6-bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potent, and selective 5-HT6 receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00320-6

A novel series of 6-bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives was synthesized and found to be potent and selective 5-HT₆ receptor antagonists. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00320-6

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1719±1721
6-Bicyclopiperazinyl-1-arylsulfonylindoles and
6-Bicyclopiperidinyl-1-arylsulfonylindoles Derivatives as
Novel, Potent, and Selective 5-HT6 Receptor Antagonists
Methvin Isaac,* Abdelmalik Slassi, Tao Xin, Neil MacLean, Julie Wilson,
Kirk McCallum, Hong Wang and Lidia Demchyshyn
NPS Allelix Corp., 6850 Goreway Drive, Mississauga, ON, Canada, L4V 1V7
Received 25 March 2000; accepted 30 May 2000
AbstractÐA novel series of 6-bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives
was synthesized and found to be potent and selective 5-HT6 receptor antagonists. # 2000 Elsevier Science Ltd. All rights reserved.
The human 5-hydroxytryptamine6 (5-HT6) receptor, one
of the most recently cloned serotonergic receptors, is a
440-amino acid polypeptide with seven transmembrane
spanning domains typical of the G-protein-coupled
receptors. It is one of the 14 receptors that mediate the
e€ects of the neurotransmitter 5-hydroxytryptamine (5-
HT, serotonin).1 Within the transmembrane region, the
human 5-HT6 receptor shows about 30±40% homology
to other human 5-HT receptors and is found to be
positively coupled to adenylyl cyclase.
nized by atropine (a muscarinic antagonist), implicating
the 5-HT6 receptor in the control of cholinergic neuro-
transmission. Therefore 5-HT6 receptor antagonists may
be useful for the treatment of memory dysfunction.4
Recently, Ro 04-6790 1, Ro 63-0563 2,5 and SB-271046 36
were reported as selective 5-HT6 receptor antagonists.
However, compounds 1 and 2 have only moderate
potency at the rat 5-HT6 receptor and were found to be
poorly brain penetrant. Compound 3, on the other
hand, has relatively high anity for the 5-HT6 receptor,
but pharmacokinetic studies indicate that it was only
moderately brain penetrant.
The prominent localization of 5-HT6 receptor mRNA in
the nucleus accumbens, striatum, olfactory tubercle, sub-
stantia nigra, and hippocampus of the brain,2 together
with its high anity for several therapeutically important
antipsychotics and antidepressants suggest a possible
role for this receptor in the treatment of schizophrenia
and depression. In fact, the prototypic atypical anti-
psychotic agent clozapine exhibits greater anity for the
5-HT6 receptor than for any other receptor subtype.3
As part of our research program directed toward the
design and synthesis of potent and selective 5-HT6
receptor antagonists, we discovered a novel series of 6-
bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclo-
piperidinyl-1-arylsulfonylindoles derivatives. We herein
report the synthesis and biological activity of these
novel 5-HT6 receptor antagonists.
Although the 5-HT6 receptor has a distinct pharmaco-
logical pro®le, in vivo investigation of receptor function
has been hindered by the lack of selective agonists
and antagonists. Recent experiments demonstrated that
chronic intracerebroventricular treatment with an anti-
sense oligonucleotide, directed at 5-HT6 receptor
mRNA, elicited a behavioral syndrome in rats consist-
ing of yawning, stretching, and chewing. This syndrome in
the antisense-treated rats was dose-dependently antago-
Chemistry
The 6-bicyclopiperazinyl-1-arylsulfonylindoles 4a±h were
synthesized as shown in Scheme 1. N-Silylation of 6-bro-
moindole 5with triisopropylsilyl chloride (TIPS-Cl) yielded
6, which was subjected to the conditions of metal-cata-
lyzed aryl amination7 to give 7. Subsequent desilylation
of 7 a€orded 8, which was then sulfonylated to give 4.
The corresponding piperidine analogues were synthesized
according to Scheme 2. The indole 5 was coupled to the
*Corresponding author. Tel.:+1-905-677-0831; fax: +1-905-677-9595;
e-mail: misaac@allelix.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00320-6

1720
M. Isaac et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1719±1721
Table 1. Structure and binding of the 6-bicyclopiperazinyl-1-arylsul-
fonylindoles and the 6-bicyclopiperidinyl-1-arylsulfonylindoles
Compound
n
Ar
Ki (5-HT6, nM)a
4a
4b
4c
4d
4e
4f
4g
16
17
13
1
1
2
2
2
2
2
1
1
1
1-Naphthyl
p-Tolyl
1-Naphthyl
2-Naphthyl
2,4-diF-phenyl
Phenyl
0.2
3.3
1.7
3.0
3.6
5.7
4.9
0.8
0.6
1.3
p-Tolyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
Figure 1.
aKi values are given as the mean of at least two independent determi-
nations performed in triplicate with less than 15% deviation.
Table 2. Receptor binding pro®le of compound 4a (Anity in%
inhibition at 100 nM)
5-HT1A
5-HT1B
5-HT1D
5-HT1F
5-HT2A
5-HT2B
5-HT2C
a1
79
2
5
5-HT7
M1+M2
D1
D2
D3
8
0
1
7
22
0
9
32
36
17
0
Scheme 1. (a) NaH, TIPS-Cl, DMF, 0 ꢀC; (b) bicyclopiperazine,
NaOt-Bu, Pd(OAc)2, t-Bu3P, Xylene, 120 ꢀC; (c) TBAF, THF; (d)
NaHMDS, ArSO2Cl, THF.
D4
D5
0
3
receptor, with H-LSD and using clozapine, a typical 5-
HT6 receptor antagonist, as a standard. Speci®c con-
centrations of the test compounds were incubated with
the radioligand (3H-LSD) and the receptor anity (Ki
in nM) was determined.
In general, all of the compounds tested above were
found to be very potent at the 5-HT6 receptor with Ki's
less than 10 nM. In the case of the bicyclopiperazines
(4a±g), the 5,6-bicyclopiperazines were more potent
than their corresponding 6,6-bicyclopiperazine. For
example, 4a (Ki=0.2 nM) and 4b (Ki=3.3 nM) have a
greater anity for the 5-HT6 receptor than their bicyclic
homologue 4c and 4g, with Ki's of 1.7 nM and 4.9 nM,
respectively. The binding results on the representative
selection of the 6,6-bicyclo-derived sulfonylated indoles
4c±4g are shown in Table 1. Of the monocyclic and
bicyclic aromatic sulfonyl groups studied, the lipophilic
bicyclic substituent such as the 1-naphthyl group were
bene®cial to 5-HT6 receptor activity. The rapid optimiza-
tion of the aryl sulfonyl groups (1-naphthyl group
favored) along with the realization that the 6,5-bicyclopi-
perazine-systems were generally more potent than the
corresponding 6,6-bicyclopiperazine homologue, promp-
ted us to examine the 6,5-bicyclopiperidine analogues (16
and 17). Both isomers 16 and 17 demonstrated sub-
nanomolar 5-HT6 receptor anity (Ki of 0.8 nM and 0.7
nM, respectively). In addition, the 6,5-bicyclopiperidine
analogues 12 and 13 maintained good 5-HT6 receptor
activity (Ki of 4.7 nM and 1.3 nM, respectively) further
indicating the degree of structural variations allowed
without compromising 5-HT6 receptor anity.
Scheme 2. (a) KH, t-BuLi, 9, THF, 78 ꢀC; (b) TFA, THF; (c)
NaHMDS, ArSO2Cl, THF; (d) H2, Pd/C, MeOH.
bicyclopiperidone 9 to give the carbinol 10. Compound
10 was then treated with tri¯uoroacetic acid to e€ect the
elimination to alkenes 11a and 11b. Both intermediate 10
and 11a were subjected to aryl sulfonylation to give 12
and 13, respectively. Palladium catalyzed hydrogenation
of 11a and/or 11b gave two diastereoisomers 14 and 15,
which were easily separated by column chromato-
graphy. Arylsulfonylation of the diastereoisomers gave
16 and 17 (designated as the more polar and less polar
isomers, respectively).
Biological activity
All compounds were evaluated in vitro for their 5-HT6
receptor binding anity (Table 1). The assay protocol
entails the incubation of membranes, prepared from
HEK293 cells expressing the human 5-HT6 subtype of
In the functional adenylyl cyclase assay, the most potent
compound 4a was found to be a competitive antagonist

M. Isaac et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1719±1721
1721
(IC50=7.2 nM) with good binding selectivity over a
number of other key receptors (Table 2).
2. Ward, R. P.; Hamblin, M. W.; Sibley, D. R.; Lachowicz, J.
E.; Ho€man, B. J.; Dorsa, D. M. Neurosience 1995, 64, 1105.
3. (a) Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W.;
Sibley, D. R. Mol. Pharmacol. 1993, 43, 320. (b) Shen, Y.; Sibley,
D. R.; Meltzer, H. Y. J. Pharmacol. Exp. Ther. 1994, 268, 1403.
4. (a) Bourson, A.; Borroni, E.; Austin, R. H.; Monsma, F. J.;
Sleight, A. J. J. Pharmacol. Exp. Ther. 1995, 274, 173. (b)
Bourson, A.; Borroni, E.; Austin, R. H.; Monsma, F. J.;
Sleight, A. J.; Behav. Brain Res. 1996, 73, 245.
In conclusion, a novel series of potent and selective 5-HT6
receptor antagonist has been developed. The compound
4a was the most potent compound from the series and has
demonstrated good in vitro receptor selectivity thus mak-
ing it a promising candidate for the possible treatment of
schizophrenia, depression and memory dysfunction.
Compound 4a is currently being further evaluated for its
therapeutic potential.
5. Sleight, A. J.; Boess, F. G.; Bos, M.; Levet-Tra®t, B.; Riemer,
C.; Bourson, A. Br. J. Pharmacol. 1998, 124, 556.
6. Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson,
K.; Gager, T.; Grassam, H. L.; Je€rey, P. M.; Joiner, G. F.; King,
F. D.; Middlemiss, D. N.; Moss, S. F.; Newmann, J.; Riley, G.;
Routledge, C.; Wymann, P. J. Med. Chem. 1999, 42, 202.
7. Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett.
1998, 39, 617.
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