Synthesis and structureactivity relationship of novel conformationally restricted analogues of serotonin as 5-HT6 receptor ligands

Article abstract of DOI:10.3109/14756366.2011.595713

5-Hydroxytryptamine 6 receptors (5-HT₆R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structureactivity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT₆ receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT₆R with the K_i of 23.4 and 20.5nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze.

Full text of DOI:10.3109/14756366.2011.595713

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(3): 443–450
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.595713
RESEARCH ARTICLE
Synthesis and structure–activity relationship of novel
conformationally restricted analogues of serotonin as
5-HT6 receptor ligands
Ramakrishna V. S. Nirogi1, Ramasastri Kambhampati1, Prabhakar Kothmirkar1,
Jagadishbabu Konda1, rinath Reddy Bandyala1, Parandhama Gudla1, Sobhanadri Arepalli1,
Narasimhareddy P. Gangadasari1, Anil K. Shinde1, Amol D. Deshpande1, Adireddy Dwarampudi1,
Anil K. Chindhe1, and Pramod Kumar Dubey2
1Discovery Research-Medicinal Chemistry, Suven Life Sciences Ltd., Banjara Hills, Hyderabad, India and 2Department of
Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, India
Abstract
5-Hydroxytryptamine 6 receptors (5-HT6R) are being perceived as the possible target for treatment of cognitive
disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structure–
activity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and
N-benzyl substituents as 5-HT receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity
at 5-HT6R with the Ki of 23.4 an6d 20.5nM, respectively. The lead compound from the series 15a has acceptable ADME
properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task
(NORT) and water maze.
Keywords: Heck reaction, cognition, NORT, serotonin, 5-HT6
Introduction
and SUVN-50217 are the phase I clinical candidates as of
today.
5-Hydroxytryptamine 6 receptor (5-HT6R), a member
of GPCR family, plays an important role in cognition
and memory formation, due to its exclusive localiza-
tion in the brain regions associated with learning and
memory1–3. Blockage of 5-HT6R enhances the cognitive
process through cholinergic and glutamatergic neu-
rotransmission, which demonstrates the therapeutic
usefulness of this receptor in the central nervous system
(CNS)-mediated disorders such as schizophrenia and
Tryptamine derivatives are reported as 5-HT6 receptor
ligands18 as they have the structural resemblance with
the 5-hydroxytryptamine (5-HT). N-Phenylsulphonyl-
5-methoxy-N,N-dimethyltryptamine (MS-245) (Figure
1) is a 5-HT6R antagonist reported by Glennon et al. in
early 200018. Russell et al.19 have reported conforma-
tional constraint of the basic amine of the tryptamine on
the adjacent phenyl ring with flexible N-arylsulphonyl
motif leading to a compound with good binding affin-
ity of 7.2 nM towards the 5-HT6 receptor (Figure 1, 36).
Mooradian et al.20 has published the 5-HT6R bind-
ing activity for some carbazole derivatives, which are
in fact the conformationally restricted tryptamines.
Several other research groups attempted modifica-
tions of N,N-dimethylamino ethyl side chain at C3 of
Alzheimer’s disease (AD)4–10
.
Up to date, a lot of research work has been done in
identifying different 5-HT6R agonists and antagonists,
out of which a few of them are currently in the different
stages of clinical development. SAM-53111, SB-74245712,13
and LY-483518 (SGS-518)14,15 are the phase II clinical
candidates, whereas Lu AE5805416, PRX-07034, SYN-1148
Address for Correspondence: Ramakrishna V.S. Nirogi, Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7,
Banjara Hills, Hyderabad–500 034, India. Tel: +91-40-23556038/23541142. Fax: +91-40-23541152. E-mail: ramakrishna_nirogi@yahoo.co.in
(Received 19 February 2011; revised 04 May 2011; accepted 06 June 2011)
443

444 R.V.S. Nirogi et al.
Figure 1. Structures of I and reported 5-HT6 ligands.
indole of MS-245. Pyrrolidine derivatives (Figure 1,
ALX1161) have been reported by Abate et al.21 as potent
5-HT6 ligands. Most studied compound from these
modifications ALX1161 has shown excellent affinity
and selectivity.22,23 is compound was shown to pos-
sess excellent brain exposure (brain/plasma 23.4, i.p.)
and reasonable oral bioavailability in rats (%F = 17).
Liu et al.24 reported the novel class of azepinoindoles
by rigidifying the amino side chain to C2 position of
indole (Figure 1, 37) to overcome the selectivity issue
of 1-sulphonyl tryptamine over its 5-HT subtypes.
Subsequently, additional classes where the pyrroli-
dine and piperidine rings are directly attached to C3
of indole (Figure 1, 38 and 39) were also reported by
Cole et al.25
Interestingly, though a lot of work has already been
published on the effect of changes made in the nature
of side chain of tryptamines with respect to activity, to
the best of our knowledge there are almost no studies
reported so far to understand the relative necessity or
required orientation of N-arylsulphonyl moiety with
respect to activity. Hence, in our efforts for identifying
the novel 5-HT6R ligands, we thought of constraining
the MS-245 compound by tethering the arylsulphonyl
groups to C2 of indole, which will result in tetracy-
clic compounds I (Figure 1). e proposed tetracyclic
derivatives of tryptamines, compounds I, include all the
components of MS-245 like arylsulphonyl substitution
and side chain at C3 of indole. Since the compounds I
bear all the necessary pharmacophoric functionalities
like a basic amine, the aromatic rings in a triangular
arrangement as well as the sulphonamide linkage7, it was
expected to bind to 5-HT6 receptors. Once the desired
activity is achieved in the series, it was further aimed to
see the effect of replacing the sulphonyl moiety of the
tetracyclic compounds with a methylene or a carbonyl
group and study the effect of the change on the binding
to 5-HT6 receptors.
Methods
General considerations
Infrared spectra were recorded in KBr disc and in solid
state using Perkin-Elmer model 1600 FT-IR spectropho-
tometer (Perkin-Elmer, Norwalk, CT). Electrospray ion-
ization mass spectra were recorded on a API 4000 triple
quadruple instrument (MDS-SCIEX, Concord, Ontario,
1
Canada). H-NMR spectra were obtained on a Bruker
proton NMR spectrometer (Fallanden, Switzerland) at
400 MHz. Deuterated reagents were used as solvents
and were commercially procured. Tetramethylsilane
(TMS) was used as an internal standard. Chemical shift
values are expressed in parts per million (δ) and cou-
pling constants 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’.
Various substituted indoles were synthesized in-house
with the help of reported procedures and were char-
acterized thoroughly before using. Substituted ben-
zenesulphonyl chlorides were synthesized in-house
from the substituted benzene by chlorosulphonation
or from the corresponding amines using the diazo
Journal of Enzyme Inhibition and Medicinal Chemistry

Novel conformationally restricted analogues of serotonin as 5-HT6R ligands 445
intermediates. Substituted benzyl chlorides were
3.21–3.25 (2H, m, CH2CH2NMe2), 3.34–3.44 (2H, m,
CH2CH2NMe2), 5.18 (2H, s, C5-CH2), 6.98–7.04 (1H,
dt, J= 9.23, 2.52 Hz), 7.36–7.42 (1H, dt), 7.43–7.49 (2H,
m), 7.53–7.56 (1H, dd, J= 10.2, 2.44 Hz), 7.60–7.62 (1H,
d, J= 7.44 Hz), 8.04–8.06 (1H, d, J= 7.52 Hz); 13C-NMR
(DMSO-d6): δ 19.41, 41.67, 48.52, 56.26, 100.44, 100.49,
104.27, 104.50, 109.38, 109.64, 110.85, 110.95, 121.48,
124.00, 127.4, 128.11, 130.09, 131.65, 131.70, 131.80,
142.22, 142.27, 155.95, 158.25; HRMS: [M+H]+ C19H19FN2
calc. 295.1610, found. 295.1610.
either commercially obtained or synthesized in-house
from the substituted toluene by N-chlorosuccinimide
reaction. Similarly, substituted benzoyl chlorides were
synthesized in-house from the corresponding benzoic
acids using thionyl chloride.
Synthesis
General procedure for the synthesis of derivatives 6–20
1-(2′-Bromophenylsulphonyl)-N,N-dimethyltryptamine
derivative (0.286 mmol) was taken in
a 100-mL
three-necked round-bottomed flask, along with N,N-
dimethylacetamide (10 mL), potassium acetate (0.343
mmol, 33.6 mg) and tetrakis (triphenyl phosphine)
palladium(0), (0.0143 mmol, 16.5 mg). e reaction
mixture was maintained under nitrogen atmosphere at
125–130°C with stirring for 5 h. After the completion of
reaction (TLC), excess of dimethylacetamide was dis-
tilled off under reduced pressure. e residue obtained
was purified by silica gel column chromatography using
methanol:ethyl acetate (2:8) as an eluent. e com-
pounds 6–20 were characterized by the spectral data.
General procedure for the synthesis of derivatives 31–35
1-(2′-Bromobenzoyl)-N,N-dimethyltryptamine
derivative (0.286 mmol) was taken in
a 100-mL,
three-necked round-bottomed flask, along with N,N-
dimethylacetamide (10 mL), potassium acetate (0.343
mmol, 33.6 mg) and tetrakis (triphenylphosphine)
palladium(0), (0.0143 mmol, 16.5 mg). e reaction
mixture was maintained under nitrogen atmosphere at
125–130°C with stirring for 5 h. After the completion of
reaction (TLC), excess of dimethylacetamide was dis-
tilled off under reduced pressure. e residue obtained
was purified by silica gel column chromatography using
methanol:ethyl acetate (2:8) as an eluent. e com-
pounds 31–35 were characterized by the following spec-
tral data.
2-Methoxy-10-[(2-N,N-dimethylamino-2-methyl)ethyl]
benzo[d]isothiazolo[3,2-a]indol-S,S-dioxide (15). Yield:
68.5%; Mp 202.4–205.3°C; IR (cm−1): 2933, 1461, 1438,
1323, 1174, 582; Mass (m/z): 371.2 (M+H)+; 1H-NMR
(CDCl3): δ 1.00–1.02 (3H, d, J = 6.44 Hz, CHCH3),
2.44 (6H, s, N(CH3)2), 2.81–2.87 (1H, dd, J = 13.44 Hz,
CH2CH(CH3)NMe2), 2.93–3.10 (1H, m, CH(CH3)NMe2),
3.18–3.23 (1H, dd, J = 13.44, 3.20 Hz, CH2CH(CH3)
NMe2), 3.87 (3H, s, OCH3), 6.99–7.02 (2H, m), 7.45–7.59
(1H, m), 7.58–7.62 (1H, m), 7.64–7.69 (1H, m), 7.79–7.85
(2H, m), 13C-NMR (CDCl3): δ 14.12, 28.23, 40.78, 55.75,
60.02, 103.59, 112.50, 114.78, 116.05, 122.26, 122.66,
127.34, 128.22, 128.44, 130.21, 133.91, 134.76, 138.11,
156.28; HRMS: [M+H]+ C20H22N2O3S calc. 371.1429,
found. 371.1422.
2-Phenyl-10-(2-N,N-dimethylaminoethyl)isoindolo[2,1-a]
indol-5-one (31). Yield; 56.1 %; Mp 148–151°C; IR (cm−1):
2939, 1716, 1606, 1458, 1361, 885, 758; Mass (m/z):
1
367.3 (M+H)+; H-NMR (CDCl3): δ 2.39 (6H, s, N(CH3)2),
3.07–3.11 (2H, m, CH2CH2NMe2), 3.65–3.70 (2H, m,
CH2CH2NMe2), 7.32–7.39 (2H, m), 7.44–7.48 (2H, m),
7.52–7.55 (2H, m), 7.57–7.64 (4H, m), 7.77–7.80 (1H,
dd), 7.91–7.93 (1H, d, J= 7.84 Hz); 13C-NMR (DMSO-
d6): δ 27.33, 50.18, 63.86, 117.91, 123.93, 124.31, 126.94,
130.21, 130.68, 131.91, 132.32, 133.93, 134.02, 137.34,
138.02, 139.18, 139.50, 139.99, 140.54, 141.32, 145.41,
166.52; HRMS: [M+H]+ C25H22N2O calc 367.1810, found.
367.1801.
General procedure for the synthesis of derivatives 21–30
1-(2′-Bromobenzyl)-N,N-dimethyltryptamine derivative
(0.286mmol)wastakenina100-mL,three-neckedround-
bottomed flask, along with N,N-dimethylacetamide
(10 mL), potassium acetate (0.343 mmol, 33.6 mg) and
tetrakis (triphenyl phosphine) palladium(0), (0.0143
mmol, 16.5 mg). e reaction mixture was maintained
under nitrogen atmosphere at 125–130°C with stirring
for 5 h. After the completion of reaction (TLC), excess of
dimethylacetamide was distilled off under reduced pres-
sure. e residue obtained was purified by silica gel col-
umn chromatography using methanol:ethyl acetate (2:8)
as an eluent. e compounds 21–30 were characterized
by the spectral data.
Radioligand-binding assay for human 5-HT6 receptor
Compounds were investigated by the reported proce-
dure. In brief, receptor source and radioligand used were
human recombinant expressed in HEK-293 cells and [3H]
LSD (60–80 Ci/mmol), respectively. e final ligand con-
centration was 1.5 nM and non-specific determinant was
methiothepin mesylate (0.1 SYMBOL 109\f “Symbol”M).
e reference compound and positive control is methio-
thepin mesylate.
Reactions were carried out in 50 mM 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 with
control values in order to ascertain any interactions of
test compound(s) with the cloned serotonin–5-HT6-
binding site.
2-Fluoro-10-(2-N,N-dimethylaminoethyl)isoindolo[2,1-a]
indole (24). Light brown syrupy mass. Yield: 66.2%;
IR (cm−1): 2952, 2458, 1483, 1189, 791, 720; Mass (m/z):
1
295.3 (M+H)+; H-NMR (CDCl3): δ 2.86 (6H, s, N(CH3)2),
© 2012 Informa UK, Ltd.

446 R.V.S. Nirogi et al.
reductive formylation procedures involving formalde-
hyde and sodium cyanoborohydride, to the substituted
tryptamines, 1.
Novel Object Recognition Task
e lead compound 15a was tested in Novel Object
Recognition Task (NORT)26 using the detailed protocol
given in the Supporting information.
e ESI-MS of all the compounds exhibited the
[M+H]+ as the parent ion. Additionally, there is a peak at
[M-72+H]+ with the typical loss of dimethylaminoethyl
Results and discussion
1
fragment. H-NMR spectra of all the compounds exhib-
ited the prominent presence of dimethylaminoethyl
side-chain protons along with the aromatic protons. All
the other spectral data was found to be satisfactory to
confirm their structures.
Chemistry
e general synthetic strategy used for the title com-
pounds 6–35 has been summarized in Scheme 1. Various
substituted tryptamines 1 were either obtained commer-
cially or synthesized using various literature methods27.
Treatment of substituted tryptamines 1, with the desired
substituted 2-bromoarylsulphonyl/carbonyl/alkyl chlo-
rides in presence of appropriate base and the polar apro-
tic solvents yielded the intermediates, N-arylsulphonyl/
carbonyl/alkyl tryptamines 2, which were isolated and
fully characterized. e N-(2′-bromo)arylsulphonyl/
carbonyl/alkyl tryptamines 2 were cyclized using various
palladium catalysts and well-known literature proce-
dures of Heck reaction28–30, to get the desired compounds
6–35.
Synthesis of α-substituted/unsubstituted tryptam-
ines was achieved by the route depicted in Scheme 2.
e various substituted indoles were converted to their
3-formyl derivatives 3, by the known literature methods.
ese substituted 3-formyl indoles were then condensed
with nitro alkane under alkaline conditions. e adducts
4 were reduced using lithium aluminium hydride to the
corresponding α-substituted/unsubstituted tryptamines
5, which were further dimethylated using well-known
Structure–activity relationship
All the synthesized compounds 6–20 (X = SO2), 21–30
(X = CH2) and 31–35 (X = CO) were evaluated for their
binding affinity towards 5-HT6 receptor using the radio-
ligand-binding assay. e inhibitory constant, Ki values
were summarized in Table 1.
All the sulphonamide compounds 6–19 show high to
moderate affinity towards the receptor with the excep-
tion of the compound 20 (Ki = >1000 nM). e lower
alkoxy racemate analogues 15 (R1 = 2-OCH3, R2 = CH3,
Ki = 11.6 nM) and 17 (R1 = 2-OC2H5, R2 = CH3, Ki = 11.1 nM)
show high affinity towards the receptor. e other ana-
logues with no substitution at R2 position (R2 = H) resulted
in 3–8-fold decrease in binding affinities compared with
those of substituted ones (R2 = CH3 or C2H5) as can be
seen by comparing the Ki values of compounds 6 (R2 = H,
Ki = 246 nM) and 14 (R2 = H, Ki = 96 nM) with compounds
11 (R2 = CH3, Ki = 87 nM) and 15 (R2 = CH3, Ki = 11.6 nM),
respectively.
Scheme 1. Reagents and conditions: (a) base, DMF at 10°C, followed by Ar-X-Cl, 3–4 h, (b) tetrakis triphenylphosphine palladium
(Pd(P(Ph)3)4), CH3COOK, DMA, 120–130°C, 3–4h.
Scheme 2. Reagents and conditions: (a) nitro alkane, piperidine, acetic acid, benzene, reflux, 5–6h, (b) LiAlH4, THF, reflux, 1–2h, (c)
CH3OH, HCHO, NaBH3CN, pH 6.5 with CH3COOH, reflux, 2h.
Journal of Enzyme Inhibition and Medicinal Chemistry

Novel conformationally restricted analogues of serotonin as 5-HT6R ligands 447
Table 1. Ki values for compounds 6–35 on 5-HT6 (h) receptors.
.
Compound No.
X
R1
-H
R2
-H
R3
-H
Ki (nM)
246
6
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-SO2-
-CH2-
-CH2-
-CH2-
-CH2-
-CH2-
-CH2-
-CH2-
-CH2-
-CH2-
-CH2-
-CO-
-CO-
-CO-
-CO-
-CO-
7
2-F
-H
-H
267
116a
8
2-F
-CH3
-H
-H
9
2-CH3
4-Cl
8-OCH3
-H
269
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
-H
126
-H
-CH3
-H
-H
87.6a
26.8
54.1a
96
2-Ph
-H
2-Br
-CH3
-H
-H
2-OCH3
2-OCH3
2-OCH3
2-OC2H5
2-OBn
2-O-iPr
2-OCH2cyHex
2-O-iPr
2-OCH3
2-OCH3
2-F
-H
-CH3
-C2H5
-CH3
-CH3
-CH3
-CH3
-CH3
-H
-H
11.6a
28.3a
11.1a
100a
239a
>1000a
73.2a
86.7
279a
24.3
80.7
104
-H
-H
-H
-H
-H
-H
-H
-CH3
-H
-H
-H
2-Cl
-H
-H
1-Cl, 4-CH3
2,4-di-F
3,4-Benzo
2-SCH3
2-F
-H
-H
-H
-H
153
-H
-H
92.6
49.7
37.6
84.6
296a
393
-H
-H
-H
7-Cl
-H
2-Ph
-H
-H
CH3
-H
-H
2-Cl
-H
-H
-H
-H
135
197.0a
2-OCH3
-CH3
-H
Ki values were calculated from the % binding at eight concentrations (n=2), experimental protocol is described in Methods section.
ae Ki values indicate that these are the results of racemic compounds.
Apart from the alkoxy substitution at second position
(R1) in sulphonamide analogues, the other substituents
like halogens (2-F, 2-Br, 4-Cl), lower alkyl groups (2-CH3)
and 2-phenyl groups are well-tolerated for 5-HT6 recep-
tor binding as can be seen from the Ki values. e higher
alkoxyanalogueslike2-O-iPr(compound19,Ki = 239 nM),
2-OBn (compound 18, Ki = 100 nM), 2-OCH2cyHex
(compound 20, Ki = >1000 nM) show decrease in bind-
ing affinity as compared with its lower alkoxy 2-OCH3
(compound 15, Ki = 11.6 nM) and 2-OC2H5 (compound
17, Ki = 11.1 nM) analogues, indicating that lower alkoxy
groups are more suitable at this position. Replacement
of methyl group at R2 position by ethyl group resulted in
2–3-fold decrease in binding affinity as can been seen by
comparing the Ki values of compound 15 (Ki = 11.6 nM)
with 16 (Ki = 28.3 nM).
e other synthesized benzyl analogues 21–30 and
benzoyl analogues 31–35 show the reverse trend, where
substitution at R2 position with alkyl groups lead to
decrease in binding affinities as compared with their
© 2012 Informa UK, Ltd.

448 R.V.S. Nirogi et al.
unsubstituted analogues as can be seen by comparing
the Ki values of compound 22 (R2 = H, Ki = 86 nM) and 34
(R2 = H, Ki = 135 nM) with 23 (R2 = CH3, Ki = 279 nM) and
32 (R2 = CH3, Ki = 296 nM), respectively.
assay was conducted at MDS Pharma Services. e assay
measured changes in cAMP level in a recombinant CHO
cell line in agonist and antagonist mode. e compound
did not exhibit any agonist activity but showed full antag-
onism of 5-HT6-induced cAMP accumulation. In fact, the
compound reduced basal cAMP level indicating a inverse
agonist activity.
To estimate the oral bioavailability in rats, pharma-
cokinetic studies were performed on compound 15a and
the results are given in Table 3.
In order to assess the brain-penetrating ability of com-
pound 15a, it was dosed at 3mg/kg, i.p. to male Wistar
rats and sacrificed at 30 min post dose and brain and
plasma exposure were measured using LC-MS/MS. e
brain exposure of compound 15a was 772 ng/g, which
is equivalent to 2.08 µM with a Cb/Cp of 6.24, indicating
that the compound has high brain penetration.
Compound 15a was further evaluated for its cogni-
tive potential in NORT paradigm and Morris water maze.
Compound 15a has shown improvement in cognitive
performance at 1 mg/kg oral dose in NORT model (Figure
2). Most of the memory-enhancing compounds show an
inverted U-shaped dose response. is could be one of
the reasons why the compound showed positive effect
only at the lowest tested doses. In Morris water maze
model, it has significantly reversed the scopolamine-in-
duced memory deficit at 1 and 3 mg/kg, p.o. dose, which
was apparent from lesser target latency (Figure 3).
Among the benzyl analogues (X = CH2), compounds
24 with fluoro substitution at second position in ring A
shows the highest affinity with Ki value 24.3 nM, whereas
its chloro analogue (compound 25, Ki = 80.7 nM) shows
nearly 3-fold decrease in binding affinity. e inser-
tion of additional fluoro group (ring A) in compound 24
resulted in 6-fold decrease in binding affinity (compound
27, Ki = 153 nM), whereas insertion of chloro at seventh
position in ring D in compound 24 resulted in marginal
decrease in affinity towards receptor (compound 30,
Ki = 37.6 nM).
Based on the Ki results, the most potent sulphon-
amides, 2-methoxy 15 and 2-ethoxy 17 analogues with
α-methyl substitution in the side chain were resolved
and tested for their specific rotation and binding affinities
at 5-HT6R. e specific rotation and Ki values are sum-
marized in Table 2. In both of the cases, laevo isomers
are more active than dextro isomers, indicating that the
specific orientation of the dimethylamino substitution in
the side chain is important as far as the 5-HT6 receptor
binding is concerned.
Compounds 15a and 17a were further evaluated for
the CYP liability and metabolic stability studies. e
compounds strongly inhibited CYP2D6 human enzyme
with IC50’s of 0.49 and 1.2 µM for 15a and 17a, respec-
tively. Inhibition of the more abundant CYP3A4 appears
to be not an issue with this series with IC50’s estimated to
be above 35 µM for both 15a and 17a. Compound 17a
is extensively metabolized (92.1% and 57.9%) compared
with compound 15a (73.8% and 41.8%) in rat and human,
respectively.
e compound 15a was tested for its functional ago-
nism/antagonism. e functional agonism/antagonism
Table 2. e comparative in vitro data of racemic and resolved
compounds 15 and 17.
Specific rotation
[α]D at 25°C
(C=0.5% in
CHCl3)
Compound
No.
Compound
identification
Ki (5-HT6)
nM
15
Racemic
—
11.6
23.4
141
15a
15b
17
17a
17b
Laevo isomer
Dextro isomer
Racemic
(−) 9.4°
(+) 9.1°
11.1
20.8
120
Figure 2. Novel Object Recognition Task. *p < 0.05 (Student’s ‘t’
test)
Laevo isomer
Dextro isomer
(−) 5.6°
(+) 5.3°
Table 3. Pharmacokinetic profile of compound 15a.
Compound 15a
Route
Oral
i.v.
n
3
3
Dose (mg/kg)
C
max (ng/mL)
AUCt (ng h/mL)
106 137
t
1/2 (h)
Vz (mL/kg)
339,516
11,107
Cl (mL/h/kg)
140,737
%F
3
3
51 71
2.44 1.37
1.6 0.5
16.6
855 457
633 198
5049
Journal of Enzyme Inhibition and Medicinal Chemistry

Novel conformationally restricted analogues of serotonin as 5-HT6R ligands 449
Figure 3. Effect of compound 15a in Morris water maze (acute dosing). *p < 0.05 (one way ANNOVA followed by Dunnett’s ‘t’ test).
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derivatives. e major finding of the study, however, was
the role of alkyl substitution at α-position of the amino
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Acknowledgement
e authors wish to acknowledge the support received
from Mr. Venkateswarlu Jasti, CEO, Suven Life Sciences
Ltd., Hyderabad, India.
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Declaration of interest
e authors report no declarations of interest.
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Supporting information
Analytical data of rest of the compounds, protocols for
Morris water maze test, NORT and CYP inhibition assay
were given in the Supporting information.
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