1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2005.01.031

4-Sulfonyl analogs of 1-(1-naphthyl)piperazine bind at human 5-HT ₆ receptors and represent a novel class of human 5-HT₆ receptor ligands.

Full text of DOI:10.1016/j.bmcl.2005.01.031

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1707–1711
1-(1-Naphthyl)piperazine as a novel template for 5-HT6
serotonin receptor ligands
Mase Lee,a Jagadeesh B. Rangisetty,a Manik R. Pullagurla,a Małgorzata Dukat,a
Vince Setola,b Bryan L. Rothb,c and Richard A. Glennona,*
aDepartment of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, USA
bDepartment of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
cDepartments of Psychiatry and Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Received 30 November 2004; revised 12 January 2005; accepted 14 January 2005
Abstract—4-Sulfonyl analogs of 1-(1-naphthyl)piperazine bind at human 5-HT6 receptors and represent a novel class of human 5-
HT6 receptor ligands.
Ó 2005 Elsevier Ltd. All rights reserved.
1-(1-Naphthyl)piperazine (1-NP; 1a), like serotonin (5-
hydroxytryptamine, 5-HT, 2) itself, is a fairly promiscu-
ous serotonergic ligand that binds in a nonselective
manner at multiple populations of serotonin (5-HT)
receptors; we have suggested that 1-NP is a general
tryptamine-mimic.1 Consistent with this notion, we have
found that 1-NP (1a, Ki = 120 nM) binds to human 5-
HT6 (h5-HT6) serotonin receptors with an affinity com-
parable to that of 5-HT (Ki = 100 nM), and with 10-fold
higher affinity than the monocyclic 2-methoxyphenyl-
piperazine 3 (Ki = 1.200 nM),2 indicating that its bicyclic
nature might contribute to binding.
findings. Although the presence of the sulfonyl moiety
is optimal, a methylene group in its place causes only
a modest decrease in affinity12 without altering antago-
nist action. We have also shown that the tryptaminergic
ligands 2-ethyl-5-methoxy-N,N-dimethyltryptamine (5;
Ki = 16 nM) and 2-phenyl-5-methoxy-N,N-dimethyl-
tryptamine (6; Ki = 20 nM) bind to h5-HT6 receptors
with relatively high affinity.13
The present investigation was focused not so much on
developing novel 5-HT6 ligands as it was on testing
H
H
N
NH
5-HT6 Serotonin receptors represent one of the seven
major types of 5-HT receptors (5-HT1–5-HT7).3–7 This
receptor population was identified about 10 years ago
and within the past few years several selective ligands
have been reported (reviewed6–9). 5-HT6 receptors are
of interest due to their possible involvement in depres-
sion, psychosis, cognition, and appetite.6–9
NH
HO
N
N
H3CO
N
H
1a
3
CH3
R
2
We identified MS-245 (4) as one of the first 5-HT6
antagonists and have studied its structure–affinity rela-
tionships.10 For example, the 5-methoxy group of MS-
245 (4) can be replaced by hydrogen with little impact
on affinity; Russell and Dias11 have reported similar
H3C
H3C
CH3
N
N
H3CO
H3CO
N
N
S
O
H
Keyword: 5-HT6 Serotonin receptors.
*
O
5 R = Et
6 R = Ph
Corresponding author. Tel.: +1 804 828 8487; fax: +1 804 828
7404; e-mail: glennon@hsc.vcu.edu
4
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.01.031

1708
M. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1707–1711
the hypothesis that 1-NP (1a) is a tryptamine-mimic at
these receptors. Toward this end, we prepared analogs
of 1a bearing tryptaminergic substituents either known
to be tolerated, or that impart enhanced 5-HT6 receptor
affinity. Specifically, we prepared 1-(1-naphthyl)piper-
azine analogs of several previously characterized MS-
245 (4) derivatives and of compounds 5 and 6, and then
measured their affinity at h5-HT6 receptors.
NH
NH
NH2
N
N
a
b
Br
(CH2)n
Br
1c, n=0
1e, n=1
15
1b
NH
Br
X
N
X
Results and discussion
Synthesis
c
d
Br
16
Piperazine intermediate 1b was obtained by treatment of
15 with bis(2-chloroethylamine) in the presence of trieth-
ylamine (Scheme 1). Reaction of 1b with phenyl or ben-
zyl 9-BBN in the presence of PdCl2(dppf) afforded 1c
and e, respectively, (Table 1).
17, X = C=O
18, X = SO2
1d, X = C=O
1f, X = SO2
Scheme 1. Reagents: (a) HN(CH2CH2Cl)2, NEt3; (b) PdCl2(dppf), Ph
or Bn 9-BBN, dioxane; (c) PhCOCl or PhSO2Cl, AlCl3; (d) piperazine,
NaOBu-t, PdCl2[P(o-tol)3]2.
Compounds 1d and f were prepared in a common man-
ner (Scheme 1). Reaction of 16 with PhCOCl or
PhSO2Cl in the presence of AlCl3 afforded 17 and 18;
subsequent coupling with piperazine provided the
desired targets. Compound 1g was prepared from N-
Boc-protected 1b by treatment with BuLi and 4-nitro-
benzenesulfonyl chloride, deprotection of the product
with trifluoroacetic acid, and SnCl2 reduction of the
nitro group.
compound 20 was converted to 21b, and 21b was con-
verted to triflate 22b. Compound 22b was allowed to re-
act with N-Boc-protected piperazine using BINAP,
Cs2CO3, and 18-crown-6 in toluene with Pd2dba3 as cata-
lyst. Deprotection of 23b afforded 1i. Compound 21b
could also be obtained directly from 19 as previously re-
ported.15 Compound 1h was obtained by a similar se-
quence of reactions using a Stille reaction by first
converting 20 to its corresponding ethyl derivative 21a
by reaction with Et4Sn/PdCl2(PPh3)2 and LiCl in DMF.
The 3-substituted naphthylpiperazines were obtained
from the protected naphthalene diol 20,14 which was
prepared in four steps from commercially available diol
19 (Scheme 2). Using a Suzuki-type coupling reaction,
Table 1. Physicochemical and h5-HT6 serotonin receptor binding properties of arylpiperazines and related derivatives
NH
N
3
R
4
1
R
Overall yield, % Melting point, °C Recrystallization solvent Empirical formulaa
h5-HT6 Ki, nM ( SEM)b
1a
1b 4-Br
H
—
45
51
39
37
38
5
—
—
MeOH
—
C14H15BrN2ÆC2H2O4
120 ( 20)
54 ( 7)
208–209
207–208
171–172
210–211
201–203
197–199
244–246
252–254
200–202c
185–186
d
1c 4-Ph
MeOH
MeOH/Et2O
MeOH
C20H20N2ÆC2H2O4
C21H20N2OÆC2H2O4
C20H20N2ÆC2H2O4
190 ( 90)
57 ( 10)
35 ( 9)
e
1d 4-C(@O)Ph
1e 4-CH2Ph
1f 4-SO2Ph
1g 4-SO2C6H4NH2-p
1h 3-Et
d
MeOH/Et2O
MeOH
C20H20N2O2SÆC2H2O4
C20H21N3O2SÆ2.75HCl
C16H20N2ÆHCl
3.8 ( 0.8)
0.9 ( 0.3)
21 ( 2)
16
15
64
18
MeOH/Et2O
MeOH/Et2O
2-PrOH
EtOAc
1i 3-Ph
C20H20N2ÆHClf
9.3 ( 1.3)
34 ( 4)
63 ( 11)
8
9
—
—
C16H13NO2S
C16H13NO3SÆHCl
a All compounds analyzed within 0.4% of theory for C, H, and N; C2H2O4 = oxalate salt. Compound 1a, as its HCl salt, was available from previous
investigations.
b Ki values were determined in triplicate.21
c Lit.23 mp 203–205 °C.
d Crystallized with 0.1 mol H2O.
e Crystallized with 0.5 mol H2O.
f Crystallized with 0.25 mol H2O.

M. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1707–1711
1709
To further test possible binding similarities between the
naphthylpiperazines and the tryptamines, we prepared
compounds 1g and 8. The 40-amine analog 1g
(Ki = 0.9 nM) was found to bind with high affinity. Fur-
thermore, as with the tryptamines, removal of the ꢀside
chainꢁ (i.e., the piperazine moiety) in the benzenesulfon-
ylnaphthylpiperazine series, also resulted in a com-
pound (i.e., 8; Ki = 34 nM) that binds to 5-HT6
receptors, albeit with about 10-fold reduced affinity
relative to 1f. Hydroxylamine 9 (Ki = 63 nM) was iso-
lated as a byproduct in the synthesis of 8; compound 9
is the first hydroxylamine shown to bind to 5-HT6
receptors.
OTs
OTf
OH
b
a
OTf
R
R
22a R = Et
22b R = Ph
21a R = Et
21b R = Ph
20
c
e
NH
N-Boc
OH
N
N
d
OH
R
R
1h R = Et
1i R = Ph
23a R = Et
23b R = Ph
19
NH
N
Scheme 2. Reagents: (a) Et4Sn, PdCl2(PPh3)2, LiCl, DMF; or
PhB(OH)2, Na2CO3, Pd(PPh3)4, THF; (b) (CF3SO2)2O, Et3N, CH2Cl2;
(c) N-Boc-piperazine, BINAP, Cs2CO3, 18-crown-6, Pd2dba3, toluene;
(d) HCl, EtOH; (e) benzene, AlCl3.
CH3
N
O
S
O
S
O
O
H2N
Compound 8 was obtained following hydrolysis of the
product obtained by heating naphthalene, trifluoroace-
tic acid, and trifluoroacetic anhydride with sulfanilic
acid. Hydroxylamine 9 was isolated in an attempt to ob-
tain 8 from 1-bromonaphthalene by reaction with BuLi
and 4-nitrobenzenesulfonyl chloride followed by reduc-
tion of the product with SnCl2.
H2N
7
1g
O
O
S
S
Pharmacology
O
O
H2N
HO-HN
MS-245 (4; Ki = 2.1 nM)10 binds with high affinity to h5-
HT6 receptors. Replacement of the benzenesulfonyl
moiety with a phenyl group (Ki = 33 nM) or benzoyl
group (Ki = 18 nM) results in about 10- to 15-fold de-
creased affinity; the corresponding benzyl analog
(Ki = 6.5 nM) binds with only 3-fold decreased affinity.12
In the present investigation, the benzenesulfonyl analog
of 1 (1f; Ki = 3.8 nM; Table 1) displayed an affinity com-
parable to that of MS-245 (4). Replacement of the benz-
enesulfonyl moiety by a phenyl group (1c; Ki = 190 nM),
benzoyl group (1d; Ki = 57 nM), or benzyl group (1e,
Ki = 35 nM) resulted in lower-affinity compounds. As
with the benzenesulfonyltryptamine series, the sulfonyl
group seems optimal for h5-HT6 serotonin receptor
affinity.
8
9
Tryptamine 4, MS-245, is a 5-HT6 antagonist.10 The
functional activity of compound 1f at h5-HT6 receptors
was examined (i.e., 5-HT-stimulated adenylate cyclase;
data not shown) and showed that 1f also is a 5-HT6
antagonist (1f pA2 = 7.5 0.2).
Given the lack of strict structural correspondence be-
tween an indole ring and a naphthyl ring, the results
support the general notion that those structural features
tolerated by, or that enhance, the 5-HT6 serotonin
receptor affinity of the tryptamine nucleus are also toler-
ated by or enhance the affinity of the corresponding 1-
(1-naphthyl)piperazines. In fact, for eight compounds
where such comparisons could be made (i.e., com-
pounds 1a,c–1i, and their corresponding tryptamine
derivatives—Ki values for which have been previously
published2,10,12) there was a significant correlation be-
tween their pKi values (r = 0.856) supporting the idea
that parallel structural modification in the two series re-
sults in parallel shifts in receptor affinity.
Compounds 1h (Ki = 21 nM) and 1i (Ki = 9.3 nM) are
the 1-(1-naphthyl)piperazine analogs of tryptamines 5
and 6 (Ki = 16 nM and 20 nM, respectively). As in the
tryptamine series, an ethyl or phenyl substituent results
in enhanced affinity relative to the parent compound 1-
NP (1a; Ki = 120 nM).
We have previously demonstrated (i) that the methoxy
substituent of 4 does not contribute to binding, (ii) that
a 40-amino substituent is tolerated, and (iii) that an in-
tact tryptamine moiety is not essential for 5-HT6 affin-
ity.16 For example, compound 7 (Ki = 12 nM),16 which
lacks the tryptamine amine moiety, binds with only
about 6-fold reduced affinity relative to 4.
Initially, it was found that simple arylpiperazines, such
as 3, bind to 5-HT6 receptors with low affinity.2 How-
ever, the arylpiperazine derivatives described here are
not the first to demonstrate significant affinity for 5-
HT6 receptors. Incorporation of specific arylsulfon-
amide moieties dramatically enhances the affinity of 3

1710
M. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1707–1711
[i.e., 10; Ki = 5 nM and 11 (SB-271046); Ki = 1 nM].17
Furthermore, ꢀreverseꢁ sulfonamides such as 12 (SB-
357134; Ki = 3 nM)18 also bind to 5-HT6 receptors with
relatively high affinity. These findings indicate that the
orientation of the sulfonamide portion of these mole-
cules might not be a critical determinant of binding.
Acknowledgments
The present work was supported in part by NIMH MH
60599. Studies of the 3-substituted arylpiperazines were
supported by BTG International.
References and notes
CH3
N
1. Glennon, R. A.; Westkaemper, R.; Bartyzel, P. In
Serotonin Receptor Subtypes; Peroutka, S., Ed.; Wiley-
Liss: NY, 1991; pp 19–64.
2. Glennon, R. A.; Bondarev, M.; Roth, B. L. Med. Chem.
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Pharmacol. Sci. 1993, 14, 233.
6. Roth, B. L.; Hanizavareh, S. M.; Blum, A. E. Psycho-
pharmacology (Berl.) 2004, 174, 17.
NH
NH
N
N
S
N
H3CO
H3CO
H3CO
Br
O
NH
NH
S
O
NH
O
O
S
O
S
O
Br
CH3
Br
F
Cl
10
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11
7. Woolley, M. L.; Marsden, C. A.; Fone, K. C. F. Curr.
Drug Top. 2004, 3, 59.
8. Slassi, A.; Isaac, M.; OꢁBrien, A. Expert Opin. Ther.
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shyn, L.; Savage, J. E.; Roth, B. L.; Hufesein, S.; Lee, M.;
Glennon, R. A. Bioorg. Med. Chem. Lett. 2000, 10, 2295.
11. Russell, M. G. N.; Dias, R. Curr. Top. Med. Chem. 2002,
2, 643.
12. Lee, M.; Rangisetty, J. B.; Dukat, M.; Slassi, A.;
MacLean, N.; Lee, D. K. H.; Glennon, R. A. Med. Chem.
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13. Glennon, R. A.; Lee, M.; Rangisetty, J. B.; Dukat, M.;
Roth, B. L.; Savage, J. E.; McBride, A.; Rauser, L.;
Hufesien, L.; Lee, D. K. H. J. Med. Chem. 2000, 43, 1011.
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Russ. J. Org. Chem. 1994, 30, 88.
In the present investigation it was found that certain 1-
(1-naphthyl)piperazine analogs of tryptamine bind to
h5-HT6 serotonin receptors, and that compound 1f, like
MS-245 (4), is a 5-HT6 antagonist. However, unlike the
sulfonamide MS-245 (4), 1f is a sulfone. Several other
sulfones have been recently shown to bind to 5-HT6
receptors;19,20 compounds 13 (Ki ca. 1 nM)19 and espe-
cially 14 (Ki ca. 0.1 nM)19 are particularly relevant to
the present work. Nevertheless, whereas 14 is the sulfone
of a 3-substituted arylpiperazine, compounds 1f and g
are sulfones of 4-substituted arylpiperazines.
NH
N
N
16. Pullagurla, M.; Setola, V.; Roth, B. L.; Glennon, R. A.
Bioorg. Med. Chem. Lett. 2003, 13, 3355.
N
N
O
O
17. 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.
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Br
S
Br
S
O
O
18. 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.
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NH2
NH2
13
14
19. Riemer, C.; Borroni, E.; Levit-Trafit, B.; Martin, J. R.;
Poli, S.; Porter, R. H.; Bos, M. J. Med. Chem. 2003, 46,
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20. Wu, Y.-J.; He, H.; Hu, S.; Huang, Y.; Scola, P. M.; Grant-
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21. The h5-HT6 radioligand binding assay was performed as
previously described.22 In brief, h5-HT6 cDNA was
transiently expressed in HEK-293 cells using Fugene6
according to the manufacturerꢁs recommendations. After
24 h transfection the medium was replaced; 24 h later,
medium containing dialyzed serum (to remove 5-HT) was
added. At 75 h after transfection, cells were harvested by
scraping and centrifugation. Cells were then washed by
The general conclusion drawn from these studies is that
1-NP (1a) represents a suitable template for the further
development of 5-HT6 serotonin receptor ligands, and
upon incorporation of appropriate substituents (e.g.,
1f,g), can result in compounds with high affinity for
the receptor. The findings also present additional
evidence for the high-affinity binding of sulfones to h5-
HT6 serotonin receptors, and demonstrate that arylpip-
erazines can bear the sulfone moiety at the ring 4-posi-
tion as opposed to arylpiperazine compounds such as
14, which bear a sulfonyl moiety at the arylpiperazine
3-position. Additional studies with such compounds
are now in progress.

M. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1707–1711
1711
centrifugation and resuspension once in phosphate buf-
fered saline (PBS; pH = 7.40) and then frozen as tight
pellets at ꢀ80 °C until use. Binding assays were performed
at room temperature for 90 min in binding buffer (50 mM
Tris-Cl, 10 mM MgCl2, 0.1 mM EDTA, pH = 7.40) with
[3H]LSD (1 nM final concentration) using 10 lM cloza-
pine for non-specific binding. Concentrations of unlabeled
test agent (1–10,000 nM) were used for Ki determinations
with Ki values calculated using the program LIGAND.
Specific binding represented 80–90% of total binding. Ki
values are the result of triplicate determinations.
22. 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.
23. Gilbert, E. E. Synth. Commun. 1971, 372.