N-arylsulfonylindole derivatives as serotonin 5-HT6 receptor ligands

Article abstract of DOI:10.1021/jm010943m

A series of N₁-arylsulfonyltryptamines were found to be potent ligands of the human serotonin 5-HT₆ receptor with the 5-methoxy-1-benzenesulfonyl analogue (19) having the highest affinity. Additionally, it was discovered that a group such as 3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl in the 2-position of the indole ring (43) can replace the arylsulfonyl substituent in the 1-position with no loss of affinity. This suggested that the binding conformation of the aminoethyl side chain at this receptor was toward the 4-position of the indole ring and was supported by the fact that the 4-(aminoethyl)indoles (45) also displayed high affinity, as did the conformationally rigid 1,3,4,5-tetrahydrobenz[c,d]indole (49). Molecular modeling showed that 19, 43, and 45 all had low-energy conformers that overlaid well onto 49. Both 19 and 49 had good selectivity over other serotonin receptors tested, with 49 also showing excellent selectivity over all dopamine receptors. In a functional adenylate cyclase stimulation assay, 19 and 49 had no agonist activity, whereas 45 behaved as a partial agonist. Finally, it was shown that 19 had good activity in the 5-HT_2A centrally mediated mescaline-induced head twitch assay, which implies that it is brain-penetrant.

Full text of DOI:10.1021/jm010943m

J . Med. Chem. 2001, 44, 3881-3895
3881
N-Ar ylsu lfon ylin d ole Der iva tives a s Ser oton in 5-HT6 Recep tor Liga n d s
Michael G. N. Russell,* Robert J . Baker, Laura Barden, Margaret S. Beer, Linda Bristow,
Howard B. Broughton, Michael Knowles, George McAllister, Smita Patel, and J ose´ L. Castro*
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road,
Harlow, Essex CM20 2QR, United Kingdom
Received J une 6, 2001
A series of N1-arylsulfonyltryptamines were found to be potent ligands of the human serotonin
5-HT6 receptor with the 5-methoxy-1-benzenesulfonyl analogue (19) having the highest affinity.
Additionally, it was discovered that a group such as 3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl
in the 2-position of the indole ring (43) can replace the arylsulfonyl substituent in the 1-position
with no loss of affinity. This suggested that the binding conformation of the aminoethyl side
chain at this receptor was toward the 4-position of the indole ring and was supported by the
fact that the 4-(aminoethyl)indoles (45) also displayed high affinity, as did the conformationally
rigid 1,3,4,5-tetrahydrobenz[c,d]indole (49). Molecular modeling showed that 19, 43, and 45
all had low-energy conformers that overlaid well onto 49. Both 19 and 49 had good selectivity
over other serotonin receptors tested, with 49 also showing excellent selectivity over all
dopamine receptors. In a functional adenylate cyclase stimulation assay, 19 and 49 had no
agonist activity, whereas 45 behaved as a partial agonist. Finally, it was shown that 19 had
good activity in the 5-HT2A centrally mediated mescaline-induced head twitch assay, which
implies that it is brain-penetrant.
Ch a r t 1
In tr od u ction
The serotonin (5-HT) receptors have been subdivided
into seven main classes (5-HT1-7).1 The cloned rat 5-HT6
receptor was found to consist of a polypeptide chain of
437 or 436 amino acids with little homology to other
5-HT receptors,2,3 while the cloned human 5-HT6 recep-
tor contains 440 amino acids and shares 96% homology
with the rat receptor within the transmembrane region.4
Hybridization studies and northern blots in the rat
indicate that the density of 5-HT6 receptor mRNA is
highest in the olfactory tubercule, followed by the
striatum, nucleus accumbens, dentate gyrus, and CA1,
CA2, and CA3 regions of the hippocampus.2,3,5 The
5-HT6 receptor mRNA seems to be present almost
exclusively in the brain since very little was detected
in peripheral tissues. Interestingly, several atypical
antipsychotic drugs (e.g., clozapine and loxapine), as
well as tricyclic antidepressants (e.g., amoxipine and
clomiprimine), bind with high affinity to the 5-HT6
receptor, which may indeed play a role in their mech-
anisms of action.6
Recent studies in rats treated with 5-HT6 receptor
antisense oligonucleotides (AOs) have shown that they
elicit a yawning, stretching, and chewing behavioral
syndrome which was dose-dependently antagonized by
the muscarinic antagonist atropine, implying that 5-HT6
receptors may control cholinergic transmission.7 In
addition, treatment with AOs significantly inhibited the
increase in 5-HT release from the prefrontal cortex
produced by conditioned fear stress, suggesting that
5-HT6 receptors may be involved in certain anxiety
disorders.8
Recently, the benzenesulfonamides Ro 04-6790 (1,
Chart 1) and Ro 63-0563 (2), and the benzo[b]thiophe-
nesulfonamide SB-271046 (3), have been reported as
selective 5-HT6 receptor antagonists.9,10 This has en-
abled some in vivo investigations of the function of the
5-HT6 receptor to be performed. Thus, Ro 04-6790 was
shown to inhibit the rotational behavior of 6-hydroxy-
dopamine (6-OHDA) lesioned rats induced by treatment
with the muscarinic antagonists scopolamine and atro-
pine, supporting the experiments with AOs that the
5-HT6 receptor is involved in the control of acetylcholine
neurotransmission.11 The same compound also produced
a stretching behavior in rats that appears to be medi-
ated by an increase in cholinergic transmission in the
CNS.12
In vivo microdialysis studies in the freely moving rat
have shown that administration of SB-271046 produced
a significant increase in extracellular levels of both
glutamate and aspartate within the frontal cortex,
suggesting that 5-HT6 receptor antagonists may have
therapeutic utility in the treatment of cognitive dys-
function.13 SB-271046 and Ro 04-6790 also produced
To further elucidate the functional role of 5-HT6
receptors, potent and selective ligands are required.
* Corresponding author: Tel 44 1279 440419; fax 44 1279 440390;
e-mail michael_russell@merck.com.
10.1021/jm010943m CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/06/2001

3882 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Russell et al.
Sch em e 1a
Sch em e 2a
a
Reagents: (i) PhSO2Cl, Bu4NHSO4, NaOH(aq), CH2Cl2; (ii)
R1R2NH, K2CO3, i-PrOH.
a
Reagents: (i) RCl, Bu4NHSO4, NaOH(aq), CH2Cl2; (ii) H2, 10%
Pd/C, 5 N HCl(aq).
(18) was synthesized by protecting the free amino group
of the corresponding tryptamine with a Boc group before
reaction with benzenesulfonyl chloride as before to give
7. The Boc group was then removed with trifluoroacetic
acid.
potent anticonvulsant activity in the rat maximal elec-
troshock seizure threshold (MEST) test, although the
magnitude is modest in comparison to known antiepi-
leptic drugs.14
The 5-hydroxy-substituted analogue (35) was pre-
pared by dimethylating 5-(benzyloxy)tryptamine hydro-
chloride, which was then reacted with benzenesulfonyl
chloride to give the 5-benzyloxy analogue (34) (Scheme
4). The benzyl group was then removed by hydrogena-
tion over palladium hydroxide to give 35. The other
5-hydroxy analogues (36 and 37) were prepared in a
similar manner from [2-(5-benzyloxy-1H-indol-3-yl)-
ethyl]dimethylamine22 by treatment with either benzoyl
chloride or di-tert-butyl dicarbonate followed by hydro-
genation over palladium on carbon.
During the preparation of this paper, Bromidge et
al.15 published on a series of analogues of SB-271046
in which the sulfonamide linker group has been re-
versed, leading to the identification of SB-357134 (4),
while others have reported on N1-(benzenesulfonyl)-
tryptamines as novel 5-HT6 receptor antagonists.16-18
Through the screening of our in-house sample collection,
we independently discovered that N-(arylsulfonyl)indole
derivatives were potent, selective 5-HT6 receptor ligands
and in this paper we report on our own work in this
area.
The 4-(aminoethyl)indole analogues23 were prepared
from methylindole-4-carboxylate24 as shown in Scheme
5. Thus, treatment with benzenesulfonyl chloride in the
presence of potassium carbonate was followed by reduc-
tion of the ester functionality of 10 to the corresponding
alcohol with DIBALH. Oxidation to the aldehyde (11)
with manganese dioxide followed by treatment in ni-
tromethane with ammonium acetate gave the nitroalk-
ene (12). This was then reduced to the aminoethyl
analogue (44) by use of zinc-mercury amalgam. Dim-
ethylation of the amino group was carried out by
reductive alkylation as described above to give 45. The
2-benzoyl derivative (47) was prepared by lithiation of
45 with tert-butyllithium, followed by addition of ben-
zaldehyde and subsequent oxidation with manganese
oxide. Finally, the benzenesulfonyl group was removed
by sodium hydroxide to give 48.
The 4-(aminopropyl)indole (46) was synthesized by a
Wittig reaction on the aldehyde (11) with (carboet-
hoxymethylene)triphenylphosphorane, followed by hy-
drogenation of the alkene (13) over palladium. The
resulting ester (14) was converted to the dimethylamide
(15) by reaction with trimethylaluminum and dimethy-
lamine hydrochloride, and the amide was then reduced
with lithium aluminum hydride to give 46.
Ch em istr y
The 1-substituted N,N-dimethyl-5-methoxytryptamines
(19-27, 32, and 33) were prepared by treating N,N-
dimethyl-5-methoxytryptamine with the appropriate
sulfonyl chloride or carboxylic acid chloride in a two-
phase reaction medium of aqueous sodium hydroxide
and dichloromethane with tetrabutylammonium hydro-
gen sulfate as a phase transfer catalyst (Scheme 1).
The indoline analogue (39) was synthesized by hydro-
genation over palladium of N,N-dimethyl-5-methoxy-
tryptamine to give 5, followed by treatment with ben-
zenesulfonyl chloride under the previously described
conditions.
Changes to the dimethylamino group were achieved
by doubly benzenesulfonylating 5-methoxytryptol, fol-
lowed by displacement of the O-benzenesulfonyl group
of 6 by treatment with the appropriate amine in the
presence of potassium carbonate to give compounds 28-
31 (Scheme 2).
In the case of the 5-cyano-substituted analogue (38),
the corresponding tryptamine19 was dimethylated first
by reductive alkylation, with formaldehyde and sodium
cyanoborohydride, before reaction with benzenesulfonyl
chloride (Scheme 3). The 5-methoxy-2-methyl derivative
(40) was prepared via the 1-unsubstituted analogue (41)
by similar chemistry. The derivative with an ethyl ester
group in the 2-position of the indole (42) was pre-
pared in an analogous fashion from the corresponding
tryptamine.20 This was then converted to the oxadiazole
(43) by reaction with sodium hydride and 3-methoxy-
benzeneacetamide oxime.21 The aminoethyl derivative
The tetrahydrobenz[cd]indole derivatives were syn-
thesized from (()-4-amino-3,4-dihydro-1-[(4-methylben-
zyl)sulfonyl]-1,3,4,5-tetrahydrobenz[cd]indol-5(1H)-
one hydrochloride25 (16) by reduction of the ketone with
sodium borohydride to give a 9:1 mixture of trans/cis
amino alcohols (17) (Scheme 6). The mixture was then
dimethylated by reductive alkylation, and the trans

N-Arylsulfonylindoles as 5-HT6 Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3883
Sch em e 3a
a
Reagents: (i) (a) NaOMe, MeOH; (b) CH2O(aq), NaCNBH3, AcOH; (ii) PhSO2Cl, Bu4NHSO4, NaOH(aq), CH2Cl2; (iii) (a) Boc2O, CH2Cl2,
RT, 25 h; (b) PhSO2Cl, NaOH, Bu4NHSO4, CH2Cl2, RT, 30 min; (iv) CF3CO2H, CH2Cl2, RT, 3 h; (v) 3-methoxybenzeneacetamide oxime,
NaH, THF, -78 °C to reflux, 3 h.
Sch em e 4a
a
Reagents: (i) (a) NaOMe, MeOH, CH2O(aq), NaCNBH3, AcOH, RT, 4 h; (b) PhSO2Cl, Bu4NHSO4, NaOH(aq), CH2Cl2, RT, 30 min; (ii)
PhCOCl or Boc2O, Et3N, DMAP, 0 °C to RT, 3-18 h; (iii) H2, 10% Pd/C or 20% Pd(OH)2, (4 N HCl), EtOH, 35-45 psi, 3-7 h.
isomer (49) was separated from the cis isomer by column
chromatography. Finally the hydroxyl group was me-
thylated in low yield by use of sodium hydride and
methyl 3-bromopropionate in the presence of benzylt-
rimethylammonium chloride to give 50.
slightly detrimental to affinity, as was substitution in
the p-position by methyl (23) or methoxy (24). The fact
that substitution of the phenyl ring by either electron-
withdrawing or electron-donating groups did not im-
prove affinity over the unsubstituted compound (19) was
also found by Glennon and co-workers.16 Replacement
of the phenyl ring by the bulkier 2-naphthyl group (25)
or by a 2-thiophene (26) gave compounds with only
slightly reduced affinity, and the sulfonyl moiety could
be replaced by a carbonyl group as in 27 with 11-fold
loss in affinity.
Resu lts a n d Discu ssion
The compounds in Tables 1-3 were evaluated for
their affinity to cloned human 5-HT6 receptors stably
expressed in HeLa cells.
It can be seen from Table 1 that monosubstitution of
the aromatic ring of the benzenesulfonyl group of 19 by
chlorine in either the o-, m-, or p-position (20-22) was
Removal of the two methyl groups on the side-chain
amino functionality to give the primary amine (18) led

3884 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Russell et al.
Sch em e 5a
a
Reagents: (i) PhSO2Cl, K2CO3, butan-2-one, reflux, 10 h; (ii) (a) DIBALH, Et2O, -70 °C, 3 h; (b) MnO2, CH2Cl2, RT, 15 h; (iii) MeNO2,
NH4OAc, reflux, 2 h; (iv) Zn/Hg, MeOH, concd HCl, 0 °C to RT, 2.5 h; (v) CH2O(aq), NaCNBH3, AcOH, MeOH, 0 °C to RT, 1 h; (vi)
Ph3PdCHCO2Et, CH2Cl2, reflux, 3 h; (vii) H2, 10% Pd/C, EtOAc-EtOH, 4 h; (viii) Me3Al, Me2NH-HCl, benzene, reflux, 18 h; (ix) LiAlH4,
THF, RT, 5 h; (x) (a) t-BuLi, THF, -78 to 0 °C, 1.5 h; (b) PhCHO, THF, -78 °C to RT, 3 h; (c) MnO2, CH2Cl2; (xi) 2 N NaOH(aq), MeOH,
80° C, 30 min.
Sch em e 6a
Some other substituents at the 5-position of the indole
ring were also explored. Thus, it was found that having
no C-5 substituent at all gave compounds with similar
affinity (cf. 19 and 32), whereas the hydroxyl (35) and
cyano (38) groups led to an 8- and 14-fold reduction,
respectively. Larger groups such as a benzyloxy group
(34) led to a further decrease (140-fold) in affinity, which
is significantly different from that reported by Glennon
and co-workers.17 However, with a 5-hydroxyl group an
N1-benzoyl substituent was not so detrimental (cf. 27
and 36). The compounds with a tert-butoxycarbonyl
substituent (37) or a methylsulfonyl group (33) on the
indole nitrogen were significantly less well tolerated.
While reduction of the indole to the indoline to give
39 also led to a significant reduction (27-fold) in affinity,
addition of a 2-methyl substituent on the indole ring
(40) was only marginally detrimental (5-fold). Removal
of the N-benzenesulfonyl group from 40 to give 41 was,
however, less well tolerated,26,27 although introduction
of an ethyl ester (42) in the 2-position, in the absence
of N-1 substitution, recovered some of this affinity, and
further elaboration of the carboxy functionality to
3-methoxybenzyloxadiazole (43) led to a compound with
comparable affinity to the original lead (19).
a
Reagents: (i) NaBH4, EtOH, -2 °C, 100 min; (ii) H2, 10%
Pd/C, CH2O(aq), AcOH, EtOH, 30 psi, 65 h; (iii) NaH,
BrCH2CH2CO2Me, BnNMe3Cl, THF-DMF, RT, 18.5 h.
to a 17-fold decrease in affinity (cf. 18 and 19). Interest-
ingly, replacement of the dimethylamino group with
larger heterocycloalkyl groups such as pyrrolidine (28)
led to a 19-fold decrease in affinity, and the six-
membered ring compounds (29-31) were a further order
of magnitude down in 5-HT6 receptor affinity.
These latter results suggested that the ethylamine
side chain may bind to the 5-HT6 receptor in a confor-
mation in which the amino group is pointing away from
the 2-position of the indole and toward the 4-position,
similar to the conformationally constrained ergot alka-

N-Arylsulfonylindoles as 5-HT6 Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3885
Ta ble 1. 5-HT6 Binding Affinity of Substituted Tryptamines
a
compd
X
NR1R2
NH2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
pyrrolidinyl
piperidinyl
4-methyl-
piperazinyl
morpholinyl
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
R3
R4
Ki (nM) h5-HT6
18
19
20
21
22
23
24
25
26
27
28
29
30
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
H
H
H
H
H
H
H
H
H
H
H
H
H
PhSO2
PhSO2
40 (34, 47)
2.3 (1.7, 3.2)
11 (7.8, 15)
7.9 (6.2, 10)
17 (19, 21)
45 (40, 50)
26 (23, 30)
9.8 (7.8, 12)
8.3 (7.1, 9.8)
25 (22, 27)
44 (40, 48)
350 (280, 430)
490 (410, 590)
2-ClC6H4SO2
3-ClC6H4SO2
4-ClC6H4SO2
4-MeC6H4SO2
4-MeOC6H4SO2
2-naphthyl-SO2
2-thienyl-SO2
PhCO
PhSO2
PhSO2
PhSO2
31
32
33
34
35
36
37
38
39b
40
41
42
43
MeO
H
H
H
H
H
H
H
H
H
H
PhSO2
PhSO2
MeSO2
PhSO2
PhSO2
PhCO
t-BuOCO
PhSO2
PhSO2
PhSO2
H
1700 (1400, 2100)
2.9 (2.1, 3.9)
620 (420, 910)
320 (280, 370)
19 (18, 21)
H
BnO
HO
HO
HO
NC
MeO
MeO
MeO
H
54 (37, 78)
370 (300, 470)
33 (13, 45)
63 (51, 78)
12 (10, 13)
89 (69, 110)
20 (13, 33)
1.3 (1.2, 1.5)
Me
Me
NMe2
NMe2
NMe2
CO2Et
H
H
H
oxc
a
Displacement of [3H]-5-HT binding to cloned h5-HT6 receptors stably expressed in HeLa cells. The figures are the geometric mean of
at least three independent determinations performed in duplicate. The values in parentheses are the upper and lower limits derived as
a result of the SEM. In each case the radioligand concentration used was approximately at the KD for the receptor. Clozapine was used
b
as a control [Ki 13 (11, 15) nM]. This is an indoline. c 3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl.
Ta ble 2. 5-HT6 Binding Affinity of 4-(Aminoalkyl)Indoles
Ta ble 3. 5-HT6 Binding Affinity of
1,3,4,5-Tetrahydrobenz[cd]indoles
a
compd
n
R
R1
R2
Ki (nM) h5-HT6
44
45
46
47
48
1
1
2
1
1
H
H
H
H
COPh
COPh
PhSO2
PhSO2
PhSO2
PhSO2
H
2.4 (1.7, 3.4)
1.5 (1.0, 2.3)
7.9 (6.3, 11)
3.0 (2.0, 4.5)
260 (240, 290)
Me
Me
Me
Me
a
compd
R
Ki (nM) h5-HT6
49
50
H
Me
7.2 (6.0, 8.7)
130 (120, 150)
a
See corresponding footnote in Table 1.
a
See corresponding footnote in Table 1.
loids and LSD, which has a high affinity for 5-HT6
receptors. This theory was further supported by the fact
that the 4-[(dimethylamino)ethyl]indole analogue (45)
displayed comparable affinity for the h5-HT6 receptor
as the corresponding N,N-dimethyltryptamine (32) (Table
2). Interestingly, the primary amine (44) had similar
affinity to 45, in contrast to the tryptamines (18 and
19). Increasing the length of the side chain by one
carbon atom, as in 46, lowered the affinity by about
5-fold. A large substituent in the 2-position such as a
benzoyl group was well tolerated in the presence of the
N-1 benzenesulfonyl group (47) but not in its absence
(48).
conformationally rigid 5-hydroxy-1,3,4,5-tetrahydroben-
z[cd]indole (49). This compound in fact displayed 6-fold
better affinity than its nearest reported acyclic analogue
(23), although some of this may be due to an additional
hydrogen-bonding interaction of the hydroxyl group
since its methylation to give 50 led to a 18-fold reduction
in affinity (Table 3). This preferred binding conforma-
tion at the 5-HT6 receptor has also recently been
postulated by Glennon et al.26 and contrasts with the
proposed binding mode of tryptamine derivatives at
5-HT1D receptors, for example.28
For some of the higher affinity compounds, the
binding affinities at other serotonin receptors, as well
as dopamine receptors, were measured (Table 4). It can
Additional support for this proposed binding confor-
mation of the basic amino group was gained from the

3886 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Russell et al.
be seen that the 1-(benzenesulfonyl)tryptamines (19 and
32) had >100-fold selectivity over all other serotonin
receptors tested, apart from the 5-HT2 receptor,29 for
which they had 28- and 29-fold selectivity, respectively.
They also showed some affinity for hD2 and hD3 recep-
tors with 32, which lacks the 5-methoxy substituent,
having particularly low selectivity against these recep-
tors. The 1-benzoyl-5-hydroxytryptamine (36) was not
so selective against the serotonin receptors, although
it did have high selectivity over all the dopamine
receptors tested. The 2-(carboxyethyl)tryptamine (42)
was also not very selective over some of the serotonin
receptors, and moreover, it displayed fairly high affinity
at hD2 and hD3 receptors. The 4-(aminoethyl)indoles (44
and 45) both showed high affinity at several other
serotonin receptors, although this series seemed to have
better selectivity over the dopamine receptors. This high
affinity for 5-HT1D receptors, for example, may be
explained by the compounds binding in the reverse
orientation to the tryptamines in which the 3- and
4-positions of the indole ring are interchanged. The
2-benzoyl-substituted analogue (47) still had high af-
finity for 5-HT2 receptors as well as some affinity for
hD3, 5-HT1B, and 5-HT1D receptors. Finally, the tet-
rahydrobenzindole (49) showed excellent selectivity over
all the serotonin and dopamine receptors tested, with
the lowest selectivity being against the 5-HT2 receptor
(44-fold).
Molecular modeling overlays with SQ30 were per-
formed of the rigid 49 with the 3- and 4-(aminoethyl)-
indoles (19 and 45), in which the sulfurs were forced to
be coincident but the remainder of the molecule was left
to find the best fit. It was found that, for both 19 and
45, a low-energy conformer (within 2 kcal/mol of the
global minima) overlaid well onto 49 with the basic N
atoms being in close proximity (Figure 1). An overlay
of 49 and the competitor compounds 1 and 3 using the
same criteria again showed a reasonably good match,
suggesting that these compounds may all bind in the
same way to the 5-HT6 receptor (Figure 2). This is
different than the binding mode proposed by Glennon
and co-workers16 for 2 since the pyridine ring of 2 is
overlaid onto the six-membered ring of the indole of 19,
leaving the basic amino groups of the two structures
some distance away from each other. However, we
believe that a positively charged N atom has an impor-
tant interaction with Asp106 in transmembrane region
III of the receptor31 and thus should be in the same
region of space for all compounds. Finally, to gain some
insight into the binding mode of 43, which does not have
a phenylsulfonyl group, this was overlaid onto the other
compounds, stipulating that the basic N atom should
be matched by another heavy atom. The energy of the
conformation depicted is only 0.6 kcal/mol above that
of the global minimum for this compound and shows
that the phenyl ring of the methoxybenzyl substituent
on the oxadiazole of 43 overlays well onto the phenyl
rings of the benzenesulfonyl group in the other com-
pounds (Figure 3). This is achieved by the indole ring
being displaced somewhat from the position that it
occupies for the other compounds, with the six-mem-
bered ring of the indole occupying some of the same
space as the methoxy substituent of 19 and the hydroxyl
group of 49.

N-Arylsulfonylindoles as 5-HT6 Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3887
F igu r e 1. Overlay of 19 (yellow) and 45 (blue) onto 49 (green).
F igu r e 2. Overlay of Ro 04-6790 (1) (red) and SB-271046 (3) (black) onto 49 (green).
F igu r e 3. Overlay of 43 (green ball-and-sticks) onto 19 (yellow) and 49 (green).
Most of the compounds in Table 4 were also examined
for their ability to stimulate adenylate cyclase in the
rat 5-HT6 receptor cell line. It was found that com-
pounds 19, 36, 42, 47, and 49 had no agonist activity
at 10 µM, whereas 32 and 45 behaved as partial
agonists, giving 59% and 49%, respectively, of the
response seen with 5-HT (Figure 4). Additionally, 19
and 42 completely inhibited the 5-HT-stimulated ade-
nylate cyclase at the single concentration of 1 µM,
suggesting that they were antagonists, although it
cannot be ruled out that they may be inverse agonists.
To determine whether these compounds penetrate the
brain and interact with receptors, advantage was taken
of the fact that compound 19 has some affinity for 5-HT2
receptors. In rodents, activation of 5-HT2 receptors by
agonists such as mescaline32 and DOI [1-(2,5-dimethoxy-
4-iodophenyl)-2-aminopropane] elicits a head twitch
response that is blocked by selective 5-HT2A receptor
antagonists such as MDL 100,907.33 In this model,
pretreatment with 19 also significantly and dose-
dependently reduced mescaline-induced head twitches
with an ID50 of 11.3 ( 0.6 mg/kg ip (Figure 5). Given

3888 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Russell et al.
F igu r e 4. Stimulation of cAMP levels following treatment with 10 µM compound.
Bruker AC250 spectrometer. Mass spectra were recorded on
a Quattro operating in an electrospray (ES) mode or a VB70-
250 instrument operating in the electron impact (EI) or
chemical ionization (CI) mode as indicated. (Note that only
the strongest peaks from the mass spectra are reported below.)
Elemental analysis for carbon, hydrogen, and nitrogen was
performed by Butterworth Laboratories Ltd. High-performance
liquid chromatography (HPLC) analysis was performed on a
Hewlett-Packard HP1090 instrument with a Spherisorb S5
ODS2 column, eluted with acetonitrile/water (containing 0.2%
triethylamine and made to pH 3 with orthophosphoric acid).
Analytical thin-layer chromatography (TLC) was conducted on
precoated silica gel 60 F254 plates (Merck). Visualization of the
plates was accomplished by using UV light and/or iodine and/
or aqueous potassium permanganate solution. Chromatogra-
phy was conducted on silica gel 60, 220-440 mesh (Fluka)
under low pressure. Solutions were evaporated on a Bu¨chi
rotary evaporator under reduced pressure. All starting materi-
als were obtained from commercial sources and used as
received unless otherwise indicated.
F igu r e 5. Effect of 19 on mescaline-induced head twitches
in the rat. Results are expressed as the mean ( SEM number
of head twitches recorded in 15 min (n ) 6 rats/dose). Data
were analyzed by analysis of variance followed by Dunnett’s t
test; *P < 0.05 compared to vehicle-pretreated rats.
that 19 has reasonble affinity for 5-HT2 receptors, the
simplest explanation for this effect is that 19 acts as a
5-HT2A receptor antagonist in vivo. In addition, plasma
and brain tissue were analyzed following dosing of 19
to rats at 3 mg/kg i.p. The mean plasma concentrations
after 30 min in the plasma and brain were 86 ( 35 and
637 ( 220 ng/mL, respectively, giving a brain:plasma
ratio of 7.4.
Thus, in conclusion, the present work has signifi-
cantly extended the structure-activity relationships of
the N-arylsulfonyltryptamines for binding at the 5-HT6
receptor and led to the discovery that a suitable sub-
stituent at the 2-position of the indole ring can replace
the arylsulfonyl group. Additionally, further delineation
of the binding conformation has been achieved through
the finding that 4-(aminoethyl)indoles and the confor-
mationally rigid 1,3,4,5-tetrahydrobenz[c,d]indoles also
bound with high affinity to this receptor.
N,N-Dim eth yl-2-(5-m eth oxy-2,3-dih ydr o-1H-in dol-3-yl)-
eth yla m in e (5). A mixture of N,N-dimethyl-2-(5-methoxy-1H-
indol-3-yl)ethylamine (0.200 g, 0.939 mmol) and palladium on
carbon (10%, 200 mg) in 5 M aqueous HCl (50 mL) was
hydrogenated at 50 psi overnight. The catalyst was removed
by filtration, and the filtrate was extracted with dichlo-
romethane (3 × 25 mL). The combined organic extracts were
evaporated and the residue was purified by flash chromatog-
raphy (silica gel, CH2Cl2-MeOH-NH3(aq) 92:8:0.8) to give 94
mg (47%) of 5: 1H NMR (250 MHz, CDCl3) δ 1.71 (1H, m),
1.99 (1H, m), 2.26 (6H, s), 2.37 (2H, m), 3.20 (1H, t, J ) 8.0
Hz), 3.27 (1H, m), 3.68 (1H, t, J ) 8.0 Hz), 3.75 (3H, s), 6.60-
6.61 (2H, m), 6.73 (1H, m).
Ben zen esu lfon ic Acid 2-(1-Ben zen esu lfon yl-5-m eth -
oxy-1H-in d ol-3-yl)eth yl Ester (6). To a stirred two-phase
mixture of 5-methoxytryptophol (0.150 g, 0.785 mmol) and
tetrabutylammonium hydrogen sulfate (27 mg, 0.0785 mmol)
in 50% aqueous NaOH (3 mL) and dichloromethane (30 mL)
was added benzenesulfonyl chloride (0.25 mL, 1.96 mmol)
dropwise over 5 min. The mixture was stirred for 20 min, more
benzenesulfonyl chloride (0.10 mL, 0.784 mmol) was added
dropwise, and the mixture was stirred for a further hour. The
organic layer was washed with brine, dried (Na2SO4), and
evaporated. The residue was purified by flash chromatography
(silica gel, 50-100% EtOAc-hexane) to afford 0.095 g (37%)
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were obtained on a
Reichert Thermovar hot stage and are uncorrected. Proton
NMR spectra were obtained on either a Bruker AM360 or a

N-Arylsulfonylindoles as 5-HT6 Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3889
of 2-(1-benzenesulfonyl-5-methoxy-1H-indol-3-yl)ethanol and
0.191 g (52%) of 6: 1H NMR (360 MHz, DMSO-d6) δ 2.98 (2H,
t, J ) 6.1 Hz), 3.71 (3H, s), 4.30 (2H, t, J ) 6.2 Hz), 6.92 (1H,
dd, J ) 8.9 and 2.5 Hz), 6.95 (1H, d, J ) 2.2 Hz), 7.47 (2H, t,
J ) 7.8 Hz), 7.53-7.59 (3H, m), 7.63-7.67 (4H, m), 7.77 (1H,
d, J ) 8.9 Hz), 7.89 (2H, m); MS (ES+) m/z 510 [M + K]+, 494
[M + Na]+, 489 [M + NH4]+, 472 [M + H]+.
1-(Ben zen esu lfon yl)-3-[2-[(ter t-bu tyloxyca r bon yl)a m i-
n o]eth yl]-5-m eth oxy-1H-in d ole (7). To a stirred solution of
5-methoxytryptamine (3.5 g, 18.4 mmol) in dichloromethane
(100 mL) was added dropwise a solution of di-tert-butyl
dicarbonate (4.02 g, 18.4 mmol) in dichloromethane (25 mL)
over 5 min. The resulting pale brown solution was allowed to
stand at room temperature for 25 h, then the solvents were
evaporated to leave a thick oil.
300 mL). The combined organic extracts were dried (MgSO4)
and evaporated. Recrystallization from ethanol gave 6.35 g
(72%) of 10 as a white solid: 1H NMR (360 MHz, CDCl3) δ
3.94 (3H, s), 7.33-7.56 (5H, m), 7.69 (1H, d, J ) 3.7 Hz), 7.84-
7.87 (2H, m), 7.96 (1H, dd, J ) 8.1 and 0.7 Hz), 8.21 (1H, d, J
) 8.3 Hz); MS (CI) m/z 316 [M + H]+.
1-(Ben zen esu lfon yl)-1H-in d ole-4-ca r boxa ld eh yd e (11).
To a cooled (-70 °C) and stirred solution of 10 (4.5 g, 14.3
mmol) in anhydrous diethyl ether (50 mL) was added diisobu-
tylaluminum hydride (1 M in toluene; 37 mL) over 30 min,
under a nitrogen atmosphere. After the mixture was stirred
at -70 °C for 3 h, excess diisobutylaluminum hydride was
destroyed by the dropwise addition of methanol (3 mL) and
the mixture was allowed to warm to room temperature. 5%
Aqueous citric acid (100 mL) was added and the mixture was
extracted with ethyl acetate (3 × 100 mL). The combined
organic phases were dried (MgSO4) and evaporated. Flash
chromatography of the residue (silica gel, 50% EtOAc-hexane)
gave 2.6 g (63%) of the intermediate 1-(benzenesulfonyl)-1H-
indole-4-methanol as a thick colorless oil. To a solution of the
above alcohol (2.5 g) in anhydrous dichloromethane (200 mL)
was added activated manganese(IV) oxide (9 g), and the
resulting mixture was stirred for 15 h at room temperature
under a nitrogen atmosphere. The manganese residues were
removed by filtration and washed with chloroform, and the
filtrates were evaporated to give 1.96 g (79%) of 11 as a white
solid: 1H NMR (250 MHz, CDCl3) δ 7.42-7.56 (5H, m), 7.72-
7.77 (2H, m), 7.86-7.90 (2H, m), 8.28 (1H, d, J ) 8.25 Hz);
10.18 (1H, s); MS (EI+) m/z 285 (M+). (Found, m/z 285.0444;
To a stirred two-phase mixture of a solution of the above
3-[2-[(tert-butyloxycarbonyl)amino]ethyl]-5-methoxy-1H-in-
dole in dichloromethane (200 mL) and 50% aqueous NaOH
(50 mL) was added tetrabutylammonium hydrogen sulfate
(611 mg, 1.8 mmol), and the mixture was stirred for 10 min.
Benzenesulfonyl chloride (3.52 mL, 27.6 mmol) was added
dropwise via syringe and the mixture was vigorously stirred
for 30 min. The mixture was diluted with diethyl ether (500
mL), washed with water (100 mL) and then brine (2 × 70 mL),
dried (MgSO4), and concentrated. Flash chromatography of the
residue (silica gel, 10% Et2O-CH2Cl2) followed by trituration
with hexane-diethyl ether (10:1; 100 mL) afforded 7.55 g
(95%) of 7 as a white solid: 1H NMR (360 MHz, CDCl3) δ 1.45
(9H, s), 2.82 (2H, t, J ) 6.8 Hz), 3.36-3.44 (2H, m), 3.82 (3H,
s), 4.55 (1H, br s), 6.90-6.96 (2H, m), 7.32 (1H, s), 7.38-7.45
(2H, m), 7.48-7.54 (1H, m), 7.80-7.84 (2H, m), 7.88 (1H, d, J
) 8.8 Hz).
[5-Ben zyloxy-3-[2-(d im et h yla m in o)et h yl]-1H -in d ol-1-
yl]p h en ylm eth a n on e (8). Benzoyl chloride (217 mL, 1.9
mmol) was added to a stirred solution of [2-(5-benzyloxy-1H-
indol-3-yl)ethyl]dimethylamine (500 mg, 1.7 mmol), triethy-
lamine (473 mL, 3.4 mmol), and 4-(dimethylamino)pyridine
(20 mg, 0.2 mmol) in anhydrous dichloromethane (5 mL) at 0
°C. The mixture was allowed to warm slowly to ambient
temperature and then stirred at this temperature overnight.
The reaction was quenched with saturated aqueous NaHCO3
and then extracted three times with dichloromethane. The
combined extracts were dried (Na2SO4) and evaporated. The
residue was purified by flash chromatography (silica gel, CH2-
Cl2-MeOH-NH3(aq) 80:8:1) to give 327 mg (48%) of 8 as a
thick oil: 1H NMR (250 MHz, CDCl3) δ 2.30 (6H, s), 2.52-
2.60 (2H, m), 2.78-2.84 (2H, m), 5.16 (2H, s), 7.06-7.10 (3H,
m), 7.30-7.64 (10H, m), 8.28 (0.5H, s), 8.32 (0.5H, s).
Ben zyloxy-3-[2-(dim eth ylam in o)eth yl]-1H-in dole-1-car -
boxylic Acid ter t-Bu tyl Ester (9). Di-tert-butyl dicarbonate
(408 mg, 1.9 mmol) was added to a stirred solution of [2-(5-
benzyloxy-1H-indol-3-yl)ethyl]dimethylamine (500 mg, 1.7
mmol), triethylamine (473 mL, 3.4 mmol), and 4-(dimethy-
lamino)pyridine (20 mg, 0.2 mmol) in anhydrous dichlo-
romethane (5 mL) at 0 °C. The reaction was allowed to warm
slowly to ambient temperature. After 3 h the mixture was
poured into saturated aqueous NaHCO3 and extracted three
times with dichloromethane. The combined extracts were dried
(Na2SO4) and evaporated. The residue was purified by flash
chromatography (silica gel, CH2Cl2-MeOH-NH3(aq) 80:8:1)
to give 630 mg (95%) of 9 as a thick oil: 1H NMR (360 MHz,
CDCl3) δ 1.65 (9H, s), 2.33 (6H, s), 2.58-2.62 (2H, m), 2.79-
2.83 (2H, m), 5.12 (2H, s), 6.99 (1H, dd, J ) 9.0 and 2.5 Hz),
7.06 (1H, d, J ) 2.5 Hz), 7.29-7.48 (6H, m), 8.0 (1H, br d).
Meth yl 1-(Ben zen esu lfon yl)-1H-in d ole-4-ca r boxyla te
(10). A mixture of methyl indole-4-carboxylate24 (5.0 g, 28.5
mmol), benzenesulfonyl chloride (10.1 g, 57.1 mmol), and
anhydrous potassium carbonate (15.78 g, 114 mmol) in butan-
2-one (150 mL) was heated at reflux under nitrogen for 15 h.
Additional benzenesulfonyl chloride (10.1 g) and anhydrous
potassium carbonate (10.1 g) were added, and heating at reflux
was continued for 5 h. After cooling, the mixture was diluted
with water (300 mL) and extracted with diethyl ether (3 ×
C
15H11NO3S requires m/z 285.0460).
1-(Ben zen esu lfon yl)-4-(2-n itr ovin yl)-1H-in d ole (12). To
a solution of 11 (1.9 g, 6.6 mmol) in nitromethane (12 mL)
was added ammonium acetate (205 mg, 2.7 mmol), and the
resulting mixture was heated at reflux for 2 h. After cooling,
water (50 mL) was added and the mixture was extracted with
ethyl acetate (2 × 100 mL). The combined organic phases were
washed with brine (30 mL), dried (MgSO4), and evaporated.
Flash chromatography (silica gel, 75% CH2Cl2-hexane) of the
residue gave 1.95 g (90%) of 12 as a pale yellow solid: 1H NMR
(250 MHz, CDCl3) δ 6.89 (1H, dd, J ) 3.7 and 0.9 Hz), 7.34-
7.62 (5H, m), 7.65 (1H, d, J ) 13.7 Hz), 7.75 (1H, d, J ) 3.7
Hz), 7.87-7.92 (2H, m), 8.14 (1H, d, J ) 8.2 Hz), 8.27 (1H, d,
J ) 13.7 Hz); MS (EI+) m/z 329 [M + H]+.
3-[1-(Ben zen esu lfon yl)-1H-in d ol-4-yl]a cr ylic Acid Eth -
yl Ester (13). A solution of 11 (2.0 g, 7 mmol) and (carbe-
thoxymethylene)triphenylphosphorane (2.69 g, 7.7 mmol) in
anhydrous dichloromethane (50 mL) was heated at reflux for
3 h under nitrogen. After cooling, the reaction was evaporated
and purified by dry flash chromatography (silica gel, CH2Cl2)
to give 2.49 g (100%) of 13 as a colorless solid: 1H NMR (360
MHz, CDCl3) δ 1.34 (3H, t, J ) 7.2 Hz), 4.27 (2H, q, J ) 7.2
Hz), 6.51 (1H, d, J ) 17.2 Hz), 6.94 (1H, d, J ) 0.7 Hz), 7.32
(1H, t, J ) 7.9 Hz), 7.43-7.67 (4H, m), 7.67 (1H, d, J ) 3.6
Hz), 7.68-7.89 (2H, m), 7.94-8.03 (2H, m).
3-[1-(Ben zen esu lfon yl)-1H-in d ol-4-yl]p r op ion ic Acid
Eth yl Ester (14). A mixture of 13 (2.48 g, 6.98 mmol) in ethyl
acetate-ethanol (4:1; 75 mL) was hydrogenated over 10%
Pd-C (500 mg) under an atmosphere of hydrogen. After 4 h
the catalyst was removed by filtration, and the solvents were
evaporated to obtain 2.47 g (100%) of 14 as a colorless oil that
crystallized on standing: 1H NMR (360 MHz, CDCl3) δ 1.10
(3H, t, J ) 6.8 Hz), 2.57 (2H, t, J ) 7.5 Hz), 3.06 (2H, t, J )
7.5 Hz), 4.02 (2H, q, J ) 7.2 Hz), 6.66 (1H, d, J ) 0.7 Hz),
6.98 (1H, d, J ) 7.5 Hz), 7.14-7.18 (1H, m), 7.34-7.38 (2H,
m), 7.43-7.48 (1H, m), 7.50 (1H, d, J ) 4.0 Hz), 7.77-7.82
(3H, m).
N,N-Dim eth yl-3-[1-(ben zen esu lfon yl)-1H-in dol-4-yl]pr o-
p ion a m id e (15). Trimethylaluminum (2 M solution in hex-
anes, 1.4 mL, 2.8 mmol) was added to a suspension of
dimethylamine hydrochloride (228 mg, 2.8 mmol) in benzene
(10 mL). The reaction was stirred for 1 h before a solution of
14 (0.5 g, 1.4 mmol) in benzene (10 mL) was added dropwise.
The reaction was heated at reflux for 18 h, allowed to cool,
and then quenched by the addition of 2 N aqueous HCl (5 mL).

3890 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Russell et al.
The mixture was partitioned between water and ethyl acetate.
The organic phase was washed with brine, dried (MgSO4), and
evaporated to leave 527 mg (100%) of 15 as an oil that
subsequently crystallized: 1H NMR (250 MHz, CDCl3) δ 2.63
(2H, t, J ) 7.5 Hz), 2.79 (2H, br s), 3.16 (2H, t, J ) 8.5 Hz),
6.74 (1H, d, J ) 0.7 Hz), 6.08 (1H, d, J ) 7.5 Hz), 7.21-7.27
(1H, m), 7.41-7.58 (4H, m), 7.84-7.90 (3H, m).
4-Am in o-1-(4-m eth yl)ben zen esu lfon yl-1,3,4,5-tetr a h y-
d r oben z[cd ]in d ol-5-ol (17).25 To a solution of sodium boro-
hydride (1 g) in absolute ethanol (75 mL) was added dropwise
via cannula a suspension of (()-4-amino-3,4-dihydro-1-[(me-
thylphenyl)sulfonyl]benz[cd]indol-5(1H)one hydrochloride (16)25
(4.55 g) in absolute ethanol (150 mL) over 15 min, keeping
the internal temperature below 3 °C. The resulting mixture
was stirred at -2 °C for 1 h 40 min under nitrogen before it
was carefully acidified with 2 N aqueous HCl (28 mL). The
ethanol was evaporated and the residue was basified with 2
N aqueous NaOH (35 mL). The products were extracted with
ethyl acetate (3 × 150 mL) and the combined organic phases
were washed with brine (50 mL), dried (Na2SO4), and evapo-
rated. Flash chromatography of the residue (silica gel, CH2-
Cl2-EtOH-NH3(aq) 170:28:3) gave 3.99 g (97%) of 17 as a 90:
10 mixture of trans and cis isomers: MS m/z 342 (M+).
N,N-Dim eth yl-2-[1-(3-ch lor oben zen esu lfon yl)-5-m eth -
oxy-1H-in d ol-3-yl]eth yla m in e (21). Yield 67%. Hydrochlo-
ride salt: mp 191-194 °C; H NMR (360 MHz, DMSO-d6) δ
2.81 (6H, s), 3.09 (2H, m), 3.34 (2H, m), 3.80 (3H, s), 7.00 (1H,
dd, J ) 9.0 and 2.5 Hz), 7.26 (1H, d, J ) 2.4 Hz), 7.61 (1H, t,
J ) 8.0 Hz), 7.73 (1H, s), 7.77 (1H, dt), 7.84 (1H, d, J ) 9.1
Hz), 7.89 (1H, dt), 7.97 (1H, t, J ) 1.9 Hz), 10.59 (1H, br s);
MS (ES+) m/z 395/393 [M + H]+. Anal. [C19H21ClN2O3S·HCl]
C, H, N.
1
N,N-Dim eth yl-2-[1-(4-ch lor oben zen esu lfon yl)-5-m eth -
oxy-1H-in d ol-3-yl]eth yla m in e (22). Yield 39%. Hydrochlo-
1
ride salt: mp 222-224 °C; H NMR (360 MHz, DMSO-d6) δ
2.82 (6H, s), 3.09 (2H, m), 3.35 (2H, m), 3.81 (3H, s), 6.99 (1H,
dd, J ) 9.0 and 2.5 Hz), 7.27 (1H, d, J ) 2.4 Hz), 7.67 (2H, d,
J ) 8.8 Hz), 7.70 (1H, s), 7.82 (1H, d, J ) 9.0 Hz), 7.94 (2H, d,
J ) 8.7 Hz), 10.65 (1H, br s); MS (ES+) m/z 395/393 [M + H]+.
Anal. [C19H21ClN2O3S·HCl‚0.2H2O] C, H, N.
N,N-Dim eth yl-2-[5-m eth oxy-1-(4-m eth ylben zen esu lfo-
n yl)-1H-in d ol-3-yl]eth yla m in e (23). Yield 72%. Hydrochlo-
1
ride salt: mp 214-215 °C; H NMR (360 MHz, DMSO-d6) δ
2.32 (3H, s), 2.81 (6H, s), 3.08 (2H, m), 3.37 (2H, m), 3.79 (3H,
s), 6.97 (1H, dd, J ) 9.0 and 2.5 Hz), 7.23 (1H, d, J ) 2.4 Hz),
7.37 (2H, d, J ) 8.1 Hz), 7.67 (1H, s), 7.79 (2H, d, J ) 8.4 Hz),
7.80 (1H, d, J ) 9.1 Hz), 10.60 (1H, br s); MS (ES+) m/z 373
[M + H]+. Anal. [C20H24N2O3S·HCl‚0.4H2O] C, H, N.
2-[1-(Ben zen esu lfon yl)-5-m et h oxy-1H -in d ol-3-yl]et h -
yla m in e Hyd r och lor id e (18). A solution of 7 (2.1 g) in a
mixture of dichloromethane and trifluoroacetic acid (1:1; 60
mL) was allowed to stand at room temperature for 3 h. The
solvents were removed under vacuum and the residue was
azeotroped with toluene-methanol (5:1; 100 mL). The residue
was dissolved in 4 N aqueous NaOH (50 mL) and extracted
with ethyl acetate (3 × 100 mL). The combined organic
solutions were washed with brine (1 × 50 mL), dried (Na2-
SO4), and concentrated. The hydrochloride salt was prepared
and recrystallized from acetonitrile to give 1.53 g (82%) of 18:
N,N-Dim eth yl-2-[5-m eth oxy-1-(4-m eth oxyben zen esu lfo-
n yl)-1H-in d ol-3-yl]eth yla m in e (24). Yield 61%. Hydrochlo-
1
ride salt: mp 152-155 °C; H NMR (360 MHz, DMSO-d6) δ
2.82 (6H, s), 3.08 (2H, m), 3.34 (2H, m), 3.80 (3H, s), 3.81 (3H,
s), 6.98 (1H, dd, J ) 9.0 and 2.5 Hz), 7.08 (2H, d, J ) 9.0 Hz),
7.24 (1H, d, J ) 2.4 Hz), 7.67 (1H, s), 7.81 (1H, d, J ) 9.0 Hz),
7.86 (2H, d, J ) 9.1 Hz), 10.55 (1H, br s); MS (ES+) m/z 389
[M + H]+. Anal. [C20H24N2O4S·HCl] C, H, N.
N,N-Dim eth yl-2-[5-m eth oxy-1-(2-n aph th alen esu lfon yl)-
1H-in d ol-3-yl]eth yla m in e (25). Yield 56%. Hydrochloride
1
mp 117-120 °C; H NMR (360 MHz, D2O) δ 3.01 (2H, t, J )
1
salt: mp 191-193 °C; H NMR (360 MHz, DMSO-d6) δ 2.81
7.6 Hz), 3.29 (2H, t, J ) 7.6 Hz), 3.78 (3H, s), 6.89 (1H, dd, J
) 9.0 and 2.3 Hz), 6.89 (1H, dd, J ) 9.0 and 2.3 Hz), 7.00 (1H,
d, J ) 2.3 Hz), 7.41 (2H, t, J ) 8.1 Hz), 7.54 (1H, t, J ) 7.5
Hz), 7.56 (1H, s), 7.74 (1H, d, J ) 9.0 Hz), 7.81 (2H, d, J ) 7.5
Hz); MS (ES) m/z 331 [M + H]+. Anal. [C17H18N2O3S·1.0HCl‚
0.6H2O] C, H, N.
(6H, s), 3.09 (2H, m), 3.35 (2H, m), 3.78 (3H, s), 6.98 (1H, dd,
J ) 9.0 and 2.4 Hz), 7.23 (1H, d, J ) 2.4 Hz), 7.72 (2H, m),
7.78 (1H, s), 7.81 (1H, dd, J ) 8.8 and 1.9 Hz), 7.90 (1H, d, J
) 9.1 Hz), 8.01 (1H, d, J ) 7.7 Hz), 8.08 (1H, d, J ) 8.8 Hz),
8.21 (1H, d), 8.76 (1H, s), 10.60 (1H, br s); MS (ES+) m/z 409
(MH+). Anal. [C23H24N2O3S·HCl] C, H, N.
N,N-Dim et h yl-2-[1-(b en zen esu lfon yl)-5-m et h oxy-1H -
in d ol-3-yl]eth yla m in e (19). To a stirred two-phase mixture
of 5-methoxy-N,N-dimethyltryptamine (2 g, 9.16 mmol) and
tetrabutylammonium hydrogen sulfate (311 mg, 0.916 mmol)
in dichloromethane (120 mL) and 50% aqueous NaOH (30 mL)
was added benzenesulfonyl chloride (2.43 g, 13.7 mmol) over
30 min. The mixture was stirred at room temperature for 20
min and then diluted with ethyl acetate (250 mL) and water
(125 mL). The organic phase was decanted off, washed with
brine (2 × 65 mL), dried (MgSO4), and evaporated. Flash
chromatography (silica gel, CH2Cl2-MeOH-NH3(aq) 95:5:0.5)
of the residue afforded 3.166 g (96%) of 19 as a thick oil that
solidified on standing. The hydrogen chloride salt was pre-
N,N-Dim et h yl-2-[5-m et h oxy-1-(2-t h iop h en esu lfon yl)-
1H-in d ol-3-yl]eth yla m in e (26). Yield 25%. Oxalate salt: mp
215-220 °C; 1H NMR (360 MHz, DMSO-d6) δ 2.78 (6H, s), 3.03
(2H, m), 3.29 (2H, m), 3.81 (3H, s), 7.16 (1H, m), 7.20 (1H, d,
J ) 2.3 Hz), 7.61 (1H, s), 7.81 (1H, d, J ) 9.2 Hz), 7.83 (1H,
m), 8.01 (1H, dd, J ) 5.1 and 1.3 Hz); MS (ES+) m/z 365 [M +
H]+. Anal. [C17H20N2O3S2·C2H2O4] C, H, N.
N,N-Dim eth yl-2-(1-ben zoyl-5-m eth oxy-1H-in d ol-3-yl)-
eth yla m in e (27). By a procedure similar to that described
for 19 but with benzoyl chloride instead of benzenesulfonyl
chloride, 27 was prepared in 53% yield as a white solid.
Oxalate salt: mp 199-201 °C; 1H NMR (360 MHz, DMSO-d6)
δ 2.78 (6H, s), 3.05 (2H, m), 3.27 (2H, m), 3.86 (3H, s), 7.02
(1H, dd, J ) 9.0 and 2.4 Hz), 7.28 (1H, d, J ) 2.4 Hz), 7.32
(1H, s), 7.61 (2H, t, J ) 7.0 Hz), 7.70 (1H, t, J ) 7.3 Hz), 7.75
(2H, d, J ) 6.9 Hz), 8.19 (1H, d, J ) 9.0 Hz); MS (ES+) m/z
323 [M + H]+. Anal. [C20H22N2O2·C2H2O4] C, H, N.
1-Ben zen esu lfon yl-5-m et h oxy-3-[(2-p yr r olid in -1-yl)-
eth yl]-1H-in d ole (28). To a stirred mixture of 6 (0.191 g,
0.405 mmol) and anhydrous potassium carbonate (0.112 g,
0.810 mmol) in anhydrous 2-propanol (10 mL) under nitrogen
was added a solution of pyrrolidine (0.17 mL, 2.03 mmol) in
anhydrous 2-propanol (3 mL). The mixture was heated at
reflux for 4 h, and the solvents were then evaporated. The
residue was partitioned between dichloromethane and water,
and the aqueous layer was extracted further with dichlo-
romethane. The combined organic extracts were washed with
brine (2 × 25 mL), dried (Na2SO4), and evaporated. The residue
was purified by flash chromatography (silica gel, CH2Cl2-
MeOH-NH3(aq) 95:5:0.5) to give 0.102 g (65%) of 28. The
oxalate salt was prepared in EtOH-Et2O as a white solid: mp
217-220 °C; 1H NMR (360 MHz, DMSO-d6) δ 1.94 (4H, s), 3.03
1
pared: mp 200-215 °C (EtOH); H NMR (360 MHz, DMSO-
d6) δ 2.81 (6H, s), 3.06-3.16 (2H, m), 3.16-3.28 (2H, m), 3.28-
3.36 (2H, m), 3.80 (3H, s), 6.98 (1H, dd, J ) 9.0 and 2.5 Hz),
7.26 (1H, d, J ) 2.5 Hz), 7.58 (2H, t, J ) 7.5 Hz), 7.65-7.72
(2H, m), 7.82 (1H, d, J ) 9.0 Hz), 7.92 (2H, dd, J ) 8.6 and
1.3 Hz), 10.82 (1H, br s); MS (ES+) m/z 359 [M + H]+. Anal.
[C19H22N2SO3·HCl] C, H, N.
Compounds 20-26 were prepared with the appropriate
sulfonyl chloride by a procedure similar to that described for
19.
N,N-Dim eth yl-2-[1-(2-ch lor oben zen esu lfon yl)-5-m eth -
oxy-1H-in d ol-3-yl]eth yla m in e (20). Yield 43%. Hydrochlo-
1
ride salt: mp 185-188 °C; H NMR (360 MHz, DMSO-d6) δ
2.84 (6H, s), 3.14 (2H, m), 3.37 (2H, m), 3.81 (3H, s), 6.93 (1H,
dd, J ) 9.0 and 2.4 Hz), 7.31 (1H, d, J ) 2.4 Hz), 7.54 (1H, d,
J ) 9.0 Hz), 7.63 (1H, td), 7.68 (1H, dd), 7.74 (1H, td), 7.78
(1H, s), 8.14 (1H, dd, J ) 7.9 and 1.5 Hz), 10.45 (1H, br s); MS
(ES+) m/z 395/393 [M + H]+. Anal. [C19H21ClN2O3S·HCl] C,
H, N.

N-Arylsulfonylindoles as 5-HT6 Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3891
(2H, m), 3.27 (4H, s), 3.40 (2H, m), 3.79 (3H, s), 6.98 (1H, dd,
J ) 9.0 and 2.3 Hz), 7.17 (1H, d, J ) 2.3 Hz), 7.58 (2H, t, J )
8.0 Hz), 7.69 (2H, m), 7.82 (1H, d, J ) 9.0 Hz), 7.92 (2H, d, J
) 7.9 Hz); MS (ES+) m/z 385 [M + H]+. Anal. [C21H24N2O3S·
C2H2O4] C, H, N.
Compounds 29-31 were prepared with the appropriate
amine by a method similar to that described for 28.
1-Ben zen esu lfon yl-5-m eth oxy-3-[(2-p ip er id in -1-yl)eth -
yl]-1H-in d ole (29). Yield 90%. Oxalate salt: mp 231-234 °C;
1H NMR (360 MHz, DMSO-d6) δ 1.55 (2H, m), 1.75 (4H, m),
3.04 (2H, m), 3.15 (4H, s), 3.27 (2H, m), 3.79 (3H, s), 6.98 (1H,
dd, J ) 9.0 and 2.4 Hz), 7.15 (1H, d, J ) 2.4 Hz), 7.58 (2H, t,
J ) 8.0 Hz), 7.68 (2H, m), 7.82 (1H, d, J ) 9.0 Hz), 7.91 (2H,
d, J ) 7.7 Hz); MS (ES+) m/z 399 [M + H]+. Anal. [C22H26N2O3S·
C2H2O4‚0.3H2O] C, H, N.
7.28-7.48 (6H, m), 7.58 (2H, t, J ) 8.0 Hz), 7.64-7.72 (2H,
m), 7.82 (1H, d, J ) 9.0 Hz), 7.90-7.94 (2H, m); MS (ES) m/z
435 [M + H]+. Anal. [C25H26N2O3S·C2H2O4] C, H, N.
N,N-Dim eth yl-2-(1-ben zen esu lfon yl-5-h yd r oxy-1H-in -
d ol-3-yl)eth yla m in e (35). A solution of 34 (2.25 g, 4.6 mmol)
in absolute ethanol (100 mL) was hydrogenated at 40 psi over
20% palladium hydroxide (600 mg) for 4.5 h. Additional
catalyst (1.6 g) was then added and hydrogenation was
resumed at 45 psi for 2.5 h. The catalyst was removed by
filtration, washed with
a mixture of dichloromethane-
methanol-ammonia (80:20:2; 3 × 70 mL), and the filtrate was
evaporated. The residue was purified by flash chromatography
(silica gel, CH2Cl2-MeOH-NH3(aq) 95:5:0.5) to give 35 as a
crystalline solid after trituration with diethyl ether (30 mL):
1
mp 185-188 °C; H NMR (360 MHz, DMSO-d6) δ 2.18 (6H,
s), 2.47 (2H, t, J ) 7.6 Hz), 2.67 (2H, t, J ) 7.6 Hz), 6.78 (1H,
dd, J ) 8.8 and 2.2 Hz), 6.82 (1H, d, J ) 2.2 Hz), 7.48 (1H, s),
7.55 (2H, t, J ) 8.0 Hz), 7.62-7.68 (1H, m), 7.69 (1H, d, J )
8.7 Hz), 7.84-7.90 (2H, m), 9.32 (1H, br s); MS (ES) m/z 345
[M + H]+. Anal. [C18H20N2O3] C, H, N.
1-Ben zen esu lfon yl-5-m eth oxy-3-[(2-p ip er a zin -1-yl)eth -
yl]-1H-in d ole (30). Yield 76%. Oxalate salt: mp 230-232 °C;
1H NMR (360 MHz, DMSO-d6) δ 2.70 (3H, s), 2.82 (8H, br s),
3.09 (4H, br s), 3.78 (3H, s), 6.96 (1H, dd, J ) 9.0 Hz), 7.08
(1H, d), 7.57 (2H, t, J ) 7.5 Hz), 7.60 (1H, s), 7.68 (1H, t, J )
7.5 Hz), 7.81 (1H, d, J ) 9.0 Hz), 7.90 (2H, d, J ) 7.6 Hz); MS
(ES+) m/z 414 [M + H]+. Anal. [C22H27N3O3S·4C2H2O4‚2H2O]
C, H, N.
1-[2-(5-Meth oxy-1-p h en ylsu lfon yl-1H-in d ol-3-yl)eth yl]-
m or p h olin e (31). Oxalate salt: mp 215-220 °C; 1H NMR
(360 MHz, DMSO-d6) δ 2.91 (8H, br s), 3.03 (4H, br s), 3.78
(3H, s), 6.97 (1H, d, J ) 9.1 Hz), 7.11 (1H, s), 7.57 (2H, t, J )
7.8 Hz), 7.64 (1H, s), 7.68 (1H, t), 7.81 (1H, d, J ) 9.0 Hz),
7.90 (2H, d, J ) 7.8 Hz); MS (ES+) m/z 401 [M + H]+. Anal.
[C21H24N2O4S·C2H2O4‚0.3H2O] C, H, N.
Compounds 32 and 33 were prepared from the appropriate
tryptamine compounds and the corresponding sulfonyl chloride
following a method similar to that described for 19.
N,N-Dim eth yl-2-(1-ben zen esu lfon yl-1H-in d ol-3-yl)eth -
yla m in e (32). Oxalate salt: mp 196-198 °C (EtOH-Et2O);
1H NMR (360 MHz, DMSO-d6) δ 2.77 (6H, s), 3.00-3.08 (2H,
m), 3.26-3.34 (2H, m), 7.29 (1H, t, J ) 7.3 Hz), 7.38 (1H, t, J
) 7.3 Hz), 7.61 (2H, t, J ) 8.0 Hz), 7.64-7.72 (2H, m), 7.74
(1H, s), 7.91-7.97 (3H, m); MS (CI) m/z 329 [M + H]+. Anal.
[C18H20N2O2S·C2H2O4] C, H, N.
N,N-Dim et h yl-2-(1-m et h ylsu lfon yl-1H -in d ol-3-yl)et h -
yla m in e (33). Oxalate salt: mp 191-193 °C (EtOH-Et2O);
1H NMR (360 MHz, DMSO-d6) δ 2.79 (6H, s), 3.05-3.14 (2H,
m), 3.28-3.36 (2H, m), 3.37 (3H, s), 7.30-7.44 (2H, m), 7.52
(1H, s), 7.75 (1H, d, J ) 7.3 Hz), 7.83 (1H, d, J ) 8.1 Hz); MS
(CI) m/z 267 [M + H]+. Anal. [C13H18N2O2S·1.1(C2H2O4)] C, H,
N.
N,N-Dim et h yl-2-(1-b en zen esu lfon yl-5-b en zyloxy-1H -
in d ol-3-yl)eth yla m in e (34). To a stirred solution of 5-ben-
zyloxytryptamine hydrochloride (2.29 g, 7.56 mmol) in metha-
nol (100 mL) was added sodium methoxide (30% w/v in
methanol; 1.44 mL) followed by glacial acetic acid (1.70 mL,
30.2 mmol) and sodium cyanoborohydride (950 mg, 15.1 mmol).
A solution of formaldehyde (38% w/v aqueous solution; 1.43
mL) in methanol (25 mL) was then added dropwise over 20
min, and the resulting solution was stirred at room temper-
ature for 4 h. Aqueous NaOH (4 N, 60 mL) was added and the
methanol was removed under vacuum. The aqueous residue
was extracted with diethyl ether (2 × 250 mL) and the
combined organic phases were washed with brine (2 × 50 mL),
dried (Na2SO4), and concentrated. The residue was dissolved
in dichloromethane (120 mL), and 50% aqueous NaOH (40 mL)
was added followed by tetrabutylammonium hydrogen sulfate
(258 mg). The mixture was vigorously stirred, benzenesulfonyl
chloride (1.45 mL) in dichloromethane (10 mL) was added
dropwise over 3 min, and stirring was continued for 30 min.
Water (120 mL) and diethyl ether (200 mL) were added and
the organic phase was decanted off, washed with brine (2 ×
50 mL), dried (Na2SO4), and evaporated. Flash chromatogra-
phy of the residue (silica gel, CH2Cl2-MeOH-NH3(aq) 95:5:
0.5) afforded 2.57 g (78%) of 34 as a colorless thick oil. The
oxalate salt was prepared: mp 212-215 °C (EtOH); 1H NMR
(360 MHz, DMSO-d6) δ 2.77 (6H, s), 2.98-3.06 (2H, m), 3.22-
3.30 (2H, m), 5.12 (2H, s), 7.06 (1H, dd, J ) 9.0 and 2.4 Hz),
[3-[2-(Dim eth yla m in o)eth yl]-5-h yd r oxy-1H-in d ol-1-yl]-
p h en ylm eth a n on e (36). A solution of 8 (300 mg, 0.75 mmol)
and 4 N aqueous HCl (190 mL, 0.76 mmol) in ethanol (10 mL)
was hydrogenated over 10% palladium on carbon (100 mg) at
35 psi for 3 h. The catalyst was removed by filtration and the
filtrate was evaporated. The residue was partitioned between
dichloromethane and saturated aqueous NaHCO3, and the
aqueous layer was further extracted twice with dichlo-
romethane. The combined extracts were dried (K2CO3) and
evaporated. The residue was purified by flash chromatography
(silica gel, CH2Cl2-MeOH-NH3(aq) 80:8:1) to give 120 mg
(52%) of 36 as a colorless solid: mp 154-156 °C. 1H NMR (360
MHz, CDCl3) δ 2.40 (6H, s), 2.70-2.75 (2H, m), 2.83-2.88 (2H,
m), 6.86-6.90 (2H, m), 7.04 (1H, s), 7.49-7.61 (3H, m), 7.68-
7.71 (2H, m), 8.17 (0.5H, s), 8.20 (0.5H, s); MS (CI+) m/z 309
[M + H]+. Anal. [C19H20N2O2‚0.2H2O] C, H, N.
3-[2-(Dim eth ylam in o)eth yl]-5-h ydr oxy-1H-in dole-1-car -
boxylic Acid ter t-Bu tyl Ester (37). This was prepared from
9 following a procedure similar to that described for 36 in 50%
yield as a colorless solid: 1H NMR (360 MHz, CDCl3) δ 1.64
(9H, s), 2.45 (6H, s), 2.73-2.80 (2H, m), 2.88-2.93 (2H, m),
6.82-6.85 (1H, m), 6.96 (1H, br s), 7.33 (1H, br s), 7.92 (1H,
m); MS (CI+) m/z 305 [M + H]+. Anal. [C17H24N2O3‚0.8H2O]
C, H, N.
N,N-Dim eth yl-2-(1-ben zen esu lfon yl-5-cya n o-1H-in d ol-
3-yl)eth yla m in e (38). To a stirred solution of 3-(2-aminoet-
hyl)-5-cyano-1H-indole hydrochloride19 (0.1208 g, 0.545 mmol)
in methanol (25 mL) was added a 30% (w/v) solution of sodium
methoxide in methanol (0.1 mL, 0.545 mmol), then acetic acid
(0.125 mL, 2.18 mmol), followed by sodium cyanoborohydride
(68 mg, 1.09 mmol). A 38% (w/v) aqueous solution of formal-
dehyde (0.103 mL, 1.31 mmol) in methanol (10 mL) was then
added dropwise over 30 min. The mixture was stirred for 3.5
h, then 4 N aqueous NaOH (25 mL) was added, and the
methanol was evaporated. The aqueous residue was extracted
with diethyl ether (3 × 25 mL), and the combined organic
extracts were washed with brine (2 × 20 mL), dried (Na2SO4),
and evaporated to give crude N,N-dimethyl 2-(5-cyano-1H-
indol-3-yl)ethylamine.
To this crude product was added dichloromethane (30 mL),
50% aqueous NaOH (2 mL), and tetrabutylammonium hydro-
gen sulfate (19 mg, 0.0545 mmol). Benzenesulfonyl chloride
(0.104 mL, 0.817 mmol) was then added dropwise over 3 min
while the mixture was stirred magnetically, and the mixture
was stirred for an additional 30 min. Ethyl acetate (50 mL)
and water (25 mL) was then added, and the organic layer was
washed with brine (2 × 25 mL), dried (Na2SO4), and evapo-
rated. The residue was purified by flash chromatography (silica
gel, CH2Cl2-MeOH-NH3(aq) 95:5:0.5) to yield 0.132 g (66%)
of 38. The oxalate salt was prepared in EtOH-Et2O as a white
1
solid: mp 213-220 °C; H NMR (360 MHz, DMSO-d6) δ 2.78
(6H, s), 3.10 (2H, m), 3.31 (2H, m), 7.63 (2H, t, J ) 7.5 Hz),
7.74 (1H, t, J ) 7.5 Hz), 7.78 (1H, dd, J ) 8.6 and 1.4 Hz),
7.98 (1H, s), 8.03 (2H, d, J ) 7.4 Hz), 8.11 (1H, d, J ) 8.4 Hz),

3892 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Russell et al.
8.31 (1H, s); MS (ES+) m/z 354 [M + H]+. Anal. [C19H19N3O2S·
aqueous layer was further extracted twice with ethyl acetate
and the combined organic extracts were washed with brine
twice, dried (MgSO4), and evaporated. The residue was purified
by flash chromatography (silica gel, 3-10% MeOH-CH2Cl2)
to yield 395 mg (46%) of 43 as a white solid. The hydrochloride
salt was prepared in ethyl acetate-diethyl ether: mp 248-
249 °C; 1H NMR (360 MHz, DMSO-d6) δ 2.78 (6H, s), 3.22 (2H,
m), 3.55 (2H, m), 3.75 (3H, s), 4.18 (2H, s), 6.86 (1H, m), 6.95
(1H, d, J ) 8.3 Hz), 6.97 (1H, s), 7.16 (1H, t, J ) 7.3 Hz), 7.28
(1H, t, J ) 8.3 Hz), 7.33 (1H, t, J ) 7.3 Hz), 7.48 (1H, d, J )
8.3 Hz), 7.85 (1H, d, J ) 8.1 Hz), 10.55 (1H, br s), 12.28 (1H,
s); MS (CI+) m/z 377 [M + H]+. Anal. [C22H24N4O2·HCl] C, H,
N.
C2H2O4] C, H, N.
N,N-Dim eth yl-2-(1-ben zen esu lfon yl-5-m eth oxy-2,3-d i-
h yd r o-1H-in d ol-3-yl)eth yla m in e (39). This was prepared in
57% yield from 5 by a procedure similar to that described for
19. Oxalate salt: mp 183-185 °C; 1H NMR (360 MHz, DMSO-
d6) δ 1.47 (1H, m), 1.94 (1H, m), 2.68 (6H, s), 2.96 (2H, m),
3.14 (1H, m), 3.63 (1H, m), 3.71 (3H, s), 4.06 (1H, m), 6.82
(2H, m), 7.42 (1H, d, J ) 9.4 Hz), 7.57 (2H, t, J ) 7.3 Hz),
7.68 (1H, t), 7.78 (2H, d, J ) 7.6 Hz); MS (ES+) m/z 361 [M +
H]+. Anal. [C19H24N2O3S·C2H2O4‚0.7H2O] C, H, N.
N,N-Dim eth yl-2-(1-ben zen esu lfon yl-5-m eth oxy-2-m eth -
yl-1H-in d ol-3-yl)eth yla m in e (40). This was prepared from
41 by a procedure similar to that described for 19. Oxalate
2-[1-(Ben zen esu lfon yl)-1H-in d ol-4-yl]eth yla m in e (44).
Zinc amalgam was prepared by mixing zinc dust (6 g) and
mercury(II) chloride (600 mg) in a mixture of water (6 mL)
and concentrated hydrochloric acid (300 µL) and stirring at
room temperature for 10 min. The aqueous phase was de-
canted off and the amalgam was then covered with methanol.
1
salt: mp 194-196 °C; H NMR (360 MHz, DMSO-d6) δ 2.54
(3H, s), 2.76 (6H, s), 2.98 (2H, m), 3.44 (2H, m), 3.80 (3H, s),
6.92 (1H, dd, J ) 9.0 and 2.5 Hz), 7.09 (1H, d, J ) 2.5 Hz),
7.56 (2H, t, J ) 7.5 Hz), 7.67 (1H, t, J ) 7.5 Hz), 7.77 (2H, d,
J ) 7.4 Hz), 7.94 (1H, d, J ) 9.1 Hz); MS (ES+) m/z 373 [M +
H]+. Anal. [C20H24N2O3S·C2H2O4‚0.4H2O] C, H, N.
To a cooled (0 °C) and stirred solution of 12 (1.9 g) in a
mixture of methanol (35 mL) and concentrated hydrochloric
acid (20 mL) was added portionwise, over 30 min, the zinc
amalgam prepared above. The mixture was stirred at 0 °C for
a further 30 min and at room temperature for 2 h before the
solvent was decanted off and evaporated under vacuum. The
remaining residue was partitioned between 1 M aqueous
ammonia (50 mL) and diethyl ether (75 mL) and the aqueous
phase was re-extracted with diethyl ether (2 × 75 mL). The
combined ethereal solutions were dried (Na2SO4) and evapo-
rated. Flash chromatography of the residue (silica gel, CH2-
Cl2-MeOH-NH3(aq) 40:8:1) gave 950 mg (55%) of 44 as a
thick colorless oil: 1H NMR (250 MHz, CDCl3) δ 3.06 (4H, s),
6.78 (1H, d), 7.04 (1H, d), 7.20 (1H, t), 7.36-7.60 (4H, m), 7.86
(3H, d); MS (EI) m/z 301 [M + H]+. Anal. [C16H16N2O2S·C2H2O4]
C, H, N.
N,N-Dim eth yl-2-(1-ben zen esu lfon yl-5-m eth oxy-2-m eth -
yl-1H-in d ol-3-yl)eth yla m in e (41). To a stirred solution of
2-(5-methoxy-2-methyl-1H-indol-3-yl)ethylamine hydrochlo-
ride34 (1.6 g, 6.55 mmol) in methanol (100 mL) was added a
30% (w/v) solution of sodium methoxide in methanol (1.24 mL,
6.55 mmol), then acetic acid (1.50 mL, 26.2 mmol), followed
by sodium cyanoborohydride (0.82 g, 13.1 mmol). A 38% (w/v)
aqueous solution of formaldehyde (1.24 mL, 15.7 mmol) in
methanol (30 mL) was then added dropwise over 40 min, and
the mixture was stirred overnight. Aqueous NaOH (4 N, 50
mL) was then added, the methanol was evaporated, and the
aqueous residue was extracted with ethyl acetate. The organic
extract was washed with brine (50 mL), dried (Na2SO4), and
evaporated to give 1.215 g (80%) of 41. The oxalate salt was
prepared in ethanol-diethyl ether: mp 212-215 °C; 1H NMR
(360 MHz, DMSO-d6) δ 2.32 (3H, s), 2.82 (6H, s), 2.95 (2H,
m), 3.09 (2H, m), 3.76 (3H, s), 6.64 (1H, dd, J ) 8.7, 2.3 Hz),
6.99 (1H, d, J ) 2.3 Hz), 7.13 (1H, d, J ) 8.7 Hz); MS (ES+)
m/z 233 [M + H]+. Anal. [C14H20N2O·C2H2O4] C, H, N.
N,N-Dim eth yl-3-(2-a m in oeth yl)-1H-in d ole-2-ca r boxy-
lic Acid Eth yl Ester (42). To a solution of 3-(2-aminoethyl)-
indole-2-carboxylic acid, ethyl ester20 (2.0 g, 8.61 mmol) in
anhydrous methanol (50 mL) was added sodium cyanoboro-
hydride (1.19 g, 18.9 mmol) and glacial acetic acid (2.46 mL,
43.1 mmol). A 38% aqueous solution of formaldehyde (1.88 mL,
25.8 mmol) in anhydrous methanol (25 mL) was then added
dropwise under nitrogen, and the mixture was stirred at room
temperature for 2 h and then quenched with aqueous K2CO3
solution (20 mL). The methanol was evaporated and residue
was partitioned between ethyl acetate and water. The aqueous
layer was extracted twice more with ethyl acetate, and the
combined organic extracts were washed twice with brine, dried
(MgSO4), and evaporated. The residue was purified by flash
chromatography (silica gel, 3-10% MeOH-CH2Cl2) to afford
800 mg (36%) of 42 as a white solid. The hydrochloride salt
was prepared in EtOAc-Et2O to give a colorless solid: mp
248-250 °C; 1H NMR (360 MHz, DMSO-d6) δ 1.39 (3H, t, J )
7.1 Hz), 2.86 (6H, s), 3.19 (2H, m), 3.49 (2H, m), 4.38 (2H, q,
J ) 7.1 Hz), 7.12 (1H, t, J ) 7.2 Hz), 7.30 (1H, t, J ) 7.1 Hz),
7.45 (1H, d, J ) 8.3 Hz), 7.83 (1H, d, J ) 8.1 Hz), 10.82 (1H,
br s), 11.76 (1H, s); MS (CI+) m/z 261 [M + H]+. Anal.
[C15H20N2O2·HCl] C, H, N.
N,N-Dim eth yl-2-[1-(ben zen esu lfon yl)-1H-in dol-4-yl]eth -
yla m in e (45). A solution of aqueous formaldehyde (38% w/v;
790 µL) in methanol (10 mL) was added dropwise to a cooled
(0 °C) and stirred mixture of 44 (750 mg), sodium cyanoboro-
hydride (345 mg), and glacial acetic acid (715 µL) in methanol
(30 mL). The mixture was then allowed to warm to room
temperature and it was stirred for 1 h before saturated
aqueous K2CO3 (20 mL) was added and the methanol was
removed under vacuum. The remaining residue was diluted
with water (20 mL) and extracted with ethyl acetate (3 × 50
mL). The combined organic solutions were washed with brine
(30 mL), dried (MgSO4), and evaporated. Flash chromatogra-
phy of the residue (silica gel, 10% MeOH-CH2Cl2) gave 550
mg (67%) of 45 as a colorless thick oil. The oxalate salt was
prepared and recrystallized from 2-propanol-ether: mp 192-
195 °C; 1H NMR (360 MHz, D2O) δ 2.89 (6H, s), 3.22-3.28
(2H, m), 3.37-3.43 (2H, m), 6.91 (1H, d, J ) 3.9 Hz), 7.19 (1H,
d, J ) 7.5 Hz), 7.35 (1H, t, J ) 8.2 Hz), 7.45-7.50 (2H, m),
7.60 (1H, t, J ) 7.6 Hz), 7.77 (1H, d, J ) 3.8 Hz), 7.89-7.93
(3H, m); MS (EI) m/z 329 [M + H]+. Anal. [C18H20N2O2S·
C2H2O4‚0.2H2O] C, H, N.
N,N-Dim eth yl-3-[1-(ben zen esu lfon yl)-1H-in dol-4-yl]pr o-
p yla m in e (46). A solution of 15 (527 mg, 1.4 mmol) in THF
(15 mL) was treated dropwise with lithium aluminum hydride
(1.0 M solution in THF, 1.4 mL) while the mixture was stirred
under a nitrogen atmosphere. The reaction was stirred for 5
h and then quenched with water (1 mL). The reaction was
N,N-Dim eth yl-2-[2-[3-(3-m eth oxyben zyl)-1,2,4-oxa d ia -
zol-5-yl]-1H-in d ol-3-yl]eth yla m in e (43). To a stirred solu-
tion of 3-methoxybenzeneacetamide oxime21 (1.24 g, 6.90
mmol) in anhydrous THF (60 mL) at -78 °C under nitrogen
was added sodium hydride (60% dispersion in oil, 258 mg, 6.44
mmol). The mixture was then allowed to warm to room
temperature over 15 min before a solution of 42 (600 mg, 2.30
mmol) in anhydrous THF (20 mL) was added dropwise. The
mixture was stirred at room temperature for 1 h and then at
reflux for a further 2 h. After cooling, aqueous NH4Cl (10 mL)
was added and the THF was evaporated. The residual aqueous
phase was partitioned between ethyl acetate and water. The
filtered through
a glass fiber pad, and the filtrate was
evaporated. The residue was partitioned between 2 N aqueous
NaOH and ethyl acetate. The organic phase was dried (Na2-
SO4), evaporated, and purified by flash chromatography (silica
gel, CH2Cl2-MeOH-NH3(aq) 95:5:0.5) to give 275 mg (50%)
of 46 as an oil. The oxalate salt was prepared in diethyl
ether: mp 142-144 °C; 1H NMR (250 MHz, DMSO-d6) δ 1.8-
2.0 (2H, m), 2.67 (6H, s), 2.78-2.84 (2H, m), 2.98-3.04 (2H,
m), 6.97 (1H, d, J ) 3.75 Hz), 7.11 (1H, d, J ) 7 Hz), 7.29 (1H,
t, J ) 7.5 Hz), 7.11 (1H, d, J ) 7 Hz), 7.29 (1H, t, J ) 7.5 Hz),
7.57-7.73 (3H, m), 7.79-7.85 (2H, m), 7.98-9.01 (2H, m); MS

N-Arylsulfonylindoles as 5-HT6 Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3893
(ES+) m/z 343 [M + H]+. Anal. [C19H20N2O3S·1.3(C2H2O4)] C,
pionate. After the mixture was stirred at room temperature
for 2.5 h, additional sodium hydride was added and stirring
was continued for 16 h. Water (50 mL) was added and products
were extracted with dichloromethane (3 × 50 mL) and then
dried (MgSO4) and concentrated. Flash chromatography of the
residue (silica gel, 5% EtOH-CH2Cl2) gave 30 mg (4%) of 50.
The oxalate salt was prepared and crystallized from 2-pro-
panol: mp 133-136 °C; 1H NMR (360 MHz, DMSO-d6) δ 2.31
(3H, s), 2.52 (6H, s), 3.08 (2H, d, J ) 5.6 Hz), 3.48-3.56 (4H,
m and s), 4.89 (1H, d, J ) 6.5 Hz), 7.29 (1H, d, J ) 7.3 Hz),
7.34-7.42 (3H, m), 7.52 (1H, s), 7.80 (1H, d, J ) 8.1 Hz), 7.86
(2H, d, J ) 8.4 Hz); MS m/z 384 (M+). Anal. [C21H24N2O3S·
C2H2O4] C, H, N.
H, N.
N,N-Dim eth yl-2-[1-(ben zen esu lfon yl)-2-ben zoyl-1H-in -
d ol-4-yl]eth yla m in e (47). To a cooled (-78 °C) and stirred
solution of 45 (1.16 g, 3.6 mmol) in anhydrous tetrahydrofuran
(8 mL) was added dropwise, under nitrogen, tert-butyllithium
(1.7 M solution in pentane, 25 mL). The resulting solution was
stirred at -78 °C for 30 min and then it was allowed to warm
to 0 °C over 1 h. After being recooled to -78 °C, a solution of
freshly distilled benzaldehyde (415 mg, 3.9 mmol) in anhy-
drous tetrahydrofuran (4 mL) was added and the mixture was
allowed to warm to room temperature over 3 h. The reaction
was quenched by addition of water (20 mL) and extracted with
ethyl acetate (2 × 75 mL). The combined extracts were dried
(MgSO4) and evaporated. Flash chromatography (silica gel,
10% EtOH-CH2Cl2 to CH2Cl2-MeOH-NH3(aq) 60:8:1) of the
residue gave 720 mg of [1-(benzenesulfonyl)-4-[2-(dimethy-
lamino)ethyl]-1H-indol-2-yl]phenylmethanol as a white solid.
To a solution of the above alcohol (350 mg) in anhydrous
dichloromethane (20 mL) was added activated manganese(IV)
oxide (250 mg), and the resulting mixture was stirred vigor-
ously at room temperature for 30 min. The manganese
residues were removed by filtration and washed with dichlo-
romethane, and the filtrates were evaporated. Flash chroma-
tography of the residual oil (silica gel, 10% EtOH-CH2Cl2 to
CH2Cl2-MeOH-NH3(aq) 60:8:1) gave 330 mg (44% over two
steps) of 47 as a yellow oil. The oxalate salt was prepared and
recrystallized from 2-propanol-diethyl ether: mp 154-156 °C;
1H NMR (360 MHz, DMSO-d6) δ 2.73 (6H, s), 3.16 (4H, s), 7.26
(1H, d, J ) 7.4 Hz), 7.46-7.51 (2H, m), 7.59-7.68 (4H, m),
7.72-7.78 (2H, m), 7.93-8.03 (5H, m); MS (CI+) m/z 433 [M
+ H]+, 293 [M - SO2Ph + 2H]+. Anal. [C25H24N2O3S·C2H2O4‚
0.2H2O] C, H, N.
N,N-Dim et h yl-2-[2-b en zoyl-1H -in d ol-4-yl]et h yla m in e
(48). To a solution of 47 (280 mg, 0.648 mmol) in methanol (5
mL) was added 2 N aqueous NaOH (1 mL), and the solution
was stirred at 80 °C under nitrogen for 30 min. The solvent
was then evaporated and the residue was purified by flash
chromatography (silica gel, 10% EtOH-CH2Cl2 and then CH2-
Cl2-EtOH-NH3(aq) 60:8:1) to afford 160 mg (84%) of 48 as a
yellow oil. The oxalate salt was prepared: mp 243-245 °C
(MeOH-i-PrOH-Et2O); 1H NMR (360 MHz, DMSO-d6) δ 2.51
(6H, s), 2.93 (2H, m), 3.13 (2H, m), 6.97 (1H, d, J ) 6.2 Hz),
7.23 (1H, s), 7.26 (1H, t, J ) 7.1 Hz), 7.38 (1H, d, J ) 8.3 Hz),
7.61 (2H, t, J ) 7.7 Hz), 7.70 (1H, t, J ) 7.4 Hz), 7.96 (2H, d,
J ) 7.1 Hz), 12.01 (1H, s); MS (CI+) m/z 294 [M + H]+. Anal.
[C21H22N2O5·0.5(C2H2O4)] C, H, N.
tr an s-4-(Dim eth ylam in o)-1-(4-m eth ylben zen esu lfon yl)-
1,3,4,5-tetr a h yd r oben z[cd ]in d ol-5-ol (49).25 A solution of
17 (3.97 g, 11.59 mmol) in absolute ethanol (150 mL), aqueous
formaldehyde (38% w/v; 9.2 mL) and glacial acetic acid (92
mL) was hydrogenated at 30 psi over 10% palladium on carbon
(1.56 g) for 65 h. The catalyst was removed by filtration and
washed with absolute ethanol, and the filtrate was evaporated.
The residue was dissolved in dichloromethane (40 mL) and
washed with 10% aqueous NaHCO3 (100 mL). The aqueous
layer was extracted with dichloromethane (2 × 120 mL), and
the combined organic phases were dried (Na2SO4) and evapo-
rated. Flash chromatography of the residue (silica gel, CH2-
Cl2-EtOH-NH3(aq) 85:15:0 to 70:9:1) gave 3.68 g (86%) of 49
together with 400 mg of the corresponding cis isomer. The
oxalate salt was prepared from ethanol-diethyl ether: mp
123-126 °C; 1H NMR (360 MHz, DMSO-d6) δ 2.32 (3H, s), 2.78
(6H, s), 2.96-3.12 (1H, m), 3.16-3.26 (1H, m), 3.38-3.54 (1H,
m), 5.14 (1H, d, J ) 9.3 Hz), 7.30 (1H, d, J ) 7.4 Hz), 7.36-
7.44 (3H, m), 7.55 (1H, s), 7.76 (1H, d, J ) 8.1 Hz), 7.86 (2H,
d, J ) 8.4 Hz); MS (EI) 371 m/z [M + H]+. Anal. [C20H22N2O3S·
C2H2O4] C, H, N.
Molecu la r Mod elin g Meth od s. Structures of compounds
19, 45, 49, 1, and 3 were sketched and then converted to sets
of 26 diverse conformations of each molecule by use of the
torsional enumeration program “et”.35 Each conformation was
subjected to energy minimization with the macromodel batch-
min engine with the MMFFs force field and default minimiza-
tion conditions. After minimization, conformations were checked
for uniqueness by alignment on all heavy atoms. Only the
lower-energy conformer of any pair in which the RMS super-
position error was less than 0.1 Å, together with conformers
that had no equivalent conformer by this definition, were
considered further. Alignment points (SQ points) were added
to each conformer, with the point corresponding to the sulfur
atom of the sulfonamide in each molecule being marked as
“essential” points, required to be matched by another atom of
the same physicochemical type (percent type of essential
point). The SQ program30 was then used to align all conformers
of each molecule on all conformers of each of the other
molecules, the best 50 ensemble alignments according to their
overall SQ score (the sum of all pairwise SQ scores in the
ensemble) being kept for further study. The overall SQ scores
for these ensembles were quite similar, ranging from 1029 to
1035. The molecular mechanics energy associated with each
ensemble was calculated by summing the energies calculated
for the conformer of each molecule present in that ensemble.
A preferred ensemble (score 1032.6, the ninth highest score)
was selected on the basis of its low total energy (338.95 kcal/
mol) with respect to the lowest total found for any ensemble
(337.28 kcal/mol) and the presence of no conformation in the
ensemble with an energy of greater than 1.66 kcal/mol higher
than the lowest-energy conformation found for that molecule,
together with the observation that this ensemble was oriented
in such a way as to present similar groups (aromatic rings,
basic nitrogen atoms) in similar volumes of space. This
preferred ensemble was then reassigned SQ points on all heavy
atoms of all molecules in the ensemble, this time marking the
basic nitrogen of compound 19 as essential by physicochemical
type (percent). Conformations of compound 43 were then
generated with et as before to provide 26 diverse conforma-
tions, which were then subjected to the same minimization
conditions as had been used previously. SQ was then used to
superimpose this molecule on the preferred ensemble of the
other five molecules previously generated, with the top-scoring
superposition having an SQ score of 391 and requiring a
conformer of compound 43 only 0.61 kcal/mol higher in energy
than the best minimum found for any conformer of 43 (79.91
kcal/mol MMFFs energy).
5-HT6 Recep tor Bin d in g Assa y. HeLa cells stably trans-
fected with the human 5-HT6 receptor (obtained from Dr. D.
Sibley, HIH) were grown to confluency in DMEM medium
supplemented with 10% fetal calf serum, 100 units/mL penicil-
lin, and 100 µg/mL streptomycin before being harvested,
pelleted in phosphate-buffered saline (pH 7.4), and stored at
-70 °C. On the day of assay the pellets were thawed and
resuspended in 10 mL of assay buffer (50 mM Tris buffer
containing 0.03% ascorbic acid, pH 7.6 at room temperature),
homogenized in a Polytron (setting 5, 10 s), and centrifuged
at 3000 rpm at 4 °C for 10 min. The resulting pellet was then
resuspended in the same 50 mM Tris buffer to give a washed
wet weight:volume ratio of 3 mg:100 µL. All assays were
carried out in duplicate. Membranes, [3H]-LSD (69.9 mCi/
4-(Dim eth ylam in o)-5-m eth oxy-1-(4-m eth ylben zen esu lfo-
n yl)-1,3,4,5-tetr a h yd r oben z[cd ]in d ole (50). To a solution
of 49 (700 mg, 1.89 mmol) in anhydrous THF (10 mL) and
anhydrous DMF (3 mL) was added sodium hydride (60%
dispersion in oil; 91 mg), followed, after 10 min, by benzyl-
trimethylammonium chloride (35 mg) and methyl 3-bromopro-

3894 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Russell et al.
(4) Kohnen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.;
Lachowicz, J . E.; Meltzer, H.; Sibley, D. R.; Roth, B. L.; Hamblin,
M. W. Cloning, Characterization, and Chromosomal Localization
of a Human 5-HT6 Serotonin Receptor. J . Neurochem. 1996, 66,
47-56.
(5) Ward, R. P.; Hamblin, M. W.; Lachowicz, J . E.; Hoffman, B. J .;
Sibley, D. R.; Dorsa, D. M. Localization of Serotonin Subtype 6
Receptor Messenger RNA in the Rat Brain by in situ Hybridiza-
tion Histochemistry. Neuroscience 1995, 64, 1105-1111.
(6) Branchek, T. A. Blackburn, T. P. 5-HT6 Receptors as Emerging
Targets for Drug Discovery. Annu. Rev. Pharmacol. Toxicol.
2000, 40, 319-334.
(7) Bourson, A.; Borroni, E.; Austin, R. H.; Monsma, F. J .; Sleight,
A. J . Determination of the Role of the 5-ht6 Receptor in the Rat
Brain: A Study Using Antisense Oligonucleotides. J . Pharmacol.
Exp. Ther. 1995, 274, 173-180.
(8) Yoshioka, M.; Matsumoto, M.; Togashi, H.; Mori, K.; Saito, H.
Central Distribution and Function of 5-HT6 Receptor Subtype
in the Rat Brain. Life Sci. 1998, 62, 1473-1477.
(9) Sleight, A. J .; Boess, F. G.; Bo¨s, M.; Levet-Trafit, B.; Riemer,
C.; Bourson, A. Characterization of Ro 04-6790 and Ro 63-0563:
Potent and Selective Antagonists at Human and Rat 5-HT6
Receptors. Br. J . Pharmacol. 1998, 124, 556-562.
(10) Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson, K.; Gager,
T.; Grassam, H. L.; J effrey, P. M.; J oiner, G. F.; King, F. D.;
Middlemiss, D. N.; Moss, S. F.; Newman, H.; Riley, G.; Rout-
ledge, C.; Wyman, P. 5-Chloro-N-(4-methoxy-3-piperazin-1-yl-
phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046): A
Potent, Selective, and Orally Bioavailable 5-HT6 Receptor
Antagonist. J . Med. Chem. 1999, 42, 202-205.
mmol, DuPont NEN) and test compounds were prepared in
assay buffer. A 100 µL aliquot of membrane suspension (3 mg
wet weight of tissue) was incubated at 37 °C in a shaking water
bath in the presence of [3H]-LSD (1 nM) with or without
competing compound to give a final volume of 500 µL. 5-HT
(10 µM) was used to define nonspecific binding. The reaction
was initiated by the addition of the membrane suspension and
was terminated after 60 min by rapid filtration through
Whatman GF/C filters, which had been presoaked in 0.3%
poly(ethylenimine)/0.5% Triton X100, using a Brandel cell
harvester. Each assay tube was washed twice with ap-
proximately 4 mL of 50 mM Tris buffer, pH 7.6 at room
temperature. The filter-bound radioactivity was then deter-
mined by scintillation spectrometry at approximately 40%
efficiency. Data were fitted to a one-site curve-fitting equation
by RS Client to yield IC50 values (the concentration that
inhibits specific binding by 50%). Apparent Ki values were
estimated from the Cheng-Prusoff equation where the ap-
parent Ki values are the IC50 values corrected for ligand
concentration as follows: IC50/(1 + [L]/[Kd], where [L] is the
ligand concentration and Kd is the ligand dissociation constant.
Ad en yla te Cycla se Assa y. CHO cells expressing the rat
5-HT6 receptor were grown in Iscoves medium containing 10%
FCS, 2 mM L-glutamine, 50 IU/mL penicillin, and 50 µg/mL
streptomycin. The cells were plated into 24-well tissue culture
plates 24 h prior to being used. Following this recovery period
the medium was removed and the cells were washed with 1
mL of warm (37 °C) DMEM containing 1 mM of the phos-
phodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX).
Warm DMEM (1 mL) containing 1 mM IBMX and 10 µM of
the appropriate compound (where required) was added to each
well, and the cells were placed back in the incubator for 60
min to allow cAMP to accumulate. The medium was then
removed and the cells were washed with 1 mL of ice-cold PBS.
The cells were then killed by the addition of 200 µL of ice-cold
5% TCA. The cells were then scraped into labeled eppendorf
vials and extracted three times with 1 mL of water-saturated
ether to remove the TCA. Following ether extraction, the
samples were dried and dissolved in 300 µL of cAMP assay
buffer from the Amersham Biotrak [3H]-cAMP assay kit
(product number TRK432). The amount of cAMP present in
each sample was then determined with the reagents and
protocol supplied with the kit.
(11) Bourson, A.; Boess, F. G.; Bo¨s, M.; Sleight, A. J . Involvement of
5-HT6 Receptors in Nigro-striatal Function in Rodents. Br. J .
Pharmacol. 1998, 125, 1562-1566.
(12) Bentley, J . C.; Bourson, A.; Boess, F. G.; Fone, K. C. F.; Marsden,
C. A.; Petit, N.; Sleight, A. J . Investigation of Stretching
Behaviour Induced by the Selective 5-HT6 Receptor Antagonist,
Ro 04-6790, in Rats. Br. J . Pharmacol. 1999, 126, 1537-1542.
(13) Dawson, L. A.; Nguyen, H. Q.; Li, P. In vivo Effects of the
5-HT6 Antagonist SB-271046 on Striatal and Frontal Cortex
Extracellular Concentrations of Noradrenaline, Dopamine, 5-HT,
Glutamate and Aspartate. Br. J . Pharmacol. 2000, 130, 23-26.
(14) Routledge, C.; Bromidge, S. M.; Moss, S. F.; Price, G. W.; Hirst,
W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.; Upton, N.;
Clarke, S. E.; Brown, A. M.; Middlemiss, D. N. Characterization
of SB-271046: A Potent, Selective and Orally Active 5-HT6
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P.; J ennings, A. J .; J oiner, G. F.; King, F. D.; Lovell, P. J .; Moss,
S. F.; Newman, H.; Riley, G.; Rogers, D.; Routledge, C.; Serafi-
nowska, H.; Smith, D. R. Phenyl Benzenesulfonamides are Novel
and Selective 5-HT6 Antagonists: Identification of N-(2,5-
Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzene-
sulfonamide (SB-357134). Bioorg. Med. Chem. Lett. 2001, 11,
55-58.
Mesca lin e-In d u ced Hea d Tw itch Assa y. Male Sprague-
Dawley rats (220-270 g; Bantin and Kingman, Hull, U.K.)
were pretreated with either 19 (10-30 mg/kg ip) or vehicle
[25% poly(ethylene glycol) in water, pH ) 6; 1 mL/kg] 30 min
prior to administration of mescaline (20 mg/kg iv). Rats were
immediately placed into individual Perspex observation boxes
and the number of head twitches was recorded for the following
15 min. Pretreatment with 19 dose-dependently reduced
mescaline-induced head twitches with an ID50 ) 11.3 ( 0.6
mg/kg ip.
(16) Tsai, Y.; Dukat, M.; Slassi, A.; MacLean, N.; Demchyshyn, L.;
Savage, J . E.; Roth, B. L.; Hufesein, S.; Lee, M.; Glennon, R. A.
N1-(Benzenesulfonyl)tryptamines as Novel 5-HT6 Antagonists.
Bioorg. Med. Chem. Lett. 2000, 10, 2295-2299.
(17) Lee, M.; Rangisetty, J . B.; Dukat, M.; Slassi, A.; Maclean, N.;
Lee, D. K. H.; Glennon, R. A. 5-HT6 Serotonin Receptor Binding
Affinities of N1-Benzenesulfonyl and Related Tryptamines. Med.
Chem. Res. 2000, 10, 230-242.
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tion of 1-(Arylsulfonyl)-3-(tetrahydropyridinyl)indoles as 5-HT6
Receptor Inhibitors. U.S. Patent 6,133,287, 2000.
Ack n ow led gm en t. We thank Matthew J enkins,
Laurie Hines, Roy Pengilley, and Andrew Madin for the
preparation of some compounds; Russell Mortishire-
Smith and Steven Thomas for spectroscopic support;
and Anne Heald for 5-HT6 receptor binding assays.
(19) Castro, J . L.; Baker, R.; Guiblin, A. R.; Hobbs, S. C.; J enkins,
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Analogues: Agonists for the 5-HT1D Receptor. J . Med. Chem.
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