N1-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists.

Article abstract of DOI:10.1016/S0960-894X(00)00453-4

N-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (BS/5-OMe DMT; 5) was shown to bind at human 5-HT6 serotonin receptors with high affinity (Ki = 2.3 nM) relative to serotonin (Ki = 78 nM). Structural variation failed to result in significantly enhanced affinity. BS/5-OMe DMT acts as an antagonist of 5-HT-stimulated adenylate cyclase (pA2 = 8.88 nM) and may represent the first member of a novel class of 5-HT6 antagonists.

Full text of DOI:10.1016/S0960-894X(00)00453-4

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2295±2299
N -(Benzenesulfonyl)tryptamines as Novel 5-HT
1
6
y
Antagonists
a
a
b
b
c
Yuching Tsai, Malgorzata Dukat, Abdelmalik Slassi, Neil MacLean,
b
c
c
Lidia Demchyshyn, Jason E. Savage, Bryan L. Roth, Sandy Hufesein,
a
a,
Mase Lee and Richard A. Glennon *
aDepartment of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, USA
bNPS Allelix Corp., Mississauga, Ontario L4V 1V7, Canada
cDepartment of Biochemistry and NIMH Psychoactive Drug Screening Program, School of Medicine,
Case Western Reserve University, Cleveland, OH 44106, USA
Received 19 June 2000; accepted 2 August 2000
AbstractÐN
serotonin receptors with high anity (K
ni®cantly enhanced anity. BS/5-OMe DMT acts as an antagonist of 5-HT-stimulated adenylate cyclase (pA
represent the ®rst member of a novel class of 5-HT antagonists. # 2000 Elsevier Science Ltd. All rights reserved.
1
-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (BS/5-OMe DMT; 5) was shown to bind at human 5-HT
=2.3 nM) relative to serotonin (K =78 nM). Structural variation failed to result in sig-
=8.88 nM) and may
6
i
i
2
6
Seven families of serotonin (1) receptors have been
identi®ed: 5-HT ±5-HT , and one of the newest of
®rst 5-HT -selective antagonists. The 2-phenyl counter-
6
1,2
part of EMDT (i.e., PMDT; 2b) also displays 5-HT
6
1
7
3
14
these are the 5-HT receptors. 5-HT receptors belong
6
antagonist character.
6
to the G-protein superfamily of receptors and are posi-
tively coupled to an adenylate cyclase second messenger
4
system. Although the exact clinical implications of
5-HT receptors remain to be identi®ed, it is of sig-
6
ni®cance that these receptors are found primarily in the
central nervous system. Importantly, various typical
and atypical antipsychotic agents and antidepressants
have been demonstrated to bind with high anity at 5-
5�7
HT receptors (i.e., with K values of <100 nM)
6
sug-
i
gesting that these receptors be targeted for the develop-
ment of novel psychotherapeutic agents. Evidence also
suggests that 5-HT receptors might modulate choliner-
6
gic neurotransmission and GABA function leading to
speculation that 5-HT6 agents could play a role in
memory impairment, anxiety, mood-dependent beha-
vior, and related disorders.8
�13
To date, relatively few 5-HT -selective agents have been
6
reported. EMDT (2a) represents the ®rst agonist show-
1
The sulfonamide-containing antagonist compounds 3
and 4 are structurally distinct from the tryptamine-con-
taining agonists 5-HT (1) and EMDT (2a). However,
PMDT (2b) is a 5-HT6 antagonist indicating that
antagonist activity can be associated with a tryptamine
sca€old. In the course of the synthesis of certain
EMDT-related compounds, a benzenesulfonyl group
4
ing selectivity for 5-HT receptors. Ro 04-6790 (3a),
6
1
5,16
17
Ro 63-0563 (3b),
and SB-271046 (4) represent the
y
Presented in part at the 77th Annual Virginia Academy of Sciences
Meeting, Norfolk, VA, 25±28 May, 1999
*Corresponding author. Tel.: +1-804-828-8487; fax: +1-804-828-7404;
e-mail: glennon@hsc.vcu.edu
was employed to protect the indole N -position during
1
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00453-4

2
296
Y. Tsai et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2295±2299
1
4
functionalization of the C -position. As a matter of
2
substituents (i.e., 7 and 8) has little e€ect on 5-HT6
receptor anity. Replacement of the N -benzenesul-
routine, some of these N -benzenesulfonyl-protected
1
1
tryptamine derivatives were examined in radioligand
binding assays and were found to bind at 5-HT recep-
fonyl group with the sterically larger 2-naphthalene-
sulfonyl (i.e., 9) or 1-naphthalenesulfonyl (i.e., 10)
groups also had little e€ect. The anities of these
derivatives were not more than four times greater than,
or less than, that of 5. The indole 5-methoxy substituent
of 8 was moved to the 4-, 6-, and 7-positions. With the
6
tors. Upon this discovery, our intent was to optimize
anity by investigating analogues where the substitu-
tion pattern in the benzenesulfonamide moiety was
varied, to subsequently vary the position of the trypt-
amine methoxy group, and to then select a member of
the series for further evaluation in a functional assay.
Disclosure of 3 and 4 prompted us to report our ®nd-
ings. In particular, we posed the following questions: (1)
exception of the 7-methoxy analogue (15; K =183 nM),
i
which binds with about 140-fold reduced anity, a-
nity was only slightly decreased when 8 (K =1.3 nM) is
i
compared with 11 (K =7.4 nM) and 12 (K =9.5 nM).
i
i
Do the N -benzenesulfonyl analogues of tryptamines
1
possess activity as 5-HT agonists or antagonists? (2) Is
6
In the absence of the N -benzenesulfonyl group, moving
1
the mode of binding of 3 and 4 related to the mode of
binding of these benzenesulfonyltryptamines?
the 5-methoxy group of 5-methoxy-N,N-dimethyl-
tryptamine (K =16 nM) to the 4-, 6-, or 7-position
i
reduces anity by about 10-fold, 500-fold, and 1225-
fold, respectively.18 Because the anity of the 7-meth-
oxy analogue 15 was higher than expected, we examined
several additional 7-methoxy-substituted compounds.
The 4-chloro (K =45 nM) and 4-methoxy (K =93 nM)
Chemistry
All compounds were prepared by a simple one-step
acylation reaction of the anion of a methoxy-substituted
N,N-dimethyltryptamine derivative with the appro-
priate benzenesulfonyl chloride. Physicochemical prop-
erties of the target compounds are provided in Table 1.
i
i
derivatives 13 and 14, respectively, displayed higher a-
nity than 15, but lower anity than 5 (K =2.3 nM).
i
Interestingly, the anity of the N -(2-naphthalenesul-
1
fonyl) derivative 16 (K =5.0 nM) was in the same range
i
as that of 5.
Compound 5, the parent member of the series, was
examined both as an agonist and as an antagonist in an
adenylate cyclase assay. Compound 5 lacked agonist
character at a concentration of 10,000 nM. However,
this single concentration completely blocked 5-HT-
stimulated cyclase activity. Subsequent testing showed
that 5 produced inhibition of adenylate cyclase activity
Results and Discussion
N -Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine
1
(BS/5-OMe DMT; 5) binds at 5-HT6 receptors with
high anity (K =2.3 nM), and with an anity higher
i
than that of 5-HT (1; K =78Æ6 nM) itself. Table 1
i
shows that introduction of an electron-withdrawing 4-
chloro group (i.e., 6) or electron-donating methoxy
in a dose-dependent manner (pA =8.88 Æ 0.2 nM).
2
6 1
Table 1. Physicochemical and 5-HT serotonin receptor binding properties of N -(arylsulfonyl)-N,N-dimethyltryptamine derivatives
a
ꢀ
b
R
Z
Yield (%)
Mp ( C)
Empirical formula
K
i
, (nM) (ÆSEM)
5
6
7
8
9
1
5-OMe
5-OMe
5-OMe
5-OMe
5-OMe
5-OMe
Ph
4-Cl Ph
4-OMe Ph
2,5-diOMe Ph
2-Naphthyl
1-Naphthyl
61
37
16
30
33
15
224±226
218±220
172±174
172±174
174±176
172±174
C
19
H
22
N
2
O
3
S.C
2
H
2
O
4
2.3 (Æ0.5)
3.1 (Æ0.1)
8.0 (Æ0.4)
1.3 (Æ0.2)
1.6 (Æ0.3)
0.9 (Æ0.2)
7.4 (Æ0.2)
9.5 (Æ0.6)
C
19
H
21ClN
2
SO
.C
3
2
H
2
O
4
20
H
21
H
23
H
24
N
26
N
24
N
2
2
2
SO
SO
SO
4.
C
.C
.C
H
2 2
H
2 2
H
2 2
O
4
O
4
O
4
C
C
C
5
3
23
21
21
19
H
24
26
26
N
2
SO
SO
SO
3.
2 2 4
C H O
c
0
1
2
C
.C
H
2
O
d
1
1
4-OMe
6-OMe
2,5-diOMe Ph
2,5-diOMe Ph
14
24
167±168
178±181
C
H
N
2
5
2
4
C
H
N
2
5
.C
2 2 4
H O
2
SO
3.
C
2
H
2
O
4
45 (Æ7)
13
14
15
16
7-OMe
7-OMe
7-OMe
7-OMe
4-Cl Ph
4-OMe Ph
2,5-diOMe Ph
2-Naphthyl
12
17
4
168±170
164±166
207±208
191±193
C
H
21ClN
SO
SO
.C
.C
H
O
e
93 (Æ7)
C
C
20
H
24
26
24
N
2
4
2
2
4
21
H
N
2
5
H
2 2
O
4
183 (Æ32)
5.0 (Æ0.6)
23
H
N
2
SO
3.
C
2
H
2
O
4
d
16
C
a
All compounds were recrystallized from a MeOH±anhydrous Et
2
O mixture.
b
c
K
i
values were determined in triplicate. Clozapine (K
O.
Crystallized with 0.25 equiv of H
i
=4.8 Æ 0.6 nM) was employed as control.
Crystallized with 1 equiv of H
2
d
2
O.
O.
e
Crystallized with 0.5 equiv of H
2

Y. Tsai et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2295±2299
2297
The structure of 5 was modeled using SYBYL, and
three families of low-energy conformations were identi-
is known that tryptamines bearing N -substituents are
1
tolerated by 5-HT receptors.
2
1
®
ed. The families possessed C ±N ±S±C torsion angles
f
7
a
1
ꢀ
within each family varied with respect to S±C rotation
ꢀ
ꢀ
(t) of approximately 60 , 180 , or 300 , and members
The results of the present study indicate that 5 binds
at 5-HT6 receptors with high anity (K =2.3 nM).
f
i
angle ꢀ. The lowest energy conformer of 5 (22.33 kcal/
mol; ꢁ=300.8 , ꢀ=323.4 , Family 3) was energetically
Structure±anity studies show that the introduction of
4-chloro, 4-methoxy, or 2,5-dimethoxy substituents into
the benzenesulfonamide moiety have little e€ect on
anity. Even replacement of the benzenesulfonyl with the
more bulky 1-naphthalene- or 2-naphthalenesulfonyl
groups had little in¯uence on anity. Unlike what was
ꢀ
ꢀ
similar to the two lowest energy conformers from the
ꢀ
other two families (Family 1: 22.41 kcal/mol, t=60.8 ,
ꢀ
8
ꢀ
=213.4C; Family 2: 22.87 kcal/mol, ꢁ=180.8 , ꢀ=
ꢀ
de®ned as Cpy-4±N±S±C ). The lowest-energy conformers
8.4 ). Similar results were obtained with 3b (where t is
seen for N,N-dimethyltryptamines lacking an N -sub-
1
f
in each family are as follows; Family 1: � 6.49kcal/mol,
stituent, moving the 5-methoxy group to the 4- or 6-
position was tolerated. This lack of parallel behavior
between N -unsubstituted tryptamines and N -benzene-
sulfonamides suggest that the two series might be bind-
ing in a di€erent manner at the receptors. Even the 7-
methoxy compound 15 binds with higher anity than
expected, and 16 binds with an anity comparable to
that of 5. In contrast, molecular modeling studies indi-
cate that the arylbenzenesulfonamide portions of 5 and
the antagonist 3b are superimposable suggesting that the
ꢀ
ꢀ
ꢀ
ꢁ
=59.8 , ꢀ=212.4 ; Family 2: � 5.29kcal/mol, ꢁ=179.8 ,
ꢀ
22.4 . The lowest energy conformers for the three
ꢀ
ꢀ
3
=87.4 , and Family 3: � 6.30kcal/mol, ꢁ=299.8 , ꢀ=
1
1
ꢀ
families of 3b and 5 were superimposed and resulted in
rmsd values of 0.176 in all three cases. This is shown for
the Family 2 pair in Figure 1. It would seem theoreti-
cally possible for members of the three conformational
families of 5 to superimpose with the corresponding
members of families of 3b. Because Family 2 of 5 places
the benzenesulfonyl aromatic moiety the greatest dis-
tance from the indole 7-position, this might be a favored
conformational family for ligand±receptor interaction.
Alternatively, the higher than anticipated anities seen
with the 7-substituted derivatives 13±16, as compared
with 5, and in particular with 16 relative to 13±15, might
re¯ect a shift in ꢁ or ꢀ angles.
N -arylsulfonyltryptamines might be binding in a man-
1
ner related to that of the antagonists. Supporting this
contention, 5 was shown to be a 5-HT antagonist. In
6
conclusion, the N -benzenesulfonyltryptamine 5 repre-
1
sents the ®rst member of a novel class of reasonably
selective tryptamine-based 5-HT receptor antagonists.
6
The goal of this investigation was not the development
of novel 5-HT -selective receptor antagonists; rather, it
was our intention to determine whether compounds
such as 5 possess agonist or antagonist action and, due
to structural similarities between 5 and recently reported
Experimental
Chemistry
6
Flash column chromatography was performed using
silica gel (220±440 mesh). Melting points were deter-
mined on a Thomas Hoover melting point apparatus and
are uncorrected. Proton NMR spectra were obtained
using a Varian Gemini 300 MHz spectrometer with tetra-
methylsilane as an internal standard and infrared spectra
were measured using a Nicolet 5ZDX FT-IR spectro-
photometer. Elemental analysis was performed by
Atlantic Microlab (Norcross, GA) and determined values
were within 0.4% of theory. All compounds were pre-
pared by the simple reaction of the appropriate meth-
oxytryptamine anion with the requisite sulfonyl chloride
3
a similar manner. Nevertheless, given the high anity of
BS/5-OMe DMT (5) for h5-HT receptors, we examined
6
, to determine whether such compounds might bind in
the binding of this compound at several other 5-HT
receptor populations. Compound 5 displayed low an-
ity for h5-HT1A (K =702 Æ 154 nM), h5-HT (K =
i
1B
i
9
210 Æ 3960 nM), h5-HT (K =4220 Æ 420 nM), h5-
1E
i
HT (K =2390 Æ 60 nM), and h5-HT (K =600 Æ 180
3 i 7 i
nM) receptors. In contrast, 5 displayed higher anity
for r5-HT2A (K =130 Æ 65 nM) and r5-HT (K =23 Æ
i
2C
i
5
nM) receptors. This latter ®nding is not unexpected. It
1
9
as exempli®ed for the preparation of 6. 4-Methoxy-, 6-
methoxy-,20 and 7-methoxy-N,N-dimethyltryptamine
were prepared according to literature procedures. 5-
Methoxy-N,N-dimethyltryptamine was available in our
laboratory as the result of previous studies.
21
1
-4-(Chlorobenzenesulfonyl)-5-methoxy-N,N-dimethyl-
tryptamine oxalate (6). A mixture of 5-methoxy-N,N-
dimethyltryptamine (220 mg, 1.0 mmol) and an unwa-
shed 60% suspension of NaH in mineral oil (40 mg) was
ꢀ
heated at 100 C under an N atmosphere until melted.
2
The cooled homogeneous mixture was dissolved in dry
DMF (2 mL). A solution of 4-chlorobenzenesulfonyl
chloride (230 mg, 1.1 mmol) in dry DMF (1 mL) was
ꢀ
added in a dropwise manner at 0 C, and the reaction
mixture was allowed to stir at room temperature over-
Figure 1. Superimposition of the lowest-energy Family 2 conformers
of 3b (light-shaded structure) and 5 (dark-shaded structure) (rmsd=
0
.176).
night (about 16 h). Saturated NaHCO solution (12 mL)
3

2
298
Y. Tsai et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2295±2299
was added and the mixture was extracted with CH Cl
2
incubation was initiated by the addition of membrane
homogenate and the plates vortexed (Baxter S/P Multi-
tube Mixer). The plates were incubated, with protection
from light, by shaking (Gyrotop Water Bath/Shaker
2
(
3Â15 mL). The combined organic portion was washed
with brine and solvent was removed under reduced
pressure to a€ord an oil. The oil was puri®ed by ¯ash
chromatography (silica gel) using CH Cl :MeOH (20:1)
ꢀ
Model G76, speed 2) at 37 C for 60 min. The binding
2
2
as eluent to give 220 mg of a homogeneous oil. The oil
in dry acetone (4 mL) was added all at once to a satu-
rated solution of oxalic acid to yield a white precipitate.
The product was collected by ®ltration and recrys-
reaction was stopped by ®ltration. The samples were
®ltered under vacuum over 96 well glass ®ber ®lters
(Packard Uni®lter GF/B), presoaked in 0.3% PEI in
ꢀ
50 mM Tris bu€er (4 C, pH 7.4) for at least 1 h, and
tallized from an anhydrous MeOH/anhydrous Et O
2
then washed six times with 1 mL of cold 50 mM Tris
bu€er (pH 7.4) using the Packard Filtermate 196 Har-
vester. The Uni®lter plates were dried overnight in a
mixture to give 180 mg (37%) of 6 as a white solid, mp
ꢀ
.56±2.61 (t, 2H, CH ), 2.77±2.82 (t, 2H, CH ), 3.82 (s,
H, OCH ), 6.92±6.94 (m, 2H, ArH), 7.26±7.38 (m, 3H,
3
1
2
2
3
18±220 C. H NMR (CDCl ) d 2.33 (s, 6H, 2ÂCH ),
3
3
ꢀ
37 C dry incubator. The Uni®lter bottoms were sealed
2 2
and 35 mL of Packard MicroScint-0 was added. The
plates were allowed to equilibrate for 1 h and were then
sealed using a Packard TopSeal P with the Packard
Plate Micromate 496. Plates were counted in a Packard
TopCount 4.1 by liquid scintillation spectrometry. Each
well was counted for 3 min. The test agents were initially
assayed at 1000 and 100 nM. If the compound was active
ArH), 7.73±7.86 (m, 3H, ArH). IR (®lm) 1371 and
�
176 cm . Anal. (C H ClN SO C H O ) C, H, N.
19 21 2 2 4
1
.
1
4 2
Molecular modeling
The structures of 3b and 5 were constructed from stan-
dard bond lengths and angles using the SKETCH
MOLECULE command in version 6.6 of SYBYL. The
structures were energy minimized with the Tripos force
3
(de®ned as causing at least 80% inhibition of [ H]lysergic
acid diethylamide binding at 1000 nM), they were further
tested for determination of a K value. The range of
i
®
eld and charges were calculated using the Gasteiger
concentrations was chosen such that the middle concen-
tration would produce approximately 50% inhibition.
Huckel algorithm as implemented in SYBYL. A full
conformational search was performed using the SYS-
TEMATIC SEARCH command; rotatable bonds (two
Methods employed for obtaining the binding pro®le are
described at the NIMH Psychoactive Drug Screening
Program website: http://pdsp/cwru.edu/pdsp.htm
ꢀ
in each compound) were rotated in 5 -increments
including the starting conformation. The results were
analyzed with the SEARCH routine of the SYBYL
program. Superimpositions were performed on the con-
formers of 3b and 5 with the FIT-ATOMS command
using the Cpy-2, N and S atoms and the C , N and S
Adenylate cyclase assay
h5-HT receptors stably expressed in HEK-293 cells were
6
S
4
1
atoms of 3b and 5, respectively.
grown in 24-well plates to near-con¯uency and 18 h
prior to assay the medium was replaced with DMEM
containing dialyzed 10% fetal calf serum. For the assay,
the medium was aspirated and replaced with fresh
DMEM without serum and incubated with various
concentrations of test agent in a total volume of 0.5 mL
for 15 min. The assay was terminated by aspiration and
the addition of 10% trichloroacetic acid (TCA). The
TCA extract was used for cAMP determinations. Data
represent the mean of n=four separate determinations.
For pA2 determinations, cells were incubated with
increasing concentrations of 5-HT Æ four di€erent con-
Radioligand binding assay
The binding assay was conducted as previously descri-
1
4
bed. Human 5-HT6 receptors stably transfected to
HEK 293 human embryonic kidney cells were used and
3
[
H]lysergic acid diethylamide (70 Ci/mmol; DuPont
NEN) was employed as the radioligand. All assays were
conducted in triplicate using polypropylene 1 mL/well
plates (Anachemia). The radioligand was diluted in
incubation bu€er in borosilicate glass vials and pro-
tected from light. Competing agents (1 mM stock solu-
centrations of test agents. Calculation of pA values
2
2
2
tions) were dissolved in DMSO or saline and stored at
ꢀ
using a Schild analysis was as previously described.
Data represent mean Æ SEM of three di€erent pA
�
20 C in 1.2-mL polypropylene tubes (ElKay). Dilu-
2
tions of compounds were made using incubation bu€er
in 96-well polypropylene plates and mixed by multi-
channel pipetting >25 times. Serial dilutions (1 in 4)
started at a ®nal concentration of 10,000 nM. Final
concentrations >10,000 nM were individually prepared
from the 1 mM stock solution. Nonspeci®c binding was
de®ned by 100 mM serotonin creatinine sulfate
determinations.
Acknowledgements
The authors thank the NIMH for supporting this
investigation.
(
Research Biochemicals) prepared fresh in incubation
bu€er at the time of each determination, and protected
from light. Reactions volumes were as follows: 200 mL
incubation bu€er (50 mM Tris, 0.5 mM EDTA, 10 mM
References and Notes
1
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ꢀ
MgCl , pH 7.4 at 22 C), 100 mL test agent or serotonin
2
3
(
100 mM) or bu€er (for total binding), 100 mL [ H]lyser-
gic acid diethylamide (2 nM ®nal concentration), and
00 mL membrane preparation (15 mg protein). The
1

Y. Tsai et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2295±2299
2299
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