Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands

Article abstract of DOI:10.3109/14756366.2010.510471

A series of novel conformationally restricted N1-arylsulfonyl-3-aminoalkoxy indoles were designed and synthesized as 5-HT6 receptor (5-HT₆R) ligands. Many of the synthesized compounds have moderate in vitro-binding affinities at 5-HT₆R. The lead compound 8b (% inhibition=97.2 at 1 μM) from this series has good pharmacokinetic profile in male Wister rats and is active in animal model of cognition like Morris water maze. The details of chemistry, SAR, pharmacokinetics and pharmacological data constitute the subject matter of this report.

Full text of DOI:10.3109/14756366.2010.510471

Journal of Enzyme Inhibition and Medicinal Chemistry, 2011; 26(3): 341–349
© 2011 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2010.510471
ReseaRch aRtIcle
Design, synthesis and pharmacological evaluation of
conformationally restricted N-arylsulfonyl-3-aminoalkoxy
indoles as a potential 5-HT6 receptor ligands
Ramakrishna V.S. Nirogia1, Ramasastri Kambhampati1, Anand V. Daulatabad1, Parandhama Gudla1,
Mohammad Shaikh1, Pramod Kumar Achanta1, Anil K. Shinde1, Pramod Kumar Dubey2
1Discovery Research-Medicinal Chemistry, Suven Life Sciences Ltd, Serene Chambers, Road-5, Avenue-7, Banjara Hills,
Hyderabad, India, and 2Department of chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, India
abstract
A series of novel conformationally restricted N1-arylsulfonyl-3-aminoalkoxy indoles were designed and synthesized
as 5-HT receptor (5-HT6R) ligands. Many of the synthesized compounds have moderate in vitro-binding affinities
at 5-HT6R. The lead compound 8b (% inhibition=97.2 at 1 μM) from this series has good pharmacokinetic profile
in male6Wister rats and is active in animal model of cognition like Morris water maze. The details of chemistry, SAR,
pharmacokinetics and pharmacological data constitute the subject matter of this report.
Keywords: 5-HT6 receptor ligands, SAR, conformationally restricted, Morris water maze
Introduction
side chain in six member ring (fused cyclohexyl type)
that makes it conformationally restricted,14 viz., tetra-
hydrocarbazole derivatives (Compound 1 in Figure 1).
Although there was change in their spatial orientations,
the compounds were active towards 5-HT6R. Similarly,
GSK and Wyeth (Compound 4 and 5 in Figure 1) also
reported potent 5-HT6R ligands with fused indole
scaffold15,16; their focus also was mainly on side chain
and indole template. Although there was substantial
amount of work reported with constrained or fused
tryptamines, not much work was reported around con-
formationally restricted sulfonamides. Recently, we at
Suven reported constrained pyrrolidinyl indoles17 and
indole sulfonamides18,19, as 5-HT6R ligands (Structures
2 and 3 in Figure 1). ese series of compounds have
good affinity towards 5-HT6R with selectivity over other
known GPCRs. e compounds were active in in vivo
models of cognition like Morris water maze and NORT.
ese compounds have acceptable pharmacokinetic
profile for further development. Based on this knowl-
edge and observations, we have designed and synthe-
sized a series of 3-aminoalkoxy indole derivatives with
5-HT6R was first identified by molecular cloning in the
rat1,2, then in man3 and subsequently in mouse4. ese
receptors are predominantly expressed in the central
nervous system, including the olfactory tubercle, nucleus
accumbens, striatum, hippocampus and cerebral cortex,
with a notably higher level of expression in the striatum
of both rat and human brains. Due to the high presence
of 5-HT6R in brain, the 5-HT6R active ligands play an
important role in CNS disorders such as schizophrenia,
dementia, Alzheimer’s disease, Parkinson’s disease and
other neurodegenerative disorders. Various structurally
diverse small molecules containing the basic nitrogen
(for primary binding) and the two other aromatic sites
(for secondary binding) have been known to bind selec-
tively at 5-HT6R5–8. In the past decade various molecules
like SB-742457, SUVN-502, PRX-07034, SAM-531, SAM-
315, LY-483518 and Lu AE58054 were reported as 5-HT6R
ligands with positive clinical data9–13
.
Among these reported 5-HT6R ligands, a few were
reported with conformationally constrained features.
ere are reports by Glennon et al. with fused tryptamine
Address for Correspondence: Ramakrishna V.S. Nirogi, Tel: +91-40-23556038 / 23541142; Fax: +91-40-23541152; E-mail: ramakrishna_nirogi@
yahoo.co.in
(Received 04 May 2010; revised 14 July 2010; accepted 19 July 2010)
341

342 R. V. S. Nirogia et al.
N
N
N
O
O
O
N
S
O
N
O
N
H
S
O
O
Tetrahydrocarbazolederivative
Ki = 168 nM
Suven Life Sciences
Ki = 88 nM
Suven Life Sciences
Ki = 52 nM
1
2
3
N
N
O
NH
O
N
N
O2S
Cl
N
S
O
GSK
Ki = 1nM
S
O
O
O
This paper
%Inhibition(1 µM) = 97.2
Wyeth
Ki = 12 nM
8b
5
4
Figure 1. Chemical structures of compounds that bind to 5-HT6R.
Table 1. 5-HT6R binding affinities.
N
α
R2
R3
β
O
1
10
2
R1
3
9
B
6
A
8
7
N
4
S
O2
5
Compound
R1
2-H
R2
H
R3
5-HT6 Ki, nM
% Inhibition at 1 µM
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
H
H
—
—
82.3
97.2
—
3-Cl
H
2-Cl
H
H
464
127
—
2-OMe
2-OiPr
2-OMe
3-F
H
H
—
H
H
67.35
68.26
74.13
48.15
61.07
74.28
61.67
60.18
46.68
86.38
—
Me
H
H
—
Me
H
—
2-Cl
Me
H
—
2-Cl
Me
H
—
2-H
Me
H
—
2-OEt
2-H
H
—
H
Me
H
—
3-F
Me
H
—
2-OMe
Me
—
1-F
H
H
>500
5-HT receptor binding studies carried out at Novascreen, USA.: Human recombinant/HEK293 cells; Radioligand: [3H] LSD
(60–80 Ci/mmol). Final ligand concentration: 1.5nM, non-specific determinant: Methiothepin mesylate: [0.1 M]; reference compound:
Methiothepin mesylate, positive control: Methiothepin mesylate.
Note: e α- and β-methyl derivatives were tested as racemic mixture. e percent inhibition at 1 µM was an average of the assay
conducted in duplicate. e Ki value reported was an average of the assay conducted in duplicate.
constrained sulfonamide ring (Compound 8b in Figure
1). e lead compound, 8b was evaluated for pharma-
cokinetic parameters, % surrogate metabolism, human
Results and discussion
Structure activity relationship
As a part of our SAR studies compounds 8a–8o were
CYP3A4 and 2D6 liabilities. Further, the compound 8b
synthesized and evaluated for their binding affinities at
was tested in animal model of cognition, viz., Morris
human 5-HT6 receptor at 1 μM concentration and a few
of them for Ki values (Table 1). Among these compounds,
water maze. e results of these studies are discussed in
this communication.

Evaluation of N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands 343
the derivatives 8a, 8b, 8g, 8j and 8n were found to have
better binding affinity (74.13% inhibition), indicating
that the position of methyl group in the side chain has
an important role to play regarding a favourable confor-
mation for binding at 5-HT6R.
highest binding affinities with percent inhibition, at 1 μM
concentration, being 82.3%, 97.2%, 74.13%, 74.28% and
86.38%, respectively.
Substitutions tried on ring A were mostly 2-alkoxy
and 2-halo. e compound 8d, with 2-methoxy substitu-
tion, was active with Ki of 127 nM, while the compound
8c, with 2-chloro substitution has a Ki of 464 nM. is
shows that 2-chloro substitution was detrimental for the
activity.
Furthermore, some of the selected compounds
were profiled for their selectivity against a few recep-
tors including 5-HT receptor subtypes like 5-HT4,
5-HT7 and Muscarinic M1. Compounds were found to
have IC50 > 10,000 nM for these panel of CNS receptors
(Table 2).
e compound 8b was tested in cell-based assay
for 5-HT4 receptor binding along with the standard,
GR113808 (IC50 = <0.1 nM). e compound 8b has no
affinity (IC50 ≥ 10,000 nM) towards this receptor (see
Figure 2).
Similarly, the compound 8b was tested in cell-based
assays for 5-HT7 receptor and Muscarinic M1 receptor
binding, the standards being Clozapine (IC50 = 1 nM) and
Atropine (IC50 = 1 nM), respectively (see Figures 3 and 4).
Based on our SAR efforts in different tryptamine
type of compounds20, modification was carried out in
N,N-dimethylaminoethoxy side chain at C-3 of indole
with the insertion of methyl at α or β positions with
respect to terminal nitrogen. Among the various deriva-
tives prepared with this modified side chain, the most
active derivative 8n (86.38% inhibition) has 2-methoxy
substitution with methyl at β position in side chain. Its
analogue with methyl substitution at α position with
respect to the tertiary nitrogen (8f) has less binding
affinity (68.26% inhibition) towards 5-HT6R. e com-
pound 8a, without any substitution in the side chain,
has 82.3% inhibition, while the α-methyl analogue 8j
has slightly reduced potency, with 74.28% inhibition.
e derivative 8m with 3-fluoro substitution on ring A
and α-methyl group in the side chain was least active
with 46.68% inhibition at 5-HT6R. Its analogue 8g, with
β-methyl group in the side chain was found to have
Table 2. Selectivity profile of compounds on other receptors.
Compound
5-HT7
M1
5-HT4
IC50 nM
>10,000
>10,000
8a
8b
>10,000
>10,000
>10,000
>10,000
Compounds were tested for IC50 value in non-radioactive cell-
based assay.
Clozapine
IC50 = 1 nM
Compound 8b
IC50 ≥ 1000 nM
150
100
50
100
80
60
40
20
0
−1
0
1
2
3
4
0
1
2
3
4
−1
Log [nM]
Log [nM]
Figure 2. Evaluation of compound 8b for 5-HT7 receptor binding in cell-based assay.
GR113808
IC50 ≤ 0.1 nM
Compound 8b
95
75
55
35
15
−5
100
80
60
40
20
0
IC50 ≥ 10,000 nM
0
1
2
3
4
−1
0
1
2
3
4
−1
Log [nM]
Log [nM]
Figure 3. Evaluation of compound 8b for 5-HT4 receptor binding in cell-based assay.

344 R. V. S. Nirogia et al.
200
180
160
140
120
100
80
60
40
20
0
100
Compound 8b
Atropine
90
80
70
60
50
40
30
20
10
0
IC50 = 1 nM
IC50 ≥ 10,000
1
2
3
4
5
1
2
3
4
5
Log [nM]
Log [nM]
Figure 4. Evaluation of compound 8b for M1 receptor binding in cell-based assay.
As can be seen the compound was inactive towards these
receptors.
Table 3. Human cytochrome P450 inhibitory data and %
surrogate metabolism for compounds 8a and 8b.
IC50 (µM)
2D6
Surrogate % metabolism
Before testing the analogs in rodent behavioral assays
in vivo, the Pharmacokinetic and ADME surrogate prop-
erties were determined in rat, the species ultimately used
for behavioral models.
Compound
3A4
>45
Human
50.98
Wister rat
100
8a
8b
7.65
5.06
37.05
95.59
77.54
e active compounds, 8a and 8b from this series,
were tested for their human cytochrome P450 inhibi-
tory potential. e selected compound, 8b was found to
have an IC50 value of 5.06 μM and 37.05 μM for CYP2D6
and CYP3A4 respectively, while the compound 8a was
having IC50 values 7.65 μM and >45 μM for CYP2D6 and
CYP3A4 respectively. Further, the compounds 8a and
8b were evaluated for their surrogate % metabolism in
rat and human liver microsomes. e compound 8b has
high metabolism (95.59%) in human liver microsomes,
while it has relatively lower metabolism in rat liver
microsomes (77.54%). is is in contrast to the metabo-
lism shown by compound 8a. e compound 8a has
low metabolism in human liver microsomes (50.98%),
whereas it has high metabolism in rat liver microsomes
(100%) (Table 3)
e most potent 5-HT6R ligand, 8b from this series
was further evaluated for its pharmacokinetic profile
in male Wister rats (Table 4). e compound has high
volume of distribution (17.5 l/kg) with high systemic
clearance (8.2 2.8 l/h/kg). e dose of 10 mg/kg was
rapidly absorbed in rats and it had an elimination half
life (t1/2) of 1.49 0.26 h, when it was administered orally.
e bioavailability (%F) was found to be 35 5% and the
observed Cmax value was 0.31 0.05 μg/ml.
e cytochrome P450 inhibitory potential was determined using
isoform-selective assays and heterologously expressed human
CYP2D6 and CYP3A4. ese values are the mean of duplicate
determinations. Microsomal metabolic stability in Wistar rat and
human at 0.5h, Con. 2.5 µM.
Table 4. Pharmacokinetic profile of compound 8b in male Wister
rats.
Compound 8b
Dose mg/kg
Route
10
Oral
10
i.v.
n
3
3
Cmax (µg/ml)
Tmax (h)
0.31 0.05
0.67
1.65 0.13
0.08
AUCt (µg·h/ml)
AUCinf (µg·h/ml)
t1/2 (h)
1.2 0.13
1.2 0.14
1.49 0.26
8.2
3.4 0.27
3.4 0.27
1.59 0.28
2.8
CL (L/h/kg)
Vz (L/kg)
17.5
6.6
MRTlast
3.46
1.81
Cb/Cp (mg/kg/h)
F (%)
9.04 1.87
35
5
Fasted male Wistar rats, vehicle used: water for injection for both
oral and i.v. routes.
Dosing volumes: 10ml/kg for oral and 2ml/kg for i.v.
Since brain penetration was an important require-
ment for agents targeting CNS disorders, the steady state
brain penetration study for compound 8b was carried out
in male Wister rats (n= 4). 5 ml/h/kg constant infusion in
50% PEG was carried out over a period of 6 h. e steady
state brain and plasma ratio (Cb/Cp) in male Wister rats
was 9.04 1.86, confirming high brain penetration for
this compound.
Morris water maze test
e following protocol was followed for the experiment.
Protocol: Wister rats 10–12 weeks old were given 4
trials/day for 5 days; each trial was of 60 s with an ITI
of 600 s. Each trial started with the rat placed facing the
wall of the maze at one of the eight designated loca-
tions (0°, 90°, 180°, 270°) on 1st, 3rd and 5th day and
(45°, 135°, 225°, 315°) on 2nd and 4th day. Compound
8b was administered by gavages during the acquisi-
tion phase. Scopolamine was administered at a dose of
e compound 8b was further evaluated for its effi-
cacy in animal model of cognition like Morris water maze
test21.

Evaluation of N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands 345
50,000
40,000
30,000
20,000
10,000
0
Vehicle (1 ml/kg, p.o.) +
Scopolamine (0.6 – 0.8 mg/kg, i.p.)
Compound 8b (10 mg/kg, p.o.) +
Scopolamine (0.6 – 0.8 mg/kg, i.p.)
*
*
1
2
3
4
5
Days
Figure 5. Latency to target in Morris water maze task. Data represents mean SEM of latency to target recorded as time taken to locate
the hidden platform in water. Compound 8b at 10mg/kg p.o. reversed scopolamine-induced deficit and significant difference from
scopolamine-treated group is indicated with asterisk (unpaired t-test; *p<0.05).
spectrophotometer (Perkin-Elmer, Norwalk, CT).
Vehicle (1 ml/kg, p.o.) +
Electrospray ionization mass spectra were recorded on
1500
Scopolamine (0.6 – 0.8 mg/kg, i.p.)
a API 4000 triple quadrupole instrument (MDSSCIEX,
Concord, Ontario, Canada). 1H-NMR spectra were
Compound 8b (10 mg/kg, p.o.) +
Scopolamine (0.6 – 0.8 mg/kg, i.p.)
obtained on
a Bruker proton NMR spectrometer
1200
900
600
300
(Fallanden, Switzerland) at 400 MHz. Deuterated
reagents were used as solvents and were commer-
cially procured. Tetramethylsilane (TMS) was used
as an internal standard. Chemical shift values are
expressed in parts per million (d) and coupling con-
stants are expressed in Hz. Chromatography refers
to column chromatography performed using 60–120
mesh silica gel and executed under nitrogen pressure
(flash chromatography) conditions. All the reagents
and chemicals used were of ‘reagent grade’. Substituted
benzene sulfonyl chlorides were synthesized in-house
from the substituted benzene by chlorosulfona-
tion or from the corresponding amines via the diazo
intermediates.
*
**
1
2
3
4
5
Days
Figure 6. Path length to target in Morris water maze task.
Data represents mean SEM of path length recorded as path
taken to locate the hidden platform in water. Compound 8b at
10mg/kg p.o. reversed scopolamine-induced deficit and
significant difference from scopolamine-treated group is indicated
with asterisk (unpaired t-test *p<0.05; **p<0.01).
Radioligand binding assay for human 5-HT6
receptor
Compounds were investigated by the reported
procedure22,23. Briefly, receptor source and radioligand
used were human recombinant expressed in HEK-293
cells and [3H] LSD (60–80 Ci/mmol), respectively. e
final ligand concentration was 1.5 nM and non-specific
determinant was methiothepin mesylate (0.1 µM). e
reference compound and positive control was methiothe-
pin mesylate. Reactions were carried out in 50mM TRIS-
HCl (pH 7.4) containing 10 mM MgCl2, 0.5 mM EDTA for
60 min at 37 °C. e reaction was terminated by rapid
vacuum filtration onto glass fibre filters. Radioactivity
trapped onto the filters was determined and compared
to control values in order to ascertain any interactions of
test compound(s) with the cloned serotonin-5-HT6 bind-
ing site.
0.6 mg/kg on the first day and the dose of scopolamine
was gradually increased at a rate of 0.05 mg/kg/day.
Compound 8b was administered 30 min before the
administration of scopolamine. Compound 8b signifi-
cantly reversed the spatial memory deficit induced by
scopolamine in the Morris water maze trial indicating
cognitive improvement potential of the compound
(Figures 5 and 6).
Materials and Methods
Infra red spectra were recorded on KBr disc and in
solid state using Perkin-Elmer model 1600 FT-IR

346 R. V. S. Nirogia et al.
gene activity was measured. e data was analyzed using
Prism GraphPad software.
Determination of IC50 values for 5-HT4 receptor
binding, using cell-based functional assay
Recombinant CHO cells were established by trans-
fecting an expression vector encoding human 5-HT4a
gene and CRE-Luc reporter system. Isolated colonies
were screened with 1000 nM 5-HT for the induction of
luciferase reporter gene. e clone demonstrating high-
est 5-HT induced reporter gene was used in the evalu-
ation of the known and novel compounds. Increasing
concentrations of the compound were incubated with or
without 1000 nM 5-HT for antagonist or agonist mode,
respectively, for 5 h in 96 well plate. After incubation,
cells were harvested, lysed and reporter gene activity
was determined. e data was analyzed using Prism
GraphPad software.
Determination of IC50 values for acetylcholine receptor
M1 binding, using cell-based functional assay
Muscarinic acetylcholine receptor M1 was cloned into
an expression vector and transfected in CHO cells along
with CRE-Luc reporter system. Isolated colonies were
screened with 10,000 nM acetylcholine. Clones exhib-
iting highest acetylcholine dependent reporter gene
induction were utilized in the evaluation of known and
novel compounds. Increasing concentrations of the
compound were incubated with or without 10,000 nM
acetylcholine for antagonist or agonist mode, respec-
tively, for 5 h in 96 well plate. After incubation, cells were
harvested, lysed and reporter gene activity was deter-
mined. e data was analyzed using Prism GraphPad
software.
Determination of IC50 values for 5-HT7 receptor
binding, using cell-based functional assay
CHO cells were transfected with an expression vector
encoding rat 5-HT7 gene and CRE-Luc reporter system.
Colonies were isolated and screened with 1000 nM 5-HT
for the induction of luciferase reporter gene. e clone
demonstrating highest 5-HT induced reporter gene was
used in the evaluation of the known and novel com-
pounds. Increasing concentrations of the compound
were incubated with or without 1000 nM 5-HT for antag-
onist or agonist mode respectively for 5 h in 96 well plate.
After incubation, cells were harvested, lysed and reporter
Synthesis
e general synthetic strategy followed for the prepa-
ration of the title compounds was summarized in
Scheme 1. Various substituted indoxyls were synthe-
sized using literature methods24,25. More often, the
indoxyls were synthesized starting from the appropri-
ately substituted 2-bromobenzoic acids. e substi-
tuted 2-bromobenzoic acids were treated with Glycine
to obtain the diacids (2). ese diacids were then
O
O
COOH
c
COOH
Br
b
a
R1
R1
R1
N
N
H
COOH
2
3
1
O
R3
N
R3
N
O
O
N
R2
d
O
e
f
R2
R1
R1
N
R1
N
H
O
O
6
5
4
R3
R3
N
N
O
O
R2
R29
1
4
g
10
2
8
R4
7
R1
R1 3
N
O2S
N
5
S
6
O2
R4
Br
7
8
Scheme 1. Reagents: (a) Glycine, water, NaOH; (b) DMF, NaOAc, Ac2O; (c) Na2SO3, MeOH/water; (d) THF, K2CO3, Me2NCH2CH2Cl, reflux;
(e) NaOH, MeOH, reflux; (f) 2-Bromobenzenesulfonyl chloride, THF, KOH powder; (g) DMA, CH3COOK, P(PPh3)4Pd, 120°C.

Evaluation of N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands 347
subjected to cyclization in presence of acetic anhydride
under reduced pressure to obtain a thick oily mass. e
residue, thus obtained, was purified by flash chroma-
tography over silica gel using 1% TEA in ethyl acetate
to get intermediate 6, which was identified by IR, NMR
and mass spectral analysis.
and N,N-dimethylformamide at higher temperature
(120 °C) followed by, in situ, decarboxylation to obtain
the corresponding 1-acetyl-3-acetyloxy indoles (3). e
compounds (3) were deacetylated under mild condi-
tions using sodium sulfite and methanol/water (1:1) at
room temperature to obtain indoxyls (4), which were
used after purification for further synthesis.
Various alternative methods were used for the etheri-
fication of indoxyls; the best system was found to be the
one involving dimethylaminoethyl chloride in tetrahy-
drofuran in presence of potassium carbonate. Further,
for the derivatization of N1 of indole, potassium hydrox-
ide powder and tetrahydrofuran was found to be the best
condition for sulfonylation. e N1 sulfonylated com-
pound was further treated with dry potassium acetate
and tetrakis triphenyl phosphino palladium (0) catalyst
in N,N-dimethyl acetamide (DMA) solvent to obtain the
desired compounds 8a–8r.
Potassium hydroxide powder (60.35 mmol) was added
to a solution of intermediate 6 (30.1 mmol) in tetrahy-
drofuran (150 ml) and stirred the reaction mass for 1 h at
25–30 °C under nitrogen atmosphere. 2-Bromobenzene-
sulfonyl chloride (45.2 mmol) dissolved in tetrahydro-
furan (100 ml) was added to the reaction mass drop wise
over a period of 15 min. e reaction mass was stirred
at 25–30 °C for 60 min. After completion (TLC) of the
reaction, the solvent was distilled off completely under
reduced pressure to get oil. Water (250 ml) was added to
the residual mass and extracted the product with dichlo-
romethane (2 × 200 ml). e combined organic layer was
washedwithbrinesolution, driedoveranhydroussodium
sulphate and concentrated under reduced pressure. e
residual mass, so obtained, was purified by flash chroma-
tography over silica gel using 1% TEA in ethyl acetate to
get intermediate 7, which was identified by IR, NMR and
mass spectral analyses.
Dry potassium acetate (2.006 mmol) was added to a
solution of intermediate 7 (1.18 mol) in DMA followed
by tetrakis triphenyl phosphine palladium (0) catalyst
(0.059 mmol) under nitrogen atmosphere. e reac-
tion mass was heated to 110–120 °C and stirred for 1 h.
After completion of the reaction (TLC), the reaction
mass was cooled to 25–30 °C. Water (50 ml) was added
and extracted product into ethyl acetate (100 ml × 3). e
combined organic layer was washed with brine solution,
dried over anhydrous sodium sulphate and concentrated
under reduced pressure to obtain oily product. e resi-
due, thus obtained, was purified by flash chromatogra-
phy over silica gel using 1% methanol in chloroform to
get compound 8d, which was identified by IR, NMR and
mass spectral analysis.
Synthesis of compounds with α-methyl and β-methyl
substituents in the side chain were obtained following
essentially the same route, using appropriately substi-
tuted dimethylamino ethyl chlorides, that were procured
commercially.
experimental
General (representative) procedure for the synthesis
of compound 8d
Potassium carbonate (872 mmol) was added to a solu-
tion of 1-acetyl-6-chloro indoxyl (4) (436.3 mmol) in
tetrahydrofuran (950 ml) and stirred at 25–30°C for
90 min. e free base of (2-Chloroethyl)dimethylam-
ine hydrochloride (1308 mmol) was liberated and
extracted into toluene by stirring over 350 ml toluene
and a solution of sodium hydroxide (1308 mmol) in
water (250 ml). e organic layer containing the free
base was then separated and transferred to the above
reaction mixture. e reaction mass was heated to
reflux at 90–95°C and maintained for 4 h. After comple-
tion of the reaction (TLC), the reaction mass was cooled
to 25–30°C and filtered the solid at suction and washed
with ethyl acetate (250 ml × 3). e filtrate was collected
and concentrated under reduced pressure to obtain
oily product. e residue, thus obtained, was purified
by flash chromatography over silica gel using 1% trieth-
ylamine (TEA) in ethyl acetate to get intermediate 5.
e intermediate 5 (61.5 mmol) dissolved in metha-
nol (100 ml) and was added to a solution of sodium
hydroxide (123 mmol) in water (100 ml), heated to
60–65°C and maintained for 2 h. After completion of
the reaction (TLC), the mass was cooled to 25–30°C
and distilled off methanol and water mixture to obtain
oily mass. Water (1000 ml) was added to the residual
mass and extracted the product with ethyl acetate
(3 × 100 ml). e separated ethyl acetate layers were
combined, washed with brine solution (100 ml), dried
over anhydrous sodium sulphate and concentrated
10-(2-N,N-Dimethylaminoethoxy)-5-Thia-4b-
azaindeno [2,1-a]indene-5,5-Dioxide (8a). ick oil; IR
(KBr, cm−1): 1179, 1334, 1441, 1620, 2944; mass (m/z):
1
343.2 [M + H]+; H-NMR (ppm): 2.37 (6H, s, N(CH3)2),
2.75–2.78 (2H, t, CH2-N(CH3)2), 4.38–4.41 (2H, t, CH2O),
7.24–7.26 (1H, m, C2-H), 7.38–7.46 (2H, m, C3-H and
C7-H), 7.66–7.69 (3H, m, C1-H, C4-H and C8-H), 7.79–
7.81 (1H, d, J = 7.84 Hz, C9-H), 7.93–7.94 (1H, d, J = 7.84
Hz, C6-H); HRMS: [M + H]+ C18H19N2O3S calc. 343.1116,
found. 343.1112.
3-Chloro-10-(2-N,N-Dimethylaminoethoxy)-5-Thia-4-
b-aza indeno [2,1-a]indene-5,5-Dioxide (8b). M.R (°C):
104.5–109.8; IR (KBr, cm−1): 1175, 1310, 1397, 1630, 2789,
3620; mass (m/z): 377.1 [M + H]+; 1H-NMR (ppm): 2.36 (6H,
s, N(CH3)2), 2.74–2.77 (2H, t, CH2-N(CH3)2), 4.35–4.38 (2H, t,
CH2O); 7.20–7.23 (1H, dd, J=8.50, 1.77 Hz, C2-H), 7.46–7.48
(1H, m, C8-H), 7.57–7.60 (1H, d, J=8.47 Hz, C1-H), 7.67–
7.69 (2H, m, C4-H and C7-H), 7.79–7.81 (1H, d, J=7.88 Hz,
C6-H), 7.92–7.94 (1H, d, J=7.83 Hz, C9-H); HRMS: [M + H]+
C18H18ClN2O3S calc. 377.0726, found. 377.0730.

348 R. V. S. Nirogia et al.
2-Chloro-10-(2-N,N-Dimethylaminoethoxy)-5-ia-4-
b-aza indeno [2,1-a]indene-5,5-Dioxide (8c). ick oil;
IR (KBr, cm−1): 1174, 1317, 1433, 1621, 3430; mass (m/z):
Dioxide (8h). ick oil; IR (KBr, cm−1): 1172, 1331, 1317,
1
1437, 1620, 3435; mass (m/z): 391.3 [M + H]+; H-NMR
(ppm): 1.15–1.16 (3H, d, J = 5.4 Hz, CH3-CH), 2.37 (6H, s,
N(CH3)2), 3.01–3.11 (1H, m, CH-N(CH3)2), 4.10–4.11 (1H,
m, O-CH2), 4.29–4.34 (1H, m, O-CH2), 7.32–7.35 (1H, dd,
J = 8.60, 1.88 Hz, C3-H), 7.48–7.49 (1H, m, C7-H), 7.58–7.60
(1H, d, J = 8.70 Hz, C4-H), 7.64–7.65 (1H, d, J = 1.68 Hz,
C1-H), 7.66–7.68 (1H, m, C8-H), 7.80–7.82 (1H, d, J = 7.80
Hz, C6-H), 7.91–7.93 (1H, d, J = 7.8 Hz, C9-H); HRMS: [M +
H]+ C19H20ClN2O3S calc. 391.0883, found. 391.0886.
1
377.1 [M + H]+; H-NMR (ppm): 2.38 (6H, s, N(CH3)2),
2.75–2.78 (2H, t, CH2-N(CH3)2), 4.34–4.37 (2H, t, CH2O);
7.32–7.35 (1H, dd, J = 8.65, 1.86 Hz, C3-H), 7.48–7.50 (1H,
m, C8-H), 7.58–7.60 (1H, d, J = 8.77 Hz, C4-H), 7.65–7.68
(2H, m, C1-H and C7-H), 7.80–7.82 (1H, d, J = 7.86 Hz,
C6-H), 7.94–7.96 (1H, d, J = 7.84 Hz, C9-H); HRMS: [M +
H]+ C18H18ClN2O3S calc. 377.0726, found. 377.0732.
2-Methoxy-10-(2-N,N-Dimethylaminoethoxy)-5-ia-
4b-azaindeno[2,1-a]indene-5,5-Dioxide (8d). ick
oil; IR (KBr, cm−1): 1155, 1170, 1324, 1442, 1614, 3436;
( )
2-Chloro-10-(2-N,N-Dimethylamino-1-
methylethoxy)-5-ia-4b-aza indeno [2,1-a]indene-5,5-
Dioxide (8i). M.R (°C): 88.6–92.0; IR (KBr, cm−1): 1177, 1346,
1443, 1598, 2931, 3436; mass (m/z): 391.2 [M + H]+; 1H-NMR
(ppm): 1.34–1.35 (3H, d, J=6.24 Hz, CH3-CH), 2.37 (6H, s,
N(CH3)2), 2.49–2.53 (1H, m, CH2-N(CH3)2), 2.76–2.81 (1H,
m, CH2-N(CH3)2), 4.52–4.57 (1H, m, J=6.24 Hz, CH-CH3),
7.32–7.34 (1H, dd, J=8.56, 1.92 Hz, C3-H), 7.47–7.49 (1H,
m, C7-H), 7.58–7.60 (1H, d, J=8.64 Hz, C4-H), 7.67–7.68
(2H, m, C1-H and C8-H), 7.80–7.82 (1H, d, J=7.88 Hz,
C6-H), 7.98–7.99 (1H, d, J=7.84 Hz, C9-H); HRMS: [M + H]+
C19H20ClN2O3S calc. 391.0883, found. 391.0887.
( )10-(2-N,N-Dimethylamino-2-methylethoxy)-5-ia-
4b-aza indeno [2,1-a]indene-5,5-Dioxide (8j). M.R (°C):
60.1–63.3; IR (KBr, cm−1): 1180, 1335, 1441, 1619, 2967;
mass (m/z): 357.1 [M + H]+; H-NMR (ppm): 1.15–1.17
(3H, d, CH3CH), 2.37 (6H, s, N(CH3)2), 3.01–3.09 (1H, m,
CH-CH3), 4.09–4.11 (1H, dd, O-CH2), 4.30–4.34 (1H, dd,
O-CH2), 7.32–7.34 (1H, dd, J=8.56, 1.92 Hz, C3-H), 7.24–
7.26 (1H, m, C2-H), 7.38–7.46 (2H, m, C6-H and C7-H),
7.66–7.69 (3H, m, C1-H, C4-H and C8-H), 7.79–7.81 (1H,
d, J=7.84 Hz, C9-H); HRMS: [M + H]+ C19H21N2O3S calc.
357.1273, found. 357.1270.
1
mass (m/z): 373.1 [M + H]+; H-NMR (ppm): 2.37 (6H,
s, N(CH3)2), 2.74–2.77 (2H, t, CH2-N(CH3)2), 3.85 (3H,
s, OCH3), 4.33–4.36 (2H, t, CH2O); 6.98–7.01 (1H, dd,
J = 8.8, 2.0 Hz, C3-H), 7.10–7.11 (1H, d, J = 2.36 Hz, C1-H),
7.44–7.45 (1H, m, C7-H), 7.55–7.57 (1H, d, J = 8.88 Hz,
C4-H), 7.63–7.67 (1H, m, C8-H), 7.78–7.80 (1H, d, J = 7.8
Hz, C6-H), 7.90–7.92 (1H, d, J = 7.8 Hz, C9-H); HRMS: [M +
H]+ C19H21N2O4S calc. 373.1222, found. 373.1218.
2-Isopropoxy-10-(2-N,N-Dimethylaminoethoxy)-5-
ia-4b-azaindeno[2,1-a]indene-5,5-Dioxide (8e). M.R
(°C): 70.4–74.1; IR (KBr, cm−1): 1177, 1333, 1461, 1686, 2975,
3461; mass (m/z): 401.4 [M + H]+; 1H-NMR (ppm): 1.35–1.37
(6H, d, (CH3)2CH-), 2.37 (6H, s, N(CH3)2), 2.74–2.77 (2H, t,
CH2-N(CH3)2), 4.33–4.36 (2H, t, CH2O); 4.53–4.59 (1H, sep-
tet, CH(CH3)2), 6.97–7.00 (1H, dd, J=8.87. 2.42 Hz, C3-H),
7.12 (1H, d, J=2.29 Hz, C1-H), 7.43–7.45 (1H, m, C8-H),
7.54–7.56 (1H, d, J=8.82 Hz, C4-H), 7.64 (1H, m, C7-H),
7.77–7.79 (1H, d, C6-H), 7.90–7.92 (1H, d, C9-H); HRMS:
[M + H]+ C21H25N2O4S calc. 401.1535, found. 401.1530.
1
( )
2-Methoxy-10-(2-N,N-Dimethylamino-2-
methylethoxy)-5-ia-4b-azaindeno[2,1-a]indene-5,5-Di-
oxide (8f). M.R (°C): 77.6–80.1; IR (KBr, cm−1): 1175, 1324,
1437, 1626, 2962, 3431; mass (m/z): 387.3 [M + H]+; 1H-NMR
(ppm): 1.15–1.17 (3H, d, CH3-CH-), 2.37 (6H, s, N(CH3)2),
3.01–3.09 (1H, m, CH-CH3), 3.87 (3H, s, OCH3), 4.09–4.11
(1H, dd, CH2-CH), 4.30–4.34 (1H, dd, O-CH2), 6.98–7.01
(1H, dd, J=8.8, 2.36 Hz, C3-H), 7.09–7.10 (1H, d, J=2.36 Hz,
C1-H), 7.43–7.45 (1H, m, C8-H), 7.55–7.58 (1H, d, J=8.80
Hz, C4-H), 7.63–7.65 (1H, m, C7-H), 7.78–7.80 (1H, d, J=7.8
Hz, C6-H), 7.88–7.90 (1H, d, J=7.76 Hz, C9-H); HRMS: [M +
H]+ C20H23N2O4S calc. 387.1378, found. 387.1375.
2-Ethoxy-10-(2-N,N-Dimethylaminoethoxy)-5-ia-4-
b-aza indeno [2,1-a]indene-5,5-Dioxide (8k). M.R (°C):
101.2–103.8; IR (KBr, cm−1): 1175, 1234, 1315, 1441, 1622,
1
3615; mass (m/z): 387.5 [M + H]+; H-NMR (ppm): 1.40–
1.46 (3H, t, CH3CH2O), 2.37 (6H, s, N(CH3)2), 2.74–2.77
(2H, t, CH2-N(CH3)2), 4.05–4.10 (2H, q, CH2O), 4.33–4.36
(2H, t, CH2O), 6.98–7.01 (1H, dd, J = 8.92, 2.44 Hz, C3-H),
7.09–7.10 (1H, d, J = 2.32 Hz, C1-H), 7.43–7.45 (1H, m,
C7-H), 7.54–7.57 (1H, d, J = 8.80 Hz, C4-H), 7.62–7.64 (1H,
m, C6-H), 7.77–7.79 (1H, d, J = 7.88 Hz, C8-H), 7.90–7.92
(1H, d, J = 7.84 Hz, C9-H); HRMS: [M + H]+ C20H23N2O4S
calc. 387.1378, found. 387.1375.
( )
3-Fluoro-10-(2-N,N-Dimethylamino-1-
methylethoxy)-5-ia-4b-aza indeno [2,1-a]indene-5,5-
Dioxide (8g). M.R (°C): 82.6–85.5; IR (KBr, cm−1): 1184,
1337, 1617, 2721, 3434; mass (m/z): 375.2 [M + H]+;
1H-NMR (ppm): 1.33–1.35 (3H, d, J = 5.4 Hz, CH3-CH),
2.37 (6H, s, N(CH3)2), 2.49–2.54 (1H, m, CH2-N(CH3)2),
2.75–2.80 (1H, m, CH2-N(CH3)2), 4.55–4.60 (1H, m, J = 5.4
Hz, CH-CH3), 6.99–7.0 (1H, m, J = 2.2 Hz, C2-H), 7.39–7.40
(1H, dd, C4-H), 7.44–7.46 (1H, m, C7-H), 7.61–7.66 (2H,
m, C1-H and C8-H), 7.79–7.81 (1H, d, J = 7.8 Hz, C9-H),
7.93–7.95 (1H, d, J = 7.8 Hz, C6-H); HRMS: [M + H]+
C19H20FN2O3S calc. 375.1178, found. 375.1175.
( )
10-(2-N,N-Dimethylamino-1-methylethoxy)-5-
ia-4b-aza indeno [2,1-a]indene-5,5-Dioxide (8l). ick
oil; IR (KBr, cm−1): 1180, 1335, 1441, 1614, 2940; mass
(m/z): 357.2 [M + H]+; H-NMR (ppm): 1.34–1.36 (3H,
1
d, J = 6.20 Hz, CH3-CH), 2.37 (6H, s, N(CH3)2), 2.51–2.55
(1H, m, CH2-N(CH3)2), 2.76–2.81 (1H, m, CH2-N(CH3)2),
4.61–4.65 (1H, m, J = 6.20 Hz, CH-CH3), 7.24–7.26 (1H, m,
C2-H), 7.35–7.46 (2H, m, C3-H and C7-H), 7.63–7.69 (3H,
m, C1-H, C4-H and C8-H), 7.79–7.81 (1H, d, J = 7.84 Hz,
C9-H), 7.95–7.97 (1H, d, J = 7.84 Hz, C6-H); HRMS: [M +
H]+ C19H21N2O3S calc. 357.1273, found. 357.1278.
( )
2-Chloro-10-(2-N,N-Dimethylamino-2-
( )
3-Fluoro-10-(2-N,N-Dimethylamino-2-
methylethoxy)-5-ia-4b-aza indeno [2,1-a]indene-5,5-
methylethoxy)-5-ia-4b-aza indeno [2,1-a]indene-5,5-

Evaluation of N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands 349
Dioxide (8m). M.R (°C): 108.9–111.9; IR (KBr, cm−1): 1154,
3. Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz
JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW. Cloning,
characterization, and chromosomal localization of a human 5-HT6
serotonin receptor. J Neurochem 1996; 66:47–56.
1184, 1336, 1618, 2778, 2968; mass (m/z): 375.2 [M + H]+;
1H-NMR (ppm): 1.15–1.17 (3H, d, CH3CH), 2.37 (6H, s,
N(CH3)2), 3.04–3.09 (1H, m, CH-CH3), 4.12–4.16 (1H, dd,
CH2-CH), 4.32–4.36 (1H, dd, CH2-CH), 6.99–7.0 (1H, m,
J=2.2 Hz, C3-H), 7.39–7.40 (1H, dd, C4-H),7.44–7.46(1H,m,
C7-H), 7.59–7.68 (2H, m, C1-H and C8-H), 7.79–7.81 (1H, d,
J=7.8 Hz, C9-H), 7.87–7.89 (1H, d, J=7.8 Hz, C6-H); HRMS:
[M + H]+ C19H20FN2O3S calc. 375.1178, found. 375.1175.
4. Kohen R, Fashingbauer LA, Heidmann DE, Guthrie CR, Hamblin
MW. Cloning of the mouse 5-HT6 serotonin receptor and
mutagenesis studies of the third cytoplasmic loop. Brain Res Mol
Brain Res 2001; 90:110–117.
5. Liu KG, Robichaud AJ. 5-HT6 antagonists as potential treatment
for cognitive dysfunction. Drug Dev Res 2009; 70:145–168.
6. Werner JG, Cornelis JV. e serotonin 5-HT6 receptor: a viable
drug target for treating cognitive deficits in Alzheimer’s disease.
Exp Rev Neurother 2009; 9:1073–1085.
( )
2-Methoxy-10-(2-N,N-Dimethylamino-1-
methylethoxy)-5-ia-4b-aza indeno [2,1-a]indene-5-
7. Witty D, Mahmood A, Tsu TC. Advances in the design of 5-HT6
receptor ligands with therapeutic potential. Prog Med Chem 2009;
48:163–224.
,5-Dioxide (8n). ick oil; IR (KBr, cm−1): 1180, 1335,
1
1441, 1614, 2940; mass (m/z): 387.2 [M + H]+; H-NMR
(ppm): 1.34–1.36 (3H, d, J = 6.20 Hz, CH3-CH), 2.37 (6H,
s, N(CH3)2), 2.51–2.55 (1H, m, CH2-N(CH3)2), 2.76–2.81
(1H, m, CH2-N(CH3)2), 3.85 (3H, s, OCH3), 4.61–4.65 (1H,
m, J = 6.20 Hz, CH-CH3), 6.98–7.01 (1H, dd, J = 8.8, 2.0 Hz,
C3-H), 7.10–7.11 (1H, d, J = 2.36 Hz, C1-H), 7.44–7.45 (1H,
m, C7-H), 7.55–7.57 (1H, d, J = 8.88 Hz, C4-H), 7.63–7.67
(1H, m, C8-H), 7.78–7.80 (1H, d, J = 7.8 Hz, C6-H), 7.90–
7.92 (1H, d, J = 7.8 Hz, C9-H); HRMS: [M + H]+ C20H23N2O4S
calc. 387.1378, found. 387.1375.
8. Gerard R, Herve S. 5-HT6 receptor antagonists as potential
therapeutics for cognitive impairment. Curr Top in Med Chem 2010;
10:207–221.
9. Zvartau-Hind M. 11th Int. Conf. on Alz. Dis. Rel. Dis. (July 26–31,
Chicago), 2008; Abst 03–04–06.
10. Mather-Edwards G. 11th Int. Conf. on Alz. Dis. Rel. Dis. (July 26–31,
Chicago), 2008; Abst P4–341.
11. Lesem M. 11th Int. Cong. of Schiz. Res. (March 28–April 1, Colorado
Springs), 2007.
12. Nirogi R, Kambhampati R, Shinde A, Kandikere V, Mudigonda K,
Bhyrapuneni G, Jayarajan P, Abraham R, Mulla SM, Jasti V. 12th Int.
Conf. on Alz. Dis. Rel. Dis. (July 11–16, Vienna), 2009; Abst P1–25.
13. Maher-Edwards G, Zvartau-Hind M, Hunter AJ, Michael G, Gillian
H, Gemma J, Maria D, Pauline W. Double-Blind, Controlled Phase
II Study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer’s
Disease. Curr Alz Res 2010; 7:374–385.
14. Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage
JE, McBride A, Rauser L, Hufeisen S, Lee DK. 2-Substituted
tryptamines: agents with selectivity for 5-HT(6) serotonin
receptors. J Med Chem 2000; 43:1011–1018.
15. Cole DC, Mahwah MA. Sulfonyltetrahydro-3H-benzo(E)indole-8-
amine compounds as 5-HT6 ligands. US 2005/0101596.
16. Liu KG, Lo JR, Comery TA, Zhang GM, Zhang JY, Kowal DM, Smith
DL, Di L, Kerns EH, Schechter LE, Robichaud AJ. A regiospecific
synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6
ligands. Bioorg Med Chem Lett 2008; 18:3929–3931.
1-Fluoro-10-(2-N,N-Dimethylaminoethoxy)-5-ia-4-
b-aza indeno [2,1-a]indene-5,5-Dioxide (8o). ick oil;
IR (KBr, cm−1): 1179, 1334, 1441, 1620, 2944; mass (m/z):
1
361.1 [M + H]+; H-NMR (ppm): 2.37 (6H, s, N(CH3)2),
2.75–2.78 (2H, t, CH2-N(CH3)2), 4.38–4.41 (2H, t, CH2O),
6.72–6.73 (1H, m, C2-H), 7.1–7.21 (2H, m, C3-H and
C4-H), 7.31–7.33 (1H, m, C8-H), 7.55–7.57 (1H, d, J = 8.88
Hz, C7-H), 7.78–7.80 (1H, d, J= 7.8 Hz, C6-H), 7.90–7.92
(1H, d, J = 7.8 Hz, C9-H); HRMS: [M + H]+ C18H18FN2O3S
calc. 361.1022, found. 361.1017.
conclusion
e results indicate that these analogues were having
moderate activity profile towards 5-HT6R. e most
potent compound 8b from this series was active in ani-
mal model of cognition like Morris water maze, having
good oral bioavailability (%F = 35) and brain penetration.
Further SAR modification to improve the binding affini-
ties, metabolic stability and to make these compounds
adequately brain penetrant, is under progress.
17. Ramakrishna VSN, Kambhampati RS, Shirsath VS, Jasti V.
Novel indeno[2,1A] indanes and isoindolo[2,1-A]indoles WO
2005/066184.
18. Jasti V, Ramakrishna VSN, Kambhampati RS, Battula SR,
Veerareddy A, Rao VSVV. Novel tetracyclic arylsulfonyl indoles
having serotonin receptor affinity useful as therapeutic agents,
process for their preparation and pharmaceutical compositions
containing them. WO 2004/000849.
19. Ramakrishna VSN, Kambhampati RS, Shirsath VS, Jasti V.
Benzothiazino indoles. WO 2005/005439.
20. Ramakrishna VSN, Kambhampati RS, Shirsath VS, Jasti V.
Tetracyclic 3-substituted indoles having serotonin receptor
affinity. WO 2004/055026.
Declaration of interest
21. Woolley ML, Bentley JC, Sleight AJ, Marsden CA, Fone KC. A role
for 5-ht6 receptors in retention of spatial learning in the Morris
water maze. Neuropharmacology 2001; 41:210–219.
22. Assays performed at Novascreen Biosciences Corporation,
Hanover, Maryland, USA.
e authors report no conflicts of interest. e authors
alone are responsible for the content and writing of the
paper.
23. Monsma FJ Jr., Shen Y, Ward RP, Hamblin MW, Sibley DR.
Molecular cloning and expression of novel serotonin receptor with
high affinity for tricyclic psychotropic drugs. Mol Pharmacol 1993;
43:320–327.
24. Conway SC, Gribble WG, Synthesis of 1-(Phenylsulfonyl)Indol-
3-yl Trifluoromethanesulfonate. Heterocycles. 1990; 30:627–633.
25. Su HCF, Tsou KC. Synthesis of bromo-substituted indoxyl esters for
cytochemical demonstration of esterase activity. J Am Chem Soc
1960; 82:1187–1189.
References
1. Monsma FJ Jr, Shen Y, Ward RP, Hamblin MW, Sibley DR. Cloning
and expression of a novel serotonin receptor with high affinity for
tricyclic psychotropic drugs. Mol Pharmacol 1993; 43:320–327.
2. Ruat M, Traiffort E, Arrang JM, Tardivel-Lacombe J, Diaz J, Leurs
R, Schwartz JC. A novel rat serotonin (5-HT6) receptor: molecular
cloning, localization and stimulation of cAMP accumulation.
Biochem Biophys Res Commun 1993; 193:268–276.