on the results of the binding affinities for compounds 1–3, it is
clear that the THIQ ring serves as an important pharmacophore for binding affinity to the 5-HT7R in
these compounds. This observation informed the next design strategy to keep the THIQ group and to
focus on modifications elsewhere in the molecule, including that of the isoindoline-1,3-dione moiety.
Replacement of the isoindoline-1,3-dione moiety in 3 with indole to obtain 4 restored nanomolar
binding affinity to the 5-HT7R, while replacement with 5-fluoro-2,3-dihydro-1H-indene to form 5, led to
significant binding affinity to both 5-HT1AR and 5-HT7R (Ki = 193 and 86 nM respectively). Excision of
a methylene group from the indene moiety in compound 5 led to ring-opened 6 with improved affinity
for both 5-HT1AR and 5-HT7R. Replacement of the benzylic methylene group in 6 with oxygen (7) and
sulfur (8) did not result in significant changes. However, oxidation of the sulfide to obtain the sulfoxide
9, increased affinity for both 5-HT1AR (Ki = 41 nM) and 5-HT7R (Ki = 22.5 nM).

Next, the sulfoxide group in 9 was replaced by a carbonyl to form 4-(3,4-dihydroisoquinolin-2(1H)-yl)-
1-(4-fluorophenyl)butan-1-one (10) which resulted in a 3-fold increase in binding affinity at the HT1AR
(Ki = 12 nM) but a decrease of 16-fold at the 5-HT7R (Ki = 364 nM). Interestingly, affinity at the 5-
HT2AR is found to have improved drastically to 14 nM. Similar low nanomolar binding affinities are
observed for compounds 11 (the defluorinated analog) and 12 (replacement of the fluoro with the
electron withdrawing and hydrophilic cyano substituent) at the 5-HT2AR while significant loss of
affinities are noted at the 5-HT1AR and 5-HT7R. However, changing the p-cyano substituent in 12 to the
carboxamide 13, the methoxy group 14, or its hydroxy analog 15, produced the desired dual 5-HT1AR
and 5-HT7R binding affinity ligands with low nanomolar affinity constants. Thus, it would appear that
various substituents covering at least three quadrants of the Craig plot did not yield a clearly defined
structure affinity relationship trend. Finally, we evaluated compound 16, with the p-fluoro atom of
compound 10 replaced by a chloro atom which yielded the most potent dual 5-HT1AR (Ki = 8.2 nM) and
5-HT7R (Ki = 3.6 nM) binding affinity ligand in the series. Comparing compound 16 and Aripiprazole,
both have high affinities at 5-HT1AR (5.6 vrs. 8.2 nM), and 5-HT7R (3.6 vrs. 10.3 nM), but differ
significantly at the other serotonin receptors evaluated, with compound 16 having little or no binding at
5-HT2AR and 5-HT2CR (Ki = 2976 nM) and moderate binding at 5-HT2BR (Ki = 232 nM), while
Aripiprazole has high affinity for 5-HT2AR (Ki = 8.7 nM) and 5-HT2BR (Ki = 0.36 nM) and moderate
affinity to 5-HT2CR (Ki = 76 nM).
Table 1
Binding affinity of analogs at selected serotonin receptors
*Ki nM (pKi)
Compound Structure
1
5-HT1A
499
(6.3 ± 0.05)
5-HT2A
MTA
5-HT7
8.6
(8.07 ± 0.05)
5-HT2B
MTA
5-HT2C
MTA
533
>10,000
330
400
37
(6.27 ± 0.07)
(6.48 ± 0.07) (6.4 ± 0.08)
(7.43 ± 0.07)
2
3
151
(6.82 ± 0.07)
MTA
1689
MTA
926
MTA
52
MTA
MTA
(5.77 ± 0.06) (6.03 ± 0.08) (7.29 ± 0.07)
MTA
MTA
4
5
193
(6.72 ± 0.04)
522.5
86.0
1247
(5.9±0.09)
141
726±117
27
1713
4440
(6.85 ± 0.06)
(7.57 ± 0.08) (5.77 ± 0.08)
(5.4 ± 0.1)
6
7
244
(6.61 ± 0.05)
322 ± 61.9
100 561
(7.00 ± 0.06) (6.25 ±0.09)
MTA

217
317
49
204
2623
(6.66±0.06)
(6.43±0.07) (7.31±0.05) (6.69± 0.07) (5.58 ± 0.09)
8
9
41
1779 22.5 1166
(7.39 ± 0.05) (5.75 ± 0.09) (7.64 ± 0.07) (5.93 ± 0.08)
MTA
12 ± 1.0
710
14 ± 1.0
3.9
364 ± 12
358
614 ± 36
273
>10,000
603
10*
(6.15 ± 0.08) (8.41 ± 0.05) (6.45 ± 0.05) (6.56 ± 0.06) (6.22 ± 0.05)
11
12
13
14
15
16
295 23 755 152 443
(6.53 ± 0.06) (7.64 ± 0.05) (6.12 ± 0.06) (6.82 ± 0.08) (6.12 ± 0.06)
38 404 12 587 1892
(7.42 ± 0.07) (6.39 ± 0.04) (7.91 ± 0.08) (6.23 ± 0,07) (5.72 ± 0.05)
23 2993 17 723 1404
(7.54 ± 0.07) (5.67 ± 0.05) (7.77 ± 0.08) (6.14 ± 0.05) (5.85 ± 0.07)
33.50 851 10 358
(7.46 ± 0.07) (6.14 ± 0.05) (7.99 ± 0.08) (6.45 ± 0.05)
MTA
2976
8.2
3.6
232
(8.09 ± 0.07)
MTA
(8.45 ± 0.07) (6.63 ± 0.07) (5.53 ± 0.06)
Aripiprazole**
5.6 ± 0.8
8.7 ± 2.0
10.3 ± 3.7 0.36 ± 0.11 76 ± 8.0
MTA = Missed 50% of threshold inhibition. *Ki values without the associated SEM, are within 20% of the mean
value. ** Binding affinity data from reference 3.
The target compounds were also screened at additional CNS receptors with clinical significance
including the D2R, D3R, D4R, H1R and SERT and the results reported in Table 2. Compounds 1 – 3
showed little if any affinities at the aforementioned receptors/transporter. Compound 4, the indolealkyl
substituted analog of 1, produced moderate affinities for D2R, D4R and SERT while the dihydroindene
analog 5 had moderate affinities for D3R, D4R and SERT. Opening the dihydroindene ring in 5 with
excision of a methylene group (6), or replacing the benzylic carbon with oxygen, sulfur, or sulfoxide (7-
9) resulted in significant loss of affinity for SERT with no clear SAR features at the other receptors in
Table 2. Replacement of the sulfoxide with a carbonyl (10) produced significant increase in binding at
the dopamine receptors, suggesting that perhaps the butyrophenone THIQ scaffold could constitute a
useful hit for further development as ligands for multiple receptor targeting. However, probing the
electron donating or withdrawing nature and/or the hydrophilic/hydrophobic nature of substituents at the
para position of the phenyl ring (10 -16) according to the Craig plot procedure34 did not produce an
increase in potency at the dopamine receptors and did not reveal any interesting SAR trend. Regarding
their histamine binding affinities, only 10 and 11 have affinity constants below 100 nM suggesting that
these compounds may have low propensity for interacting at the histamine H1 receptor and hence less
sedative effect.
Of the sixteen compounds reported, three, compounds 13, 14 and 16 (13: Ki = 13 nM, 14: Ki = 38
nM, 16: Ki = 17 nM respectively) show significant binding affinities to the D3R. Given their

concentration in limbic and cortical regions of the brain, D3Rs have been hypothesized to be potential
targets for the design of new antipsychotics with limited extrapyramidal side effects. However, there
have been reports that selective D3R blockade only resulted in marginal antipsychotic effects. This has
led to the suggestion and indeed demonstration that dual D2/D3 receptor blockade produce effective
antipsychotic actions.35-37
The moderate binding affinities of these compounds for the D2 receptors (13: Ki = 218 nM, 14: Ki = 249
nM, 16 Ki = 126 nM), combined with their serotonin binding profiles make them potential drug leads
for further exploitation. In particular, the preferential and more potent binding of 16 at D3R (Ki = 17
nM) compared to D2R (7 fold) suggest further evaluation for intrinsic activities and subsequent
exploitation in the treatment of CNS conditions including the negative and cognitive symptoms of
schizophrenia and bipolar mania.38-40 Interestingly, the D3R binding of compound 16 is similar to that of
aripiprazole (Ki = 17 vrs. 9.7 nM), while the D2R binding affinity is similar to that of clozapine41 (Ki =
126 nM vrs. pKi = 6.87 or Ki = 130 nM). Strong binding to the D3R may also be associated with
procognitive effects, as reported.42
In conclusion, using compound 1 which showed significant selectivity (>50 fold) for 5-HT7 receptor
compared to the 5-HT1AR as our starting hit, and guided by results from our SAR studies, we were able
to obtain very potent dual 5-HT1A and 5-HT7 receptor affinity ligands. In addition, compound 16 showed
moderate binding affinity at D2R, high affinity at D3R, and a 7-fold selectivity for D3R over D2R, which
portends a lead with great potential for further development in treating the negative and cognitive
symptoms of schizophrenia, as well as bipolar mania. We opine that butyrophenone derivatives of
THIQ such as 16 could serve as important leads to exploit for more potent CNS drugs with multi-
receptor affinity features.
Table 2
Binding affinity of analogs at dopamine subtype receptors, histamine H1 receptor, and SERT
Ki nM (pKi)
Compound
1
D2
D3
D4
H1
SERT
MTA
491
(6.3 ± 0.10)
630
(6.2±010)
MTA
240
(6.62 ± 0.08)
>10,000
(<5.0)
1,361
(5.87 ± 0.09)
35
MTA
MTA
>10,000
MTA
3632
(5.44 ± 0.06)
MTA
>10,000
(<5.0)
MTA
2
3
4
170
(6.8 ± 0.10)
469
(6.33 ± 0.09)
836
(6.08 ± 0.08)
113.0
(7.46 ± 0.06)

1150
319
(6.5 ± 0.07)
166
(6.78±0.05)
123
(6.91±0.04)
422
(6.37 ± 0.08)
49 ± 3
646
(6.19 ± 0.06)
1456
(5.84 ± 0.09)
218
(6.66 ± 0.05)
249
(6.6 ± 0.07)
366
(6.44 ± 0.08)
126
(6.9 ± 0.06)
3.3 ± 1.1
162
6007 ± 1491
NA
769±161
NA
118
(6.93±0.04)
161
(6.79 ± 0.04)
72 ± 5
161
(6.79 ± 0.04)
336
(6.47 ± 0.04)
18
(7.75 ± 0.06)
38
(7.42 ± 0.05)
143
(6.84 ± 0.05)
123
160
(6.8±0.05)
83
(7.08±0.05)
146
(6.84±0.06)
NA
738
(6.13±0.06)
382
(6.42±0.08)
NA
163.0
4284
5*
6
MTA
MTA
MTA
7
8
9
460
NA
(6.39 ± 0.06)
2.3 ± 0.2
MTA
86.3 ± 7.26
68
(7.2±0.20)
177
(6.8 ± 0.10)
1427
(5.8 ± 0.10)
216
MTA
1534
10*
11
345
(6.46 ± 0.04)
205
(6.69 ± 0.04)
210
(6.68 ± 0.05)
773
(6.11 ± 0.04)
895
MTA
12
13
2442
14
(6.7 ± 0.10)
MTA
MTA
15
16
17
86
597
(6.22 ± 0.05)
25.1 ± 2.6
MTA
(7.77 ± 0.04)
9.7 ± 5.4
8.09 ± 0.07
510 ± 93
1080 ± 180
Aripiprazole
MTA= Missed 50% of threshold inhibition. *Only Ki values reported. NA = Not available. Ki values
without the associated SEM, are within 20% of the mean value.
4. EXPERIMENTAL:
Melting points were determined on a Gallenkamp (UK) apparatus and are uncorrected. All NMR spectra
were obtained on a Varian 300 MHz Mercury Spectrometer and the free induction decay (FID) data
were processed using Mestrelab’s Mnova NMR software (version 8.1) to obtain the reported NMR data.
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 using CombiFlash® with Davisil
grade 634 silica gel. Starting materials were obtained from Sigma–Aldrich and were used without
further purification. All microwave assisted syntheses (MW) were carried out using a Biotage Initiator®.
4.1. Synthesis of 2-(4-Bromobutyl)isoindoline-1,3-dione, 1b
A mixture of potassium phthalimide 1a (0.93 g, 5 mmol) and 1,4-dibromobutane (5.4 g, 25 mmol) was
o
stirred in dry DMF (10 mL) at 100 C for 12 h. The condenser was then set for distillation, and the
excess of 1,4-dibromobutane and DMF was removed under reduced pressure. The crude product
obtained was purified by column chromatography (silica gel, ethyl acetate/light petroleum 1:50) to
1
afford intermediate 1b as a colorless solid. H NMR (CDCl3): δ 7.87-7.84 (2H, m), 7.74-7.71 (2H, m),
3.73 (2H, t, J = 6.9 Hz), 3.45 (2H, t, J = 6.3 Hz), 1.90-1.88 (4H, m).

4.2. General alkylation procedure for compounds 1-3
A mixture of 1b (1 equiv), an appropriate amine (1.2 equiv), KI (100 mg), and K2CO3 (10 equiv), in
CH3CN (15 mL) or DME was refluxed for 12-24 h. The reaction progress was monitored by TLC and at
completion, the mixture was cooled to room temperature, solvent removed, the resulting residue loaded
onto a cartridge and purified by flash chromatography using an EtOAc/hexane gradient up to 80%
EtOAc) to give the pure desired products.
4.2.1. 2-(4-(3,4-Dihydroisoquinolin-2(1H)-yl)butyl)isoindoline-1,3-dione, 1
Following the general alkylation procedure described in section 4.2 and using THIQ as the amine,
compound 1 was obtained as the free base. Yield: 22%, mp: 68-69 oC. 1H NMR (DMSO-d6): δ 7.86-7.79
(4H, m), 7.07-6.98 (4H, m), 3.58 (2H, t, J = 6.9 Hz), 3.47 (2H, s), 2.75 (2H, t, J = 5.4 Hz), 2.58 (2H, t, J
= 6.0 Hz), 2.43 (2H, t, J = 6.9 Hz), 1.68-1.48 (4H, m). Calcd for C21H22N2O2·0.2H2O; C 74.62, H 6.68,
N 8.29; Found: C 74.55, H 6.55, N 8.25.
4.2.2. 2-(4-(Octahydroisoquinolin-2(1H)-yl)butyl)isoindoline-1,3-dione, 2
Using decahydroisoquinoline as the amine, compound 2 was prepared similarly to 1 above. Yield: 12%,
mp: 64-65oC. 1H NMR (CDCl3): δ 7.84-7.82 (2H, dd, J = 3.0, 8.7 Hz), 7.70 (2H, dd, J = 3.0, 9.0 Hz),
3.70 (2H, t, J = 7.2 Hz), 2.91 (1H, d, J = 8.1 Hz), 2.75 (1H, d, J = 9.0 Hz), 2.31 (2H, s), 1.77 (1H, t, J =
7.2 Hz), 1.71-1.48 (1H, m), 1.26-1.19 (4H, m), 0.98-0.87 (2H, m). Calcd for C21H28N2O2 ; C 74.08, H
8.29, N 8.23; Found: C; 73.82, H; 8.09, N; 8.19.
4.2.3. 2-(4-(Isoindolin-2-yl)butyl)isoindoline-1,3-dione, 3
Following the general alkylation procedure in section 4.2 and using isoindoline as the amine, compound
1
3 was obtained as the free base. Yield: 21%, mp: 95-96oC. H NMR (DMSO-d6): δ 7.88-7.78 (m, 4H),
7.20-7.12 (m, 4H), 3.76 (s, 4H), 3.59 (t, 2H, J = 5.7 Hz), 2.63 (t, 2H, J = 7.2 Hz), 1.70-1.44 (m, 4H).
Calcd for C20H20N2O2·0.11 H2O; C 72.78, H 6.11, N 8.49; Found: C 72.75, H 6.16, N 8.12.
4.3. Synthesis of 3-(4-iodobutyl)-1H-indole, 2b
To a solution of indole-3-butyric acid 2a (2 g, 9.8 mmol) dissolved in dry THF (30 mL) and cooled to 0
oC was added portionwise LiAlH4 (2.2 g, 59 mmol, 6 eq) in dry THF. The mixture was allowed to warm
o
to room temperature (rt) with stirring for 18h. The reaction mixture was cooled to 0 C 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 washed with EtOAc (2 x 100 mL), the pooled organic phase
washed with water (50 mL) and saturated brine solution (50 mL), dried over anhydrous Na2SO4 and the

solvent removed under reduced pressure to obtain the crude product. The crude 3-(4-hydroxybutyl)-1H-
indole was used for the next step without further purification.
The crude obtained was converted to compound 2b following a procedure reported in literature.21
Briefly, to a stirred solution of PPh3 (4.46 g, 17.0 mmol) and imidazole (1.58 g, 17.0 mmol) in DCM (45
o
mL) at 0 C, was added I2 (4.32 g, 17.0 mmol) and the reaction mixture was stirred at this temperature
for 30 min. Thereafter, a solution of crude 3-(4-hydroxybutyl)-1H-indole (2.30 g, 12.2 mmol) in DCM
(5 mL) was added, the reaction mixture was allowed to warm to rt and stirred for 12 h. The crude
product was directly purified using silica gel on CombiFlash with gradient up to 40% EtOAc in hexanes
1
to afford compound 2b (2.40 g) as an oily liquid. Yield: 66%. H NMR (CDCl3): δ 7.91 (1H, s). 7.59
(1H, d, J = 8.1Hz), 7.35 (1H,d, J = 8.1 Hz), 7.22-7.17 (1H, t, J = 6.9 Hz), 7.12 (1H, m), 6.97 (1H, d, J =
2.1 Hz), 3.22 (2H, t, J = 6.9 Hz), 2.84 (2H, t, J = 6.9 Hz), 1.96-1.76 (4H, m).
4.4. 2-(4-(1H-indol-3-yl)butyl)-1,2,3,4-tetrahydroisoquinoline, 4
Following the general alkylation procedure described above (section 4.2.) and using the obtained 2b as
the alkylating agent, compound 4 was obtained. Yield: 52%, mp: 139-140 oC. 1H NMR (CDCl3): δ 7.96
(1H, s), 7.62-7.60 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.21-7.15 (1H, m), 7.13-7.07 (4H, m),
7.01-6.98 (2H, m), 2.90 (2H, t, J = 5.7 Hz), 2.81 (2H, t, J = 6.9 Hz), 2.73 (2H, t, J = 6.0 Hz), 2.56 (2H, t,
J = 7.2 Hz), 1.80-1.69 (6H, m,). Calcd for C21H24N2; C 82.85, H 7.97, N 9.20; Found: C 82.65, H 7.97,
N 8.97.
4.5. Synthesis of 2-(2-chloroethyl)-5-fluoro-2,3-dihydro-1H-indene, 3b
Amalgamated zinc was prepared by stirring a mixture of zinc (1.2 g), HgCl2 (0.12 g) in 5 mL water with
conc. HCl (0.1 mL) at room temperature. After stirring for 5 min, the mixture was decanted and
followed by adding in order water (1 mL), conc HCl (1.75 mL), toluene (10 mL), and then 2-(2-Chloro-
ethyl)-5-fluoro-indan-1-one 3a (2 g, 9.43 mmol), synthesis of which was previously reported by us.23
The mixture was refluxed with stirring for 12 h. The solid was filtered off, aqueous layer was diluted
with EtOAc (200 mL), washed with water, and then saturated NaHCO3 (50 mL). The organic layer was
dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo followed by column
chromatography on silica gel to afford 3b, 1.68 g, Yield 90%. 1H NMR (CDCl3): δ 7.09 (1H, dd, J = 4.8,
7.8 Hz), 6.85 (2H, m), 3.60 (2H, t, J = 7.2 Hz), 3.04 (2H, m), 2.70 (1H, m), 2.56 (2H, m), 1.98 (2H, m).
4.6. 2-(2-(5-Fluoro-2,3-dihydro-1H-inden-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride,
5
Alkylating agent 3b was reacted with THIQ following the general alkylation procedure described in
1
section 4.2 to obtain compound 5 as its HCl salt. Yield: 42%, mp: 211-212 ºC. H NMR (DMSO-d6):

10.85 (1H, s), 7.19 (5H, m), 7.02 (1H, d, J = 9.0 Hz), 6.92 (1H, t, J = 9.0 Hz), 4.51 (1H, m), 4.27 (1H,
m), 3.67 (1H, m), 3.40 (1H, m), 3.23 (4H, m), 3.02 (4H, m), 2.60 (1H, m), 1.98 (2H, m). Calcd for
C20H23ClFN: C 72.00, H 6.95, N 4.20; Found: C 71.89, H 6.97, N 4.28.
4.7. General alkylation procedure for compounds 6-8, 10-12a, 14, and 16:
A mixture of alkylating agent (1 equiv), THIQ (1.1 equiv) K2CO3 (1.1 equiv), and KI (catalytic) in DME
(10 mL) was placed in a 20 mL microwave vial with a stirrer and tightly sealed. The mixture was
subjected to microwave heating at 120oC for 60 mins. The mixture was directly purified on silica by
flash chromatography (gradient up to 70% EtOAc in hexanes) to afford compound 7. The free base
where necessary, was converted to the HCl salt and crystallized out of a MeOH-Et2O solvent mixture.
4.7.1. 2-(4-(4-Fluorophenyl)butyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 6
The synthesis of 1-(4-chlorobutyl)-4-fluorobenzene 4a was previously reported by us23 and following
the procedure described in section 4.7., 4a was reacted with THIQ to afford compound 6 as its HCl salt
1
form. Yield: 75%, mp: 205–206 °C. H NMR (DMSO-d6): δ 7.30-7.06 (6H, m); 6.99-6.92 (2H, m);
4.60-4.55 (1H, m); 4.01-3.94 (1H, m), 3.65-3.59 (1H, m), 3.51-3.42 (1H, m), 3.27-3.17 (1H, m), 3.07-
2.93 (4H, m), 2.66 (2H, t, J = 7.5); 2.08-1.96 (2H, m), 1.75-1.63 (2H, m). Calcd for
C19H23ClFN·0.2H2O: C 70.55, H 7.17, N 4.33; Found: C 70.73, H 7.36, N 4.45.
4.7.2. 2-(3-(4-Fluorophenoxy)propyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 7
Following the general alkylation procedure described above (section 4.7.), previously reported
alkylating agent 3-(4-fluorophenoxy)propyl methanesulfonate 4b23 was reacted with THIQ to give
compound 7 as a white crystalline HCl salt. Yield: 30%, mp: 196-197 ºC. 1H NMR (DMSO-d6): δ 11.23
(1H, brs), 7.25 (4H, m), 7.15 (2H, m), 6.95 (2H, m), 4,54 (1H, d, J = 15.6 Hz), 4.28 (1H, dd, J = 8.4,
15.6 Hz), 4.06 (2H, t, J = 6.0 Hz), 3.69 (1H, m), 3.24 (2H, m), 3.34 (2H, m), 3.00 (1H, m), 2.28 (2H, m).
Calcd for C18H21ClFNO: C 67.18, H 6.58, N 4.35; Found: C 67.10, H 6.55, N 4.38.
4.7.3. 3-((4-Fluorophenyl)thio)propyl 4-methylbenzenesulfonate, 4c
To a solution of 3-(4-fluorophenylthio)propan-1-ol23 (1 g, 5.4 mmol), Et3N (2 mL) in CH2Cl2 (10 mL)
was added at room temperature TsCl (1.54 g, 8.1 mmol). The mixture was stirred at room temperature
for 12 h, followed by direct purification using column chromatography on silica gel to provide 4c, 1.72
1
g, Yield 94%. H NMR (CDCl3): δ 7.77 (2H, J = 8.4 Hz), 7.34 (2H, J = 8.4 Hz), 7.30 (2H, dd, J = 5.4,
8.4 Hz), 6.97 (2H, J = 8.7 Hz), 4.13 (2H, t, J = 8.0 Hz), 2.86 (2H, J = 7.2 Hz), 1.89 (2H, m).
4.7.4. 2-(3-((4-Fluorophenyl)thio)propyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 8

Reacting alkylating agent 4c and THIQ under the general alkylation conditions (section 4.7.) produced
compound 8 as an HCl salt. Yield: 29%, mp: 172-173 ºC. 1H NMR (DMSO-d6): δ 11.31 (1H, m), 7.44
(2H, m), 7.22 (6H, m), 4.46 (1H, d, J = 15.3 Hz), 4.22 (1H, dd, J = 7.5, 15.3 Hz), 3.61 (1H, m), 3.27
(4H, m), 3.04 (2H, t, J = 6.0 Hz), 2.95 (1H, m), 2.08 (2H, m). Calcd for C18H21ClFNS: C 63.98, H 6.26,
N 4.15; Found: C 63.77, H 6.27, N 4.18.
4.7.5. 2-(3-((4-Fluorophenyl)sulfinyl)propyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 9
To a solution of 8 (0.2g, 0.59 mmol) in MeOH (5 mL) was added with stirring m-CPBA (0.2 g) at 0 ºC.
After stirring for 1 h. at room temperature, the mixture was diluted with Et2O (10 mL). A solid
precipitate was collected by filtration. Further crystallization from MeOH-Et2O gave 0.15g of 9 as an
1
HCl salt. 73% Yield: 73%, mp: 177-178 ºC. H NMR (DMSO-d6): δ 10.53 (1H, brs), 7.74 (2H, dd, J =
4.8, 8.4 Hz), 7.45 (2H, t, J = 8.7 Hz), 7.22 (4H, m), 4.50 (1H, d, J = 15.3 Hz), 4.25 (1H, dd, J = 7.5, 15.3
Hz), 3.63 (1H, m), 3.27 (3H, m), 3.14 (2H, m), 3.98 (1H, m), 2.88 (1H, m), 2.15 (1H, m), 2.00 (1H, m).
Calcd for C18H21ClFNOS·0.3H2O: C 60.17, H 5.89, N 3.90; Found: C 60.09, H 5.82, H 3.94.
4.7.6. 4-(3,4-Dihydroisoquinolin-2(1H)-yl)-1-(4-fluorophenyl)butan-1-one, 10
Using 4-chloro-1-(4-fluorophenyl)butan-1-one 6a as the alkylating agent, compound 10 was obtained as
a white solid (free base) following the general alkylation method (section 4.7.). Yield: 38%, mp: 104-
105 oC. 1H NMR (CDCl3): 7.96 (2H, dd, J = 5.4, 9.0 Hz), 6.98-7.11 (6H, m), 3.61 (2H, m), 3.03 (2H, t, J
= 7.2 Hz), 2.86 (2H, t, J = 6.0 Hz), 2.72 (2H, t, J = 6.0 Hz), 2.58 (2H, t, J = 6.9 Hz), 2.03 (2H, q, J = 6.9
Hz). Calcd for C19H20FNO: C 76.74, H 6.78, N 4.71; Found: C 76.51, H 6.83, N 4.69.
4.7.7. 4-(3,4-Dihydroisoquinolin-2(1H)-yl)-1-phenylbutan-1-one, 11
Following the general alkylation procedure (section 4.7.), 4-chloro-1-phenylbutan-1-one 6b was reacted
with THIQ to produce compound 11 as its HCl salt to afford a white crystalline solid (1.2g). Yield: 69%,
o
1
mp: 185-187 C. H NMR (DMSO-d6) δ 11.39 (s, 1H), 7.98 (2H, d, J = 7.6 Hz), 7.63 (1H, d, J = 7.3
Hz), 7.53 (2H, dd, J = 7.5 Hz), 7.28 – 7.17 (4H, m), 4.53 (1H, dd, J = 3.1, 15.4 Hz), 4.27 (1H, dd, J =
7.7, 15.6 Hz), 3.68 (1H, s), 3.35 – 3.17 (6H, m), 2.98 (1H, dd, J = 3.3, 12.6 Hz), 2.24 – 2.07 (2H, m). 13C
NMR (75 MHz, DMSO-d6) δ 199.18, 136.82, 133.77, 131.96, 129.19, 129.01, 128.95, 128.36, 127.95,
127.09, 127.00, 54.97, 51.91, 48.93, 35.68, 25.19, 18.40. Calcd for C19H22ClNO: C 72.25, H 7.02, N
4.43; Found: C 71.97, H 7.01, N 4.30.
4.7.8. 1-(4-Bromophenyl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)butan-1-one hydrochloride, 12a

Following the procedure in section 4.7., the alkylating agent 1-(4-bromophenyl)-4-chlorobutan-1-one 6c
1
was reacted with THIQ to obtain 12a as its HCl salt. Yield: 54%, mp: 211-212oC. H NMR (DMSO-d6)
δ 11.44 (1H, s), 7.90 (2H, dd, J = 8.5, 1.9 Hz), 7.73 (2H, dd, J = 8.5, 1.9 Hz), 7.29 – 7.16 (4H, m), 4.51
(1H, d, J = 15.5 Hz), 4.34 – 4.19 (1H, m), 3.69 – 3.62 (1H, m), 3.36 – 3.19 (6H, m), 2.97 (1H, d, J =
13
13.1 Hz), 2.13 (2H, q, J = 7.5 Hz). C NMR (75 MHz, DMSO-d6) δ 198.43, 135.84, 132.23, 131.96,
130.38, 128.99, 128.93, 127.94, 127.81, 127.07, 126.99, 54.90, 51.90, 48.92, 35.74, 25.17, 18.32. Calcd
for C19H21BrClNO : C 57.81, H 5.36, N 3.55; Found: C 57.67, H 5.29, N 3.65.
4.8. 4-(4-(3,4-Dihydroisoquinolin-2(1H)-yl)butanoyl)benzonitrile, 12
To a 25 mL flask equipped with a stirrer was added 12a (0.79 g, 2.6 mmol) in its free base form,
dimethylacetamide (DMAC) (15 mL), K4[Fe(CN)6].3H2O (0.93 g, 2.2 mmol), Na2CO3 (0.23 g, 2.2
mmol), KI (73.0 mg, 20 mol%), and Pd(OAc)2 (0.4 mol%). The flask was evacuated and filled with N2
and heated to 120 °C for 12 hours. Reaction conversion was monitored by TLC. Upon completion, the
reaction mixture was cooled to rt, 5% NH4OH (20 mL) was added, extracted with 20 mL x 3 of EtOAc,
the pooled organic layers was washed with brine (20 mL), dried over Na2SO4 and the filtrate was
concentrated in-vacuo. The crude was purified on silica by flash chromatography (Hexanes: EtOAc
gradient up to 80% EtOAc) to afford 12 which was converted to the HCl salt (0.508 g) as white crystals.
o
Yield: 68%, mp: 199-200 C. 1H NMR (DMSO-d6) δ 11.11 (1H, s), 8.12 (2H, dd, J = 1.8, 8.5 Hz), 8.03
(2H, dd, J = 2.1, 8.5 Hz), 7.31 – 7.16 (4H, m,), 4.55 (1H, dd, J = 3.2, 14.7 Hz), 4.28 (1H, dd, J = 7.7,
15.5 Hz), 3.70 (1H, d, J = 9.7 Hz), 3.36 – 3.21 (6H, m), 3.02 (1H, d, J = 3.6 Hz), 2.15 (2H, q, J = 6.9,
7.9 Hz).13C NMR (75MHz, DMSO-d6) δ 198.70, 140.17, 134.68, 134.28, 132.29, 128.58, 128.38,
126.52, 126.13, 125.56, 118.10, 115.77, 57.15, 55.93, 50.81, 36.51, 28.96, 22.03. Calcd for
C20H21ClN2O: C 70.48; H 6.21; N 8.22. Found: C 70.30, H 6.36, N 8.15.
4.9. 4-(4-(3,4-Dihydroisoquinolin-2(1H)-yl)butanoyl)benzamide, 13
A mixture of 12 (0.3 g, 1 mmol) and KOH (0.22 g, 4 mmol) in t-BuOH (10 mL) was refluxed for 12 h.
The reaction was allowed to cool to room temperature and extracted with EtOAc (15 mLx2). The
organic layers were pooled and washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate
reduced in-vacuo. The crude was purified by flash chromatography (Hexanes: EtOAc gradient up to
80% EtOAc) to obtain 13 (0.40 g) as white crystals. Yield: 46%, mp: 177-178oC. 1H NMR (DMSO-d6) δ
8.11 (1H, s), 7.97 (2H, dd, J = 2.5, 8.8 Hz), 7.92 (2H, dd, J = 2.5, 8.8 Hz), 7.54 (1H, s), 7.10 – 6.95 (4H,
m), 3.48 (2H, s), 3.06 (2H, t, J = 7.0 Hz), 2.71 (2H, t, J = 5.8 Hz), 2.59 (2H, t, J = 5.8 Hz), 2.48 (2H, t, J

13
= 7.1 Hz), 1.86 (2H, q, J = 7.1 Hz). C NMR (75 MHz, DMSO-d6) δ 200.07, 167.50, 139.17, 138.25,
135.30, 134.61, 128.75, 128.17, 128.15, 126.80, 126.28, 125.80, 57.32, 55.86, 50.85, 36.46, 29.06,
21.79. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.59; H, 6.70; N, 8.58.
4.10. 4-(3,4-Dihydroisoquinolin-2(1H)-yl)-1-(4-methoxyphenyl)butan-1-one hydrochloride, 14
Following the alkylation procedure described in section 4.7. above and using 4-chloro-1-(4-
methoxyphenyl)butan-1-one 6d as the alkylating agent, compound 14 was obtained as the HCl salt.
Yield: 60%, mp: 194-195oC. 1H NMR (DMSO-d6) δ 11.57 (1H, s), 7.97 (2H, dd, J = 2.1, 8.8 Hz), 7.31 –
7.19 (4H, m), 7.05 (2H, dd, J = 2.0, 8.7 Hz), 4.53 (1H, d, J = 15.5 Hz), 4.29 (1H, d, J = 11.1 Hz), 3.84
(3H, s), 3.67 (1H, s), 3.35 – 3.11 (6H, m), 2.99 (1H, d, J = 12.7 Hz), 2.16 (2H, q, J = 7.9 Hz,).13CNMR
(75 MHz, DMSO-d6) δ 197.55, 163.63, 132.01, 130.69, 129.83, 129.03, 128.94, 127.95, 127.10, 127.00,
114.35, 56.04, 55.06, 51.89, 48.89, 35.32, 25.19, 18.56. Calcd for C20H24ClNO2: C 69.45, H 6.99, N
4.05. Found: C 69.28; H 6.87, N 4.09.
4.11. 4-(3,4-Dihydroisoquinolin-2(1H)-yl)-1-(4-hydroxyphenyl)butan-1-one hydrochloride, 15
To a dry microwave vial equipped with a stirrer and charged with NaI (0.17 g, 1.10 mmol) in HBr
solution (48% aq., 10 mL) was added compound 14 in its free base form (0.31 g, 1.0 mmol). The
o
mixture was subjected to microwave heating at 110 C for 30 mins. The reaction vial was allowed to
cool to room temperature (rt) and the mixture directly purified using flash column chromatography
(gradient elution up to 80% EtOAc in hexane). The product obtained was converted to its HCl salt to
obtain compound 15 as a white flaky solid (0.21g). Yield: 63%, mp: 218-219oC. 1H NMR (DMSO-d6) δ
11.13 (1H, s), 10.51 (1H, s), 7.84 (2H, d, J = 8.0 Hz), 7.33 – 7.15 (4H, m), 6.87 (2H, d, J = 7.9 Hz), 4.48
(1H, s), 4.28 (1H, s), 3.66 (1H, s), 3.35 – 2.93 (7H, m), 2.11 (2H, t, J = 7.8 Hz).13C NMR (75 MHz,
DMSO-d6) δ 197.24, 162.69, 131.95, 130.85, 128.94, 128.40, 127.98, 127.09, 127.01, 115.69, 55.20,
52.14, 49.06, 35.00, 25.28, 18.74. Calcd. for C19H22ClNO2·0.75H2O; C 66.08, H 6.86, N 4.06; Found: C
66.17, H 6.49, N 4.03.
4.12. 1-(4-Chlorophenyl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)butan-1-one hydrochloride, 16
THIQ was alkylated with 4-chloro-1-(4-chlorophenyl)butan-1-one 6e and the product converted to its
o
1
HCl salt to afford compound 16 as its HCl salt. Yield: 61%, mp: 209-210 C. H NMR (DMSO-d6): δ
11.00 (brs, 1H), 7.97 (2H, d, J = 9.0 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.27-7.18 (4H, m), 5.4 (1H, d, J =
14.4 Hz), 4.31-4.23 (1H, m), 3.74-3.64 (1H, m), 3.50-3.38 (2H, m), 3.36-3.25 (4H, m), 3.08-2.90 (1H,
m), 2.17-2.10 (2H, m). 13C NMR (75 MHz, DMSO-d6): δ 198.25, 138.62, 135.55, 131.96, 130.29,

129.29, 128.97, 128.94, 127.97, 127.08, 127.08, 127.01, 54.93, 51.94, 48.95, 35.75, 25.17, 18.34. Calcd.
C19H21Cl2NO; C 65.15, H 6.04, N 4.00; Found: C 65.03, H 6.16, N 3.99.
Receptor Binding studies;
Binding affinities reported in Tables 1 and 2 were conducted by the National Institute of Mental Health
Psychoactive Drug Screening Program (NIMH-PDSP) unless otherwise stated. Details of the methods
and radioligands used for the binding assays were previously reported.3
Acknowledgements
This work would not have been possible without the continuing financial support of the NIH/NIGMS
SCORE grant number 2SC1GM08845, RCMI grant number G12 RR 03020 from NIMHD and a Title III
Grant to Florida A&M University. The work was also supported in part by the Pharmaceutical Research
Center NIH/NCRR 1C06-RR12512-01 Grant. 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.
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Design and Synthesis of Dual 5-HT1A and 5-HT7 Receptor Ligands
Edward Ofori,a Xue Y. Zhu,a Jagan R. Etukala,a Kwakye Peprah,a Kamansky R. Jordan,a Adia A. Adkins,a Barbara A.
Bricker,a X. P. Huang,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.
Graphical Abstract: