Tetrahydrothienopyridylbutyl-tetrahydrobenzindoles: New selective ligands of the 5-HT7 receptor

Article abstract of DOI:10.1016/S0960-894X(02)00485-7

The synthesis and the affinity for the 5-HT₇ receptor and other receptors of a novel series of fused-ring tetrahydropyridine derivatives are described. Some of the compounds showed high affinity for the 5-HT₇ receptor. Tetrahydrothienopyridylbutyl-tetrahydrobenzindoles 5d and 5h are potent ligands for the 5-HT₇ receptor, with high selectivity over the 5-HT₂ receptor and other receptors. These compounds should be useful tools for clarifying the biological role of the 5-HT₇ receptor.

Full text of DOI:10.1016/S0960-894X(02)00485-7

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2549–2552
Tetrahydrothienopyridylbutyl-tetrahydrobenzindoles: New
Selective Ligands of the 5-HT7 Receptor
Chika Kikuchi,* Toyokazu Hiranuma and Masao Koyama
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku,
Yokohama 222-8567, Japan
Received 20 May 2002; accepted 24 June 2002
Abstract—The synthesis and the affinity for the 5-HT7 receptor and other receptors of a novel series of fused-ring tetra-
hydropyridine derivatives are described. Some of the compounds showed high affinity for the 5-HT7 receptor. Tetra-
hydrothienopyridylbutyl-tetrahydrobenzindoles 5d and 5h are potent ligands for the 5-HT7 receptor, with high selectivity over the
5-HT2 receptor and other receptors. These compounds should be useful tools for clarifying the biological role of the 5-HT7 receptor.
# 2002 Elsevier Science Ltd. All rights reserved.
The neurotransmitter serotonin (5-hydroxytryptamine,
5-HT) plays important roles in a variety of physiological
and pathophysiological processes through the activation
of seven types of 5-HT receptors, 5-HT1–5-HT7. The
5-HT7 receptor is the most recent addition to the family
of 5-HT receptors.1À6 Its biological functions are still
poorly understood. Early pharmacological data sug-
gested that the 5-HT7 receptor may be involved in the
vasodilation of blood vessels.7À10 High levels of 5-HT7
receptor mRNA have also been observed in the brain
(hypothalamus, thalamus, brainstem and hippo-
campus),1,3,5,11 and the distribution of 5-HT7 receptor
binding sites in rat and guinea pig brain was essentially
the same as the mRNA distribution.11À13 The 5-HT7
receptor is involved in the control of circadian rhythms
of spontaneous electrical activity in the suprachiasmatic
nucleus (SCN) of the hypothalamus.3,14À16 It may be
involved in disturbance of circadian rhythms, such as jet
lag, delayed sleep phase syndrome (DSPS) and non-24-h
sleep–wake disorder (non-24).17 Strongly, it is suggested
that the 5-HT7 receptor should be a valuable drug target.
To examine this possibility, the development of potent and
selective ligands for the 5-HT7 receptor is highly required.
(DR4004)18 and 2 (DR4365)19 (Chart 1) are highly
potent antagonists for the 5-HT7 receptor, and the
tetrahydropyridoindole derivative 2 showed high selec-
tivity for this receptor over the 5-HT2 receptor. The
tetrahydropyridoindoles have the phenyl ring fixed to
the tetrahydropyridine ring by C–N bonds, and we
considered that this planar structure might be important
for high selectivity of these compounds for the 5-HT7
receptor.
Chart 1. Chemical structures of compound 1 and 2.
In previous papers, we reported the synthesis and affi-
nities for the 5-HT7 receptor and other receptors of a
In the present paper, the medicinal chemistry was
extended to include other fused-ring tetrahydropyridine
derivatives (Scheme 1). We synthesized and tested a
range of modified compounds, including the tetrahydro-
isoquinoline derivatives 5a–c. Other fused heterocycles
5d–g were also investigated. The tetrahydrothieno-
pyridine derivative 5d was a highly potent and selective
series of tetrahydrobenzindoles.18,19 Compounds
1
*Corresponding author. Tel.: +81-45-545-3133; fax: +81-45-543-
9771; e-mail: chika_kikuchi@meiji.co.jp
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00485-7

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C. Kikuchi et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2549–2552
Scheme 1.
Scheme 3. (a) POCl3, DMF (77%); (b) (i) HSCH2COOC2H5, Et3N,
pyridine; (ii) 50% KOH aq (27%); (c) 3.5 N KOH aq, reflux (83%);
(d) 47% HBr aq, reflux (95%).
Table 1. 5-HT7 and 5-HT2 receptor affinities of compounds 5a–i
Compd
n
Xb
R
pKia
Scheme 2. (a) Corresponding dibromide, 55% NaH, DMF, À40 to
c
d
5HT7
5HT2
0 ꢀC; (b) corresponding amine, K2CO3, DMF, 60 ꢀC.
5a
5b
5c
5d
5e
5f
5g
5h
5i
3
4
5
4
4
4
4
4
4
I
I
I
II
III
IV
V
II
II
H
H
H
H
H
H
H
CH3
C2H5
8.08Æ0.18
8.35Æ0.05
7.90Æ0.14
8.19Æ0.15
7.80Æ0.21
6.25Æ0.23
6.09Æ0.10
8.01Æ0.09
6.76Æ0.16
6.31Æ0.07
6.21Æ0.16
6.16Æ0.05
6.08Æ0.04
<6
5-HT7 receptor ligand. The N-methyltetrahy-
drobenzindole analogue 5h and the N-ethyltetrahy-
drobenzindole analogue 5i, corresponding to 5d, were
also synthesized.
<6
<6
6.02Æ0.05
The synthetic procedures to the target compounds are
shown in Scheme 2. Compound 4b was prepared by
reacting the tetrahydrobenzindole 3a with sodium
hydride and 1,4-dibromobutane. Compounds 4a,c–e
were synthesized in a similar manner to compound 4b.
Compounds 5a–i20 were obtained by allowing com-
pounds 4a–e to react with the corresponding amines in
the presence of K2CO3.18,19
6.31Æ0.10
aThe pKi values are means ÆSE of 8–12 values.
bSee Scheme 2.
cBinding affinity (human recombinant receptors in mammalian cells;
[3H]5-CT).
dBinding affinity (rat cerebral cortex membranes; [3H]ketanserin).29
receptor was assayed in terms of the ability to displace
the radioligand [3H]5-carboxyamidotryptamine ([3H]5-CT)
from cloned human 5-HT7 receptor expressed in COS-7
cells. The results, expressed as pKi, are summarized in
Table 1.
1,2,3,4-Tetrahydroisoquinoline is commercially available.
4,5,6,7 - Tetrahydro-furo[3,2-c]pyridine,21 4,5,6,7- tetra-
hydro - 3H - imidazo[4,5 - c]pyridine,22 and 4,5,6,7 - tetra-
hydro-1H-pyrazolo[4,3-c]pyridine23 were prepared by
literature methods. 4,5,6,7-Tetrahydrothieno[3,2-c]pyri-
dine 10 was synthesized starting from compound 6, and
compounds 7–9 were prepared by the method of Mat-
sumura et al.24 Reaction of compound 6 with Vilsmeier
reagent, which was prepared from DMF and POCl3, gave
compound 7. Compound 8 was obtained by treatment of 7
with ethyl mercaptoacetate followed by cyclization in the
presence of KOH. The 5-position ethoxycarbonyl group in
compound 8 was removed by alkaline hydrolysis to pro-
vide compound 9. Compound 10 was obtained by the
decarboxylation of compound 9 in 95% yield (Scheme 3).
Compound 5b was a potent ligand for the 5-HT7 recep-
tor, being at least 2-fold more selective than compounds
5a and 5c. This result is consistent with findings in our
previous series of phenylpiperazine derivatives, whose
optimum carbon chain length was also n=4.18 These
results suggests that the distance between the basic
nitrogen atom and the tetrahydrobenzindole ring is
important in determining the selectivity for the 5-HT7
receptor.
Next, we fixed the carbon chain length at the optimum
value (n=4) and synthesized other fused heterocycles.
The thienopyridine 5d, as well as the isoquinoline 5b,
Compounds 5a–i were evaluated for affinity for the
5-HT7 and 5-HT2 receptors. The affinity for the 5-HT7

C. Kikuchi et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2549–2552
2551
showed both high affinity and high selectivity for the
5-HT7 receptor, and the furopyridine 5e had moderate
affinity for this receptor. This may be due to the differ-
ence of their aromaticity,25 because affinity for the
5-HT7 receptor appeared to depend on aromaticity in
our previous study.26 The imidazopyridine 5f and the
pyrazolopyridine 5g showed very low affinity for the
5-HT7 receptor, and were not further evaluated.
Compound 5h, which is the N-methyl-tetra-
hydrobenzindole analogue of compound 5d, was a
potent 5-HT7 ligand with high selectivity for this recep-
tor over the 5-HT2 receptor,27 while the N-ethyl-tetra-
hydrobenzindole 5i showed very low affinity and
selectivity for the 5-HT7 receptor. These results sug-
gested that the size of R group influences the binding to
the 5-HT7 receptor. The small R groups may be pre-
ferred for the 5-HT7 receptor binding. The N-methyl-
benzindole 5h (DR4446) should be suitable for positron
emission tomography (PET) studies,28 because the
N-methyl group is available for introduction of a 11C
isotope label.
Figure 1. 5-HT-induced stimulation of cAMP accumulation in
HEK273 cells expressing the 5-HT7 receptor and its inhibition by
compound 5d. Data represent the meanÆSE of at least three
determinations.
On the basis of its potential utility for investigation of
the 5-HT7 receptor, the thienopyridine derivatives 5d
and 5h were selected for further evaluation. As can be
seen from Table 2, compound 5d was found to be highly
selective for the 5-HT7 receptor over the 5-HT1A, 5-HT1B,
5-HT2C, 5-HT3, 5-HT4 and 5-HT6 receptors, and
N-methyl derivative 5h was as selective as compound 5d.
Thus, compounds 5d and 5h were confirmed to be high-
affinity ligands for the 5-HT7 receptor with high selectivity.
In summary, we have described the synthesis and the
affinity for the 5-HT7 receptor and other receptors of a
novel series of fused-ring tetrahydropyridine derivatives.
A limited structure–activity relationship study for these
derivatives indicated that the distance between the basic
nitrogen atom and the tetrahydrobenzindole ring was
important in determining the selectivity for the 5-HT7
receptor. Some of the compounds showed high affinity
and high selectivity for the 5-HT7 receptor. In partic-
ular, the thienopyridine derivatives 5d and 5h were
potent and highly selective ligands for the 5-HT7 recep-
tor, and should be useful tools for clarifying the biological
role of the 5-HT7 receptor.
Compound 5d was evaluated for influence on 5-HT-
induced stimulation of cAMP accumulation in HEK293
cells expressing the human 5-HT7 receptor. Intracellular
cAMP formation was measured by enzyme-immuno-
assay. Compound 5d on its own did not stimulate basal
activity, that is it lacked agonist activity, but it inhibited
5-HT-induced stimulation of cAMP accumulation (Fig.
1). Compound 5d is thus a 5-HT7 receptor antagonist.
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5-HT1B
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2a,3,4,5-tetra-hydrobenz[cd]indol-2(1H)-one (5d): 1H NMR
(CDCl3) d 1.03–1.16 (1H, m), 1.29–1.41 (2H, m), 1.41–1.56
(2H, m), 1.77–1.93 (3H, m), 2.06–2.20 (2H, m), 2.38–2.50 (2H,
m), 2.59–2.73 (3H, m), 2.79–2.89 (3H, m), 3.48 (2H, s), 6.66–
6.69 (2H, m), 6.79 (1H, d, J=7.8 Hz), 7.04 (1H, d, J =5.1
Hz), 7.11 (1H, dd, J=7.6 Hz), 8.00 (1H, br s); EIMS m/z 366
(M+). 1-Methyl-2a-[4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-
5-yl)butyl]-2a,3,4,5-tetrahydrobenz[cd]indol-2(1H)-one (5h):
1H NMR (CDCl3) d 0.95–1.07 (1H, m), 1.14–1.33 (2H, m),
1.39–1.53 (2H, m), 1.74–1.94 (3H, m), 2.07–2.19 (2H, m),
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(3H, s), 3.47 (2H, s), 6.63 (1H, d, J=7.6 Hz), 6.69 (1H, d,
J =5.1 Hz), 6.82 (1H, d, J=7.8 Hz), 7.05 (1H, d), 7.17 (1H,
dd); TSPMS m/z 381 (M+H+).
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