Conformationally constrained N1-arylsulfonyltryptamine derivatives as 5-HT6 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.07.028

Several series of conformationally constrained N₁- arylsulfonyltryptamine derivatives were prepared and tested for 5-HT₆ receptor binding affinity and ability to modulate cAMP production in a cyclase assay. The 3-piperidin-3-yl-, 3-(1-methylpyrrolidin-2-ylmethyl)-, and 3-pyrrolidin-3-yl-1H-indole arrays (8-13) appear to be able to adopt a conformation that allows high affinity 5-HT₆ receptor binding, while the β-carboline array 14 binds with a significantly weaker (10- to 100-fold) affinity. N₁-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a high affinity full agonist with EC₅₀ = 24 nM. Several of the N₁-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC₅₀ = 0.8, 1.0 nM).

Full text of DOI:10.1016/j.bmcl.2005.07.028

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4780–4785
Conformationally constrained N1-arylsulfonyltryptamine
derivatives as 5-HT6 receptor antagonists
Derek C. Cole,a,* William J. Lennox,a Joseph R. Stock,a John W. Ellingboe,a
Hossein Mazandarani,b Deborah L. Smith,b Guoming Zhang,b
Gregory J. Tawac and Lee E. Schechterb
aChemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA
bNeurosciences, Wyeth Research, Princeton, NJ 08852, USA
cChemical and Screening Sciences, Wyeth Research, Princeton, NJ 08852, USA
Received 20 May 2005; revised 21 July 2005; accepted 21 July 2005
Available online 25 August 2005
Abstract—Several series of conformationally constrained N1-arylsulfonyltryptamine derivatives were prepared and tested for 5-HT6
receptor binding affinity and ability to modulate cAMP production in a cyclase assay. The 3-piperidin-3-yl-, 3-(1-methylpyrrolidin-
2-ylmethyl)-, and 3-pyrrolidin-3-yl-1H-indole arrays (8–13) appear to be able to adopt a conformation that allows high affinity
5-HT6 receptor binding, while the b-carboline array 14 binds with a significantly weaker (10- to 100-fold) affinity. N1-Benzenesulfo-
nyl-3-piperidin-3-yl-1H-indole 9a is a high affinity full agonist with EC50 = 24 nM. Several of the N1-arylsulfonyl-3-(1-methylpyrr-
olidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC50 = 0.8, 1.0 nM).
ꢀ 2005 Elsevier Ltd. All rights reserved.
The human 5-HT6 receptor was cloned in 1996 and con-
sists of a 440 amino acid residue, seven-transmembrane
protein, with <40% protein sequence homology with the
other 5-HT receptors.1 The 5-HT6 receptor is positively
coupled to adenylyl cyclase,2 and located almost exclu-
sively in the central nervous system, with highest density
in the cerebral cortex, nucleus accumbens, caudate-puta-
men, and hippocampus, and moderate densities in the
thalamus and substantia nigra.3 A wide range of anti-
psychotic agents and antidepressants have high affinity
for the 5-HT6 receptor,4 stimulating considerable effort
to understand its role in treatment of CNS disorders,
including schizophrenia, depression, and impaired learn-
ing and memory.5–10
357134 (4),13 with improved affinity and physical prop-
erties, were reported. N1-arylsulfonyltryptamines, such
as MS-245 (5; Ki = 2.3 nM), have also been shown to
Cl
MeHN
N
NHMe
X
NH
NH
H
O
O
N
N
NH
S
S
S
O O
OMe
3
Br
O O
S
NH2
N
F
N
1: X = N
2: X =CH
H
Br
OMe
N
4
H
N
Among the first 5-HT6 receptor antagonists was a series
of bismethylaminopyrimidinyl- and bismethylaminopy-
ridinyl-sulfonamides, Ro-04-6790 (1) and Ro-63-0563
(2) (Fig. 1).11 Subsequently, a series of piperazinyl-ben-
zenesulfonamide antagonists SB-271046 (3)12 and SB-
N
MeO
MeO
N
N
N
O
O
O
S
S
S
O
O
O
Keywords: N1-Arylsulfonyltryptamine; 5-HT6; Serotonin; Receptor;
Antagonist.
5
6
7
*
Corresponding author. Tel.: +1 845 602 4619; fax: +1 845 602
5561; e-mail: coledc@wyeth.com
Figure 1. Structures of 5-HT6 receptor ligands.
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.028

D. C. Cole et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4780–4785
4781
bind to the 5-HT6 receptor with high affinity,14,15 as
N
Boc
NH
N
Bn
have the conformationally constrained N1-arylsulfonyl-
3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (6; Ki =
2 nM)16,17 and the (9-arylsulfonyl-2,3,4,9-tetrahydro-
1H-carbazol-4-yl)-methylamine (7; Ki = 1.5 nM).18
b, c
d, e
N
N
N
H
H
O
a
S
O
Ar
In this report, we present the results of a study into the
structural–activity relationships of a series of conforma-
tionally constrained N1-arylsulfonyltryptamine deriva-
tives. The effect of indole substitution on 5-HT6
receptor binding affinity of N1-arylsulfonyltryptamine
derivatives has been studied and, in general, substitution
on the 4-, 5-, 6-, or 7-positions does not increase the affin-
ity, relative to the unsubstituted indole14,16. Thus, the fo-
cus of this work is on the conformationally constrained
aminoethyl portion and the N1-arylsulfonyl substituents.
16
8
15
N
H
N
Boc
d, e
NH
N
Boc
f
g
N
N
N
H
H
O
S
O
Ar
17
18
9
Scheme 1. Reagents and conditions: (a) 1-benzyl-3-piperidone, KOH,
IPA, D; (b) (i) ACE-Cl, DCE, rt; (ii) MeOH, D; (c) (Boc)2O, K2CO3,
acetone, water, rt; (d) ArSO2Cl, t-BuOK, THF, rt; (e) 2 N HCl,
dioxane, rt; (f) 1-Boc-3-piperidone, KOH, IPA, D; (g) H2, Pd/C
MeOH, rt.
Seven arrays, represented by the generic structures 8–14
(Fig. 2), were prepared. Array 8 was prepared, as shown
in Scheme 1, by coupling indole with 1-benzyl-3-piperdi-
none hydrate in refluxing isopropylalcohol (IPA) with
excess 1 N KOH to give 3-(1-benzyl-1,2,5,6-tetrahydro-
pyridin-3-yl)-1H-indole 15.19 Removal of the benzyl
group was carried out by a modified version of a proce-
dure by Olofson et al.20 in which the benzylamine was
stirred at room temperature with a-chloroethyl chloro-
formate (ACE-Cl) in dichloroethane (DCE) to give the
a-chloroethyl carbamate, which was cleaved to the free
amine by refluxing in MeOH. Subsequent protection
gives the N-Boc core 16, which was coupled with a set
of sulfonyl chlorides in THF with potassium tert-butox-
ide. Finally, the Boc group was removed by stirring with
2 N HCl in dioxane. The compounds were purified by
reverse-phase semi-preparative HPLC.21
The reaction of the magnesium salt of indole with either
(S)- or (R)-N-Cbz-proline acid chloride in toluene affor-
ded the 3-ketoindole 19 (Scheme 2: (S)-enantiomer
shown).23 Removal of the Cbz group was effected by
hydrogenation over palladium on carbon with formic
acid in methanol. The keto group was reduced with
LiAlH4 in refluxing THF and the pyrrolidine protected
as the N-Boc derivative 20. Array 10 was prepared, as
described above for array 8. Reduction of 19 with
LiAlH4 in refluxing THF afforded the 3-(1-methyl-pyrr-
olidin-2-ylmethyl)-1H-indole 21, which was converted to
array 11 by sulfonylation.
Coupling of indole with 1-Boc-3-piperdinone leads to
the formation of the enamine isomer 17, due to the
electron with-drawing nature of the N-substituent.22
Hydrogenation gives the reduced N-Boc-3-piperidin-3-
yl-1H-indole 18. Array 9 was then prepared, as de-
scribed above for array 8.
The synthesis of the N1-arylsulfonyl-3-(1-alkyl-pyrroli-
din-3-yl)-1H-indole arrays 12–13 was carried out by
coupling indole with N-methyl- and N-benzylmaleimide
in refluxing acetic acid, followed by reduction with
LiAlH4 to give the 3-(1-methyl- and 3-(1-benzylpyrroli-
din-3-yl)-1H-indole cores 22–23 (Scheme 3)23 that were
sulfonylated.
Boc
H
H
R
N
N
H
NH
NH
N
e, f
N
H
N
N
N
N
N
H
O
S
O
O
O
S
S
S
b, c, d
O
Ar
O
O
O
Ar
Ar
Ar
a
S-20
S-10
8
9
10 (R = H)
11 (R = Me)
Cbz
H
R
N
N
N
N
H
H
O
NH
c
e
N
N
H
N
N
N
H
O
O
O
S
S
S
O
O
O
Ar
Ar
Ar
S-19
S-21
S-11
12 (R = Me)
13 (R = Bn)
14
Scheme 2. Reagents and conditions: (a) (S)-N-Cbz-Pro-Cl, EtMgBr,
DCM, 0 ꢁC; (b) HCO2H, Pd/C, MeOH, rt; (c) LiAlH4, THF, D; (d)
(Boc)2O, K2CO3, acetone, water, rt; (e) ArSO2Cl, t-BuOK, THF, rt.
Figure 2. Conformationally constrained N1-arylsulfonyltryptamine
arrays.

4782
D. C. Cole et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4780–4785
R
R
significantly weaker affinity than the corresponding
N-Me analogs.16
N
N
a, b
c
The 9-arylsulfonyl-2,3,4,9-tetrahydro-1H-b-carbolines
(14a–14m; Ki = 41–252 nM) had weaker 5-HT6 receptor
affinity.
N
H
N
H
N
O
S
O
Ar
22 (R = Me)
23 (R = Bn)
12 (R = Me)
13 (R = Bn)
Each of the compounds 5–9, 11–12, and 14 was
expanded to a set of roughly 200 molecule conforma-
tions (OMEGA software, OpenEye Scientific), generat-
ing 2400 total molecule conformations that were
aligned (ROCS software, OpenEye Scientific) with each
other. An overlap score was assigned to each alignment
based on the molecule shape and pharmacophore ori-
entation. These alignments were analyzed to find out
the conformation that had the largest average overlap
with the remaining conformations. This conformation
was defined as the reference conformation. A consen-
sus of those conformations, which match that of the
reference conformation, was obtained and is shown in
Figure 3.
Scheme 3. Reagents and conditions: (a) N-methyl- or N-benzylmalei-
mide, AcOH, D; (b) LiAlH4, THF, D; (c) ArSO2Cl, t-BuOK, THF, rt.
The
9-arylsulfonyl-2,3,4,9-tetrahydro-1H-b-carboline
array 14 was prepared by Boc protection of the b-carb-
oline, followed by sulfonylation and deprotection, as
described for array 8.
All the conformationally constrained N1-arylsulfonyl-
tryptamine derivatives were assayed for their ability to
displace [3H]-LSD from cloned human 5-HT6 receptors
stably expressed in HeLa cells.16 N1-Benzenesulfonyl-3-
(1,2,5,6-tetrahydropyridin-3-yl)- 1H-indole 8a had excel-
lent affinity (Ki = 4.6 nM) for the 5-HT6 receptor.
Mono- and dihalo, alkyl and alkoxy substituted aryl-
sulfonamides (8b–8q; Ki = 8.5–48 nM) all had slightly
reduced affinity, as did the heteroaryl sulfonamides
(8t–8w; Ki = 8–58 nM) (Table 1).
With the N1-phenylsulfonylindole groups aligned, the
basic amine of compounds 5–9 and 11–12 can adopt a
similar position. This is in contrast to 14 that cannot
adopt a conformation where the basic amine overlays
with the basic amine of the other molecules.
Glennon has shown that in the N1-arylsulfonylskatole
series absence of a basic amine results only in a 3-fold loss
in affinity, relative to the tryptamine with the
4-aminophenylsulfonyl group.25 However, we show here
that compound 14m (Ki = 116 nM), which has this
4-aminophenylsulfonyl group and where the basic amine
is restricted to a position that does not overlap with the
basic amines of the other cores, is about 100-fold less po-
tent than the corresponding N1-(4-aminophenylsulfonyl)-
3-(1-methyl-pyrrolidin-3-yl)-1H-indole 12m (Ki = 1 nM).
The racemic N1-arylsulfonyl-3-piperidin-3-yl-1H-indole
series 9 showed similar SAR trends with the unsubstitut-
ed benzenesulfonamide having high affinity (9a;
Ki = 2 nM) and the substituted benzenesulfonamides
and heteroarylsulfamides having equal or slightly lower
binding affinity (9f–9x; Ki = 2–44 nM). The enantiomers
of 9a were separated24 and showed a 3-fold difference in
binding affinity (Ki = 1 nM vs. 3 nM).
In general, the (S)-N1-arylsulfonyl-3-pyrrolidin-2-yl-
methyl-1H-indole series 10 had lower 5-HT6 receptor
affinity (10a–10x; Ki = 20–283 nM), with the exception
of 4-aminophenylsulfonamide (10m; Ki = 7 nM). In-
creased binding affinity for 4-aminophenylsulfonamide
tryptamines has been previously reported.25 The corre-
sponding (R)-N1-arylsulfonyl-3-pyrrolidin-2-ylmethyl-
1H-indoles were not prepared. Both (R)- and (S)-enanti-
omers of N1-arylsulfonyl-3-(1-methyl-pyrrolidin-2-ylm-
ethyl)-1H-indole series 11 had high affinity (11a–11x;
Ki = 3–19 nM). The unsubstituted phenyl-, 3-, and 4-hal-
ophenyl-, 4-aminophenyl-, and 5-halothiophenesulfonyl
derivatives had the highest affinity. Interestingly, even
the large 5-chloro-3-methylbenzothiophene analog re-
tains high affinity (11x; Ki = 11 nM).
High affinity compounds were assayed for their ability
to modulate cAMP production in a cyclase assay (Table
1).16 None of the N1-arylsulfonyl-3-(1,2,5,6-tetrahydro-
pyridin-3-yl)-1H-indole derivatives 8 showed any antag-
onist activity; however, several compounds of the series
did show a modest ability to stimulate cAMP produc-
tion indication agonist activity. Several racemic N1-aryl-
sulfonyl-3-piperidin-3-yl-1H-indole analogs had agonist
activity. Of particular interest is 9a that stimulated
cAMP production with an EC50 value of 24 nM and be-
haved as a full agonist, and although the enantiomers
had only 3-fold difference in affinity (Ki = 1 nM vs.
3 nM) all the agonist activity could be attributed to
one enantiomer, while the diastomer failed to show
any functional activity. The N1-(4-methoxybenzene)sul-
fonyl-3-piperidin-3-yl-1H-indole 9l (IC50 = 7 nM) be-
haved as a partial antagonist.
All members of the racemic N1-arylsulfonyl-3-(1-meth-
yl-pyrrolidin-3-yl)-1H-indole array 12 had excellent
5-HT6 receptor affinity (12c–12r; Ki = 1–5 nM).
Surprisingly, members of the N1-arylsulfonyl-3-(1-ben-
zyl-pyrrolidin-3-yl)-1H-indole array 13 also had high
affinity (13k–13y; Ki = 1–9 nM), in spite of a large N-
benzyl substituent. This was in contrast to the N1-aryl-
sulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole
series where the larger N-Bn derivatives had
Several of the N1-arylsulfonyl-3-(1-methylpyrrolidin-2-
ylmethyl)-1H-indole derivatives were very potent antag-
onists in the cAMP stimulation assay, in particular,
(S)-11r and (S)-11t were full antagonists with IC50
values of approximately 1 nM. Members of the N1-aryl-
sulfonyl-3-(1-methyl- and N1-arylsulfonyl-3-(1-benzyl-

D. C. Cole et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4780–4785
4783
Table 1. 5-HT6 binding affinity and functional activity of constrained N1-arylsulfonyltryptamines
Compound
Ar-SO2
Ki (nM)a
cAMP assay IC50 (nM)b Imax (%)
cAMP assay EC50 (nM)c Emax (%)
8a
8b
Ph
2-F-Ph
2-Cl-Ph
4.6 0.4
9.2 0.5
13.0 1.8
21.7 0.9
8.5 1.3
14.0 0.6
44.7 2.1
10.5 1.1
22.0 0.9
16.0 0.6
13.0 1.4
20.0 2.9
26.0 1.5
48.0 2.9
22.7 2.7
58.0 2.4
8.0 0.2
2.0 0.1
3.0 0.1
1.0 0.1
2.0 0.1
10.0 0.3
10.0 1.0
7.0 1.0
9.8 2.6
3.0 0.3
44.0 3.0
27.7 7.6
43.0 7.0
22.0 2.0
49.0 4.0
34.0 4.0
33.0 5.0
40.0 5.0
7.0 1.0
49.0 3.0
23.0 3.0
25.0 3.0
20.0 1.0
159.0 8.5
51.0 0.7
41.0 1.4
52.0 0.0
51.5 0.4
62.0 0.7
8c
8d
2-CF3-Ph
3-F-Ph
3-Cl-Ph
8e
269.5 15.9
344.5 11.0
8f
8g
3-CF3-Ph
4-F-Ph
4-Cl-Ph
8h
8i
8l
8n
4-MeO-Ph
2,4-diF-Ph
2,3-diCl-Ph
3,4-diF-Ph
3,4-diCl-Ph
5-Cl-thienyl
diMe-oxazole
5-Cl-1,3-diMe-pyrazole
Ph
8o
8p
8q
8t
8v
8w
9a (racemic)
89.5 8.8
24.0 3.5
0.0
50.0 0.0
100.0 0.0
0.0
9a (enantiomer 1) Ph
9a (enantiomer 2) Ph
0.0
0.0
36.0 6.4
100.0 0.0
9f
3-Cl-Ph
9j
4-CF3-Ph
4-MeO-Ph
3,4-diF-Ph
thienyl
9l
9p
7.3 1.0
65.5 1.1
66.0 5.0
58.5 0.4
60.5 0.4
93.0 1.4
9s
9t
9x
5-Cl-thienyl
5-Cl-3-Me-benzothiophene
Ph
(S)-10a
(S)-10c
(S)-10f
(S)-10i
(S)-10j
(S)-10k
(S)-10l
(S)-10m
(S)-10q
(S)-10r
(S)-10t
(S)-10u
(S)-10x
(R)-11a
(R)-11u
(S)-11a
(S)-11c
(S)-11f
(S)-11i
(S)-11j
(S)-11k
(S)-11l
(S)-11m
(S)-11q
(S)-11r
(S)-11t
(S)-11u
(S)-11x
12c
2-Br-Ph
3-Cl-Ph
4-Cl-Ph
4-I-Ph
4-Me-Ph
4-MeO-Ph
4-NH2-Ph
3,4-diCl-Ph
3,4-diMeO-Ph
5-Cl-thienyl
5-Br-thienyl
7.6 0.3
79.2 0.1
5-Cl-3-Me-benzothiophene 283.7 4.5
Ph
8.0 1.0
4.0 0.2
5.0 1.0
7.0 1.0
4.0 0.3
7.0 0.4
3.0 0.2
5.0 1.0
19.3 6.3
3.0 0.1
12.0 3.0
8.0 0.2
4.0 0.1
0.6 0.1
75.0 0.7
5-Br-thienyl
Ph
2-Br-Ph
102.8 18.5
76.5 0.4
81.4 0.4
76.5 10.2
96.2 2.3
8.2 1.7
87.0 1.4
87.5 1.0
77.0 0.0
86.0 0.0
99.5 0.4
78.5 0.4
3-Cl-Ph
4-Cl-Ph
4-I-Ph
4-Me-Ph
49.5 13.8
56.3 14.4
4-MeO-Ph
4-NH2-Ph
3,4-diCl-Ph
3,4-diMeO-Ph
5-Cl-thienyl
5-Br-thienyl
5-Cl-3-Me-benzothiophene
2-Br-Ph
24.5 1.1
7.3 0.6
0.8 0.2
1.0 0.0
100.0 0.0
86.5 0.3
100.0 0.0
99.0 0.0
96.0 1.4
87.5 1.1
98.5 1.1
83.5 1.8
86.5 1.1
93.5 0.4
89.5 1.8
100.0 0.0
100.0 0.0
62.0 1.0
72.0 1.4
97.0 2.1
63.0 1.4
3.0 0.1 112.0 12.7
11.0 2.0
1.0 0.1
2.0 0.1
1.0 0.2
1.0 0.2
1.0 0.2
11.0 0.0
53.3 12.2
52.5 5.3
85.5 11.7
43.6 5.3
15.5 2.5
12h
12i
4-F-Ph
4-Cl-Ph
4-I-Ph
12j
12m
4-NH2-Ph
3,4-diCl-Ph
3,4-diMeO-Ph
2-Br-Ph
12q
12r
3.0 0.4 107.1 18.3
5.0 1.0
93.7 0.3
21.0 5.6
8.0 1.0 123.0 2.1
13c
13k
14.0 1.0
4-Me-Ph
4-NH2-Ph
3,4-diCl-Ph
13m
13q
1.0 0.2
15.0 0.3
25.0 0.7
61.0 9.2
(continued on next page)

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D. C. Cole et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4780–4785
Table 1 (continued)
Compound
Ar-SO2
Ki (nM)a
cAMP assay IC50 (nM)b
Imax (%)
cAMP assay EC50 (nM)c
Emax (%)
13u
13y
14a
14f
5-Br-thienyl
4-Me-2-NH2-thiazole
Ph
9.0 1.0
3.0 0.1
110.0 5.7
110.0 7.1
69.0 0.7
97.0 1.4
252.7 63.8
41.7 10.7
271.3 37.3
116.0 5.5
3-Cl-Ph
4-Me-Ph
4-NH2-Ph
14k
14m
a Displacement of [3H]-LSD binding to cloned h5-HT6 receptors stably expressed in HeLa cells. Mean of three determinations.16
b Inhibition of cAMP production in HeLa cells stably transfected with human 5-HT6 receptors. Mean of three determinations.
c Agonism of cAMP production in HeLa cells stably transfected with human 5-HT6 receptors. Mean of three determinations.
References and notes
1. Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.;
Huebner, K.; Lachowicz, J. E.; Meltzer, H. Y.; Sibley,
D. R.; Roth, B. L.; Hamblin, M. W. J. Neurochem. 1996,
66, 47.
2. Sebben, M.; Ansanay, H.; Bockaert, J.; Dumuis, A.
Neuroreport 1994, 5, 2553.
3. Woolley, M. L.; Marsden, C. A.; Fone, K. C. Curr. Drug
Target CNS Neurol. Disord. 2004, 3, 59.
4. Roth, B. L.; Craigo, S. C.; Choudhary, M. S.; Uluer, A.;
Monsma, F. J., Jr.; Shen, Y.; Meltzer, H. Y.; Sibley, D. R.
J. Pharmacol. Exp. Ther. 1994, 268, 1403.
5. Pullagurla, M.; Bondareva, T.; Young, R.; Glennon, R. A.
Pharmacol. Biochem. Behav. 2004, 78, 263.
6. Minabe, Y.; Shirayama, Y.; Hashimoto, K.; Routledge,
C.; Hagan, J. J.; Ashby, C. R., Jr. Synapse 2004, 52, 20.
7. Lacroix, L. P.; Dawson, L. A.; Hagan, J. J.; Heidbreder,
C. A. Synapse 2004, 51, 158.
8. King, M. V.; Sleight, A. J.; Woolley, M. L.; Topham, I.
A.; Marsden, C. A.; Fone, K. C. Neuropharmacology 2004,
47, 195.
Figure 3. Alignment of conformationally constrained N1-arylsulfonyl-
tryptamine derivatives 5, 6, 7 (R and S), 8, 9 (R and S), 11 and 12 (R
and S), and 14 (Ar = Ph). Compound 14 is shown in green, while
others are shown in grey.
9. Woolley, M. L.; Marsden, C. A.; Sleight, A. J.; Fone, K.
C. Psychopharmacology (Berl) 2003, 170, 358.
pyrrolidin-3-yl)-1H-indole array 12–13 functioned as
antagonists with modest IC50 values (15–100 nM).
10. Lindner, M. D.; Hodges, D. B., Jr.; Hogan, J. B.; Orie, A.
F.; Corsa, J. A.; Barten, D. M.; Polson, C.; Robertson, B.
J.; Guss, V. L.; Gillman, K. W.; Starrett, J. E., Jr.;
Gribkoff, V. K. J. Pharmacol. Exp. Ther. 2003, 307, 682.
11. Sleight, A. J.; Boess, F. G.; Bos, M.; Levet-Trafit, B.;
Riemer, C.; Bourson, A. Br. J. Pharmacol. 1998, 124, 556.
12. Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson,
K.; Gager, T.; Grassam, H. L.; Jeffrey, P. M.; Joiner, G.
F.; King, F. D.; Middlemiss, D. N.; Moss, S. F.; Newman,
H.; Riley, G.; Routledge, C.; Wyman, P. J. Med. Chem.
1999, 42, 202.
In summary, several arrays of conformationally
constrained N1-arylsulfonyltryptamines were prepared
and tested for 5-HT6 receptor binding and functional
assessment. Similar SAR, as has been reported for the
N1-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
indole derivatives, was observed with various substi-
tuted phenyl-, heteroaryl-, and fused arylsulfonyl groups
being tolerated.16
13. Bromidge, S. M.; Clarke, S. E.; Gager, T.; Griffith, K.;
Jeffrey, P.; Jennings, A. J.; Joiner, G. F.; King, F. D.;
Lovell, P. J.; Moss, S. F.; Newman, H.; Riley, G.; Rogers,
D.; Routledge, C.; Serafinowska, H.; Smith, D. R. Bioorg.
Med. Chem. Lett. 2001, 11, 55.
14. Tsai, Y.; Dukat, M.; Slassi, A.; MacLean, N.; Demchy-
shyn, L.; Savage, J. E.; Roth, B. L.; Hufesein, S.; Lee, M.;
Glennon, R. A. Bioorg. Med. Chem. Lett. 2000, 10, 2295.
15. Russell, M. G.; Baker, R. J.; Barden, L.; Beer, M. S.;
Bristow, L.; Broughton, H. B.; Knowles, M.; McAllister,
G.; Patel, S.; Castro, J. L. J. Med. Chem. 2001, 44, 3881.
16. Cole, D. C.; Ellingboe, J. W.; Lennox, W. J.; Mazanda-
rani, H.; Smith, D. L.; Stock, J. R.; Zhang, G.; Zhou, P.;
Schechter, L. E. Bioorg. Med. Chem. Lett. 2005, 15, 379.
17. Slassi, A.; Edwards, L.; OÕBrien, A.; Xin, T.; Tehim, A.
WO 2000 063203.
The 3-piperidin-3-yl, 3-pyrrolidin-2-ylmethyl, and 3-
pyrrolidin-3-yl constrained aminoethyl groups (8–13) ap-
pear to be able to adopt a conformation that allows high
affinity 5-HT6 receptor binding, while the b-carboline 14
binds with a significantly weaker (10- to 100-fold) affinity.
N1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a
high affinity full agonist with an EC50 of 24 nM. Several
of the N1-arylsulfonyl-3-(1-methylpyrrolidin-3-ylmeth-
yl)-1H-indole derivatives behave as very potent antago-
nists ((S)-11r, (S)-11t; IC50 = 0.8, 1.0 nM).
Acknowledgment
18. Chang-Fong, J.; Rangisetty, J. B.; Dukat, M.; Setola, V.;
Raffay, T.; Roth, B.; Glennon, R. A. Bioorg. Med. Chem.
Lett. 2004, 14, 1961.
We thank Murthy Damarla, Wyeth Discovery Analyti-
cal Chemistry, for chiral HPLC separation of 9a.

D. C. Cole et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4780–4785
4785
19. Gharagozloo, P.; Miyauchi, M.; Birdsall, B.; Birdsall, N.
J. J. Org. Chem. 1998, 63, 1974.
Schulz, D. W.; Koe, B. K. J. Med. Chem. 1994, 37,
2509.
20. Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau, M.;
Malfroot, T. J. Org. Chem. 1984, 49, 2081.
21. Cole, D. C.; Pagano, N.; Kelly, M. F.; Ellingboe, J.
J. Comb. Chem. 2004, 6, 78.
22. Gharagozloo, P.; Miyauchi, M.; Birdsall, N. J. Tetra-
hedron 1996, 52, 10185.
24. Chiral HPLC separation. Column: Chiralcel-OJ
20 · 250 mm; mobile phase—87% heptane (containing
0.1% TFA) and 13% IPA; sample dissolved in EtOH
10 mg/mL; flow rate—8 mL/min. Enantiomer 1: reten-
tion time 23.4 min, enantiomer 2: retention time
27.4 min.
23. Macor, J. E.; Blank, D. H.; Fox, C. B.; Lebel, L. A.;
Newman, M. E.; Post, R. J.; Ryan, K.; Schmidt, A. W.;
25. Pullagurla, M. R.; Dukat, M.; Setola, V.; Roth, B.;
Glennon, R. A. Bioorg. Med. Chem. Lett. 2003, 13, 3355.