1-(Bicyclopiperazinyl)ethylindoles and 1-(homopiperazinyl)ethyl-indoles as highly selective and potent 5-HT7 receptor ligands

Article abstract of DOI:10.1016/S0960-894X(02)00438-9

A novel series of 1-(bicyclopiperazinyl)ethylindole and 1-(homopiperazinyl)ethyl-indole derivatives was synthesized and found to be potent and selective 5-HT₇ receptor ligands.

Full text of DOI:10.1016/S0960-894X(02)00438-9

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2451–2454
1-(Bicyclopiperazinyl)ethylindoles and 1-(Homopiperazinyl)ethyl-
indoles as Highly Selective and Potent 5-HT7 Receptor Ligands
Methvin B. Isaac,* Tao Xin, Anne O’Brien, David St-Martin, Angela Naismith,
Neil MacLean, Julie Wilson, Lidia Demchyshyn, Ashok Tehim and Abdelmalik Slassi
NPS Pharmaceuticals Inc., 6850 Goreway Drive, Mississauga, ON, Canada L4V 1V7
Received 14 January 2002; accepted 9 May 2002
Abstract—A novel series of 1-(bicyclopiperazinyl)ethylindole and 1-(homopiperazinyl)ethyl-indole derivatives was synthesized and
found to be potent and selective 5-HT7 receptor ligands. # 2002 Elsevier Science Ltd. All rights reserved.
Serotonin (5-hydroxytriptamine, 5-HT) is a neuro-
transmitter that mediates a wide variety of sensory,
motor, and cortical functions through multiple 5-HT
receptor subtypes.1 Recently, application of molecular
cloning has led to the identification and isolation of the
5-HT7 receptor subtype from four mammalian species:
rat,2 mouse,3 guinea pig,4 and human.5 The human 5-
HT7 receptor (h5-HT7 ) is a 445 amino acid protein with
39–53% sequence homology when compared to other
5-HT receptor subtypes. This receptor is positively
coupled to adenylyl cyclase.6
The 5-HT7 receptor is located centrally, in the thalamus,
hypothalamus (particularly in the suprachiasmatic
nucleus) and several limbic and cortical regions. Such a
distribution of this receptor implicates it in the control
of circadian rythyms.3,7 The affinity of a number of
antipsychotic agents for the 5-HT7 receptor also sug-
gests that this receptor may mediate the therapeutic
actions of these compounds.4 In addition, high levels of
5-HT7 receptor mRNA have been found in human cor-
onary arteries suggesting a possible role in the vasodi-
lation of blood vessel.8
Figure 1. Selective 5-HT7 receptor ligands.
*Corresponding author. Fax: +1-905-677-9595; E-mail: misaac@npsp.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00438-9

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M. B. Isaac et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2451–2454
Scheme 1. Reagents and conditions: (a) NaH, DMF, BrCH2CO2C2H5, 0 ꢁC; (b) 2 equiv DIBAL-H, THF, rt; (c) (i) MsCl, Et3N, CH2Cl2, rt; (ii).
HNR1R2, THF, 70 ꢁC; (d) MsCl, NaH, DMF, 0 ꢁC–rt; (e) NaH, K2CO3, toluene, 110 ꢁC; (f) 1.5 equiv DIBAL-H, toluene, ꢀ78 ꢁC; (g) NaBH3CN,
NaOAc, HOAc, homopiperazine, rt; (h) NaBH3CN, NaOAc, HOAc, aldehydes or ketones.
Whilst the 5-HT7 receptor displays a unique pharma-
cology, only very recently has the identity of selective
ligands been reported (1, 2, 3, 4, and 5).9ꢀ13 Clearly, the
5-HT7 receptor may be a valuable, novel therapeutic
drug target and the development of potent and selective
ligands is highly desirable. As part of our research pro-
gram directed toward the design and synthesis of potent
and selective 5-HT1D receptor ligands, we serendipi-
tously discovered that the intermediate 6 (Fig. 1) was a
potent human 5-HT7 receptor ligand (Ki=70 nM).
Compound 6 was identified as an initial lead and opti-
mization was immediately pursued. We report here on
the synthesis and structure–activity relationship (SAR)
that led to a novel class of selective 5-HT7 receptor
ligands.
The synthesized compounds were primarily evaluated
for their binding affinities to the human 5-HT7 receptor
in vitro. The assay protocol entails the incubation of
membranes, prepared from HEK293 cells expressing the
human 5-HT7 receptor, with H-LSD and using cloza-
pine, a typical 5-HT7 receptor antagonist, as a standard.
3
Table 1. In vitro affinity of piperazinyl and homopiperazinyl ethyl
indoles
The synthesis of a series of aminoethylindoles of general
structures 10 and 14 is shown in Scheme 1. N-Alkyl-
ation of the substituted indoles 7 with ethylbromoacetate
afforded compound 8. Subsequent reduction of the ester
function with DIBAL-H gave the corresponding alcohol
9. Treatment of 9 with methanesulphonylchloride fol-
lowed by displacement with the various amines deliv-
ered compounds of general structure 10.
Compd
NR1R2
5-HT7
Bindinga
Compd
NR1R2
5-HT7
Bindinga
61
52
26
93
36
15
6
78
72
16
17
19
22
18
20
21
Compounds of general structure 14 were synthesized by
mesylation of the indole nitrogen followed by treatment
with the aminoethylalcohol in the presence of sodium
hydride, potassium carbonate in toluene giving the pro-
duct of structure 14. Alternatively, compound 14 was
synthesized from the common and versatile intemediate
8 from partial reduction with DIBAL-H to aldehyde 11,
followed by reductive amination with homopiperazine
to afford compound 13. Further reductive amination of
13 with various aldehydes and ketones gave compounds
of structure 14.
71
99
aPercent inhibition @1 mM.

M. B. Isaac et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2451–2454
2453
Various concentrations of the test compound were
incubated with the radioligand (3H-LSD) and the
receptor affinity (Ki in nM, or m% inhibition @ 1 uM)
was determined.
Removal of the N-methyl group from 19 gave ligand 47
with reduced receptor affinity (Table 4). However,
introduction of various alkyl and cycloalkyl groups
onto the nitrogen atom of the homopiperazine (47)
afforded a series of 5-HT7 ligands with enhanced recep-
tor potency. For example, replacement of the methyl
group of 19 with a cyclopropylmethyl and cyclopentyl
Initially, we examined the various piperazinylethyl and
homopiperazinylethyl indole analogues of 6 (15–22,
Table 1) and found that the N-methylhomopiperazine
19 and 6,7-bicyclohomopiperazine 21 retained potency
at the human 5-HT7 receptor with Kis of 31 and 3 nM,
respectively. The relatively high affinity of 6, 19, and
21 encouraged us to further examine the effect of the
position of the bromo substituent on the indole ring
system. By keeping the indole nitrogen substituent
fixed as the N-methylhomopiperazinylethyl and 6,6-
bicyclopiperazinylethyl groups, the various bromine
substituted indole analogues were examined. It was
found that the 5- and 6-bromosubstituted indoles
were more potent than the corresponding 4- and 7-
substituted indoles (Table 2). However, the 6-bromo-
substituted indole derivatives (6 and 19) were gen-
erally shown to have higher 5-HT7 receptor affinity
than the corresponding 5-sustituted analogues (11 and
14, Table 2).
Table 3. In vitro affinity of 6-substituted N-methylhomopiperazinyl
ethyl indoles
Compd
X
5-HT7 binding
29
30
19
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
F
Cl
Br
NH2
OH
H2NCO
CF3
NO2
PhCH2O
CH3O
60%a
288b
34b
85%a
93%a
0%a
31b
—
—
—
23b
139b
182b
1573b
109b
140b
125b
166b
145b
70b
28%a
33%a
89%a
72%a
28%a
50%a
79%a
79%a
62%a
66%a
72%a
72%a
6%a
With the above information in hand, the nitrogen sub-
stituent was fixed as a N-methylhomopiperazinylethyl
group and the steric and electronic effects of the sub-
stituents at the 6-position of the indole were thoroughly
examined (29–46, Table 3). Replacement of the 6-bromo
substituent of 19 with chlorine (30) resulted in a ligand
with very similar 5-HT7 receptor affinity, whereas the 6-
fluoro-analogue 29 led to a 9-fold decrease in receptor
affinity. However, hydrogen bond donors such as 6-
hydroxyl (31) and 6-amino (32) groups were found to be
detrimental to receptor activity. Interestingly, the 6-tri-
fluoromethyl group (34) led to a slight increase in
receptor affinity (Ki=23 nM).
CH2¼CH
CHꢂC
CH3
CH3CH2
i-Propyl
i-Propenyl
1-Hydoxy-i-propyl
3-Pyridyl
3-Thienyl
—
—
109b
35%a
68%a
a% inhibition @ 1 mM.
bKi, nM (see ref 14).
Some other substituents at the 6-position of the indole
were also explored (35–46, Table 3) demonstrating the
electronic and steric flexibility inherent in this novel 5-
HT7 pharmacophore. Nonetheless, the majority of sub-
stituents led to ligands with reduced affinity at the 5-
HT7 receptor compared to compound 19.
Table 4. In vitro affinity of 6-bromo N-substituted homo-
piperazinylethylindoles
Table 2. In vitro affinity of bromo substituted piperazinyl and
homopiperazinylethylindoles
Compd
R0
5-HT7 binding
93%a
19
47
48
49
50
51
52
53
54
55
Methyl
H
Isopropyl
Isobutyl
31b
—
77%a
92%a
95%a
70%a
95%a
96%a
98%a
96%a
18%a
14b
37b
163b
9b
Neopentyl
Cyclopropylmethyl
Cyclopropyl
Cyclopentyl
Cyclohexyl
Phenyl
Compd
X
5-HT7 binding
Compd
X
5-HT7 binding
23
24
6
4-Br 43%a
5-Br 65%a
6-Br 78%a
7-Br 13%a
—
158b
70b
—
26
27
19
28
4-Br 33%a
5-Br 65%a
6-Br 93%a
7-Br 18%a
—
88b
31b
—
16b
10b
17b
—
25
a% Inhibition @ 1 mM.
bKi, nM (see ref 14).
a% inhibition @ 1 mM.
bKi, nM (see ref 14).

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M. B. Isaac et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2451–2454
Table 5. Receptor binding profile of compound 21
In conclusion, a novel series of potent and selective 5-
HT7 receptor ligands has been discovered. Compound
21 was the most potent in this series and has demon-
strated good in vitro receptor selectivity, thus making it
a valuable tool with which to further characterize the
distribution and function of 5-HT7 receptors in native
tissue and to elucidate their potential role in disease
states. Compound 21 will be further evaluated for its
functional activity at this receptor.
Receptor % Inhibition @ 1 mM Receptor % Inhibition @ 1 mM
5-HT1A
5-HT1B
5-HT1D
5-HT1F
5-HT2A
5-HT2C
5-HT6
1
0
0
5-HT7
M1+M2
D1
D2
D3
3a
35
2
15
27
4
0
20
26
4066a
D4
D5
17
aKi values in nM (see ref 14).
References and Notes
1. Barnes, N.; Sharp, T. Neuropharmacology 1999, 38, 1083.
2. Plassat, J.; Amlaiky, N.; Hen, R. Mol. Pharmacol. 1993, 44,
229.
3. Lovenberg, T.; Baron, B.; De Lecea, L.; Miller, J.; Prosser,
R.; Rea, M.; Foye, P.; Racke, M.; Slone, A.; Siegel, B.;
Danielson, P.; Sutcliffe, J.; Erlander, M. Neuron 1993, 11, 449.
4. Tsou, A.; Kosaka, A.; Bach, C.; Zuppan, P.; Yee, C.; Tom,
L. J. Neurochem. 1994, 63, 456.
5. Bard, J.; Zgombick, J.; Adham, N.; Vaysse, P.; Branchek,
T.; Weinshank, R. J. Biol. Chem. 1993, 268, 23422.
6. Shen, Y.; Monsma, F.; Metcalfe, A.; Jose, P.; Hamblin, M.;
Sibley, D. J. Biol. Chem. 1993, 268, 18200.
Figure 2. Potent 6,7-bicyclohomopiperazine analogues.
7. Ruat, M.; Traiffort, E.; Leurs, R.; Tarddivel-Lacombe, J.;
Diaz, J.; Arrang, J.; Schwartz, J. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 8547.
8. Terron, J.; Falcon-Neri, A. Br. J. Pharmacol. 1999, 127, 609.
9. Linnanen, T.; Brisander, M.; Unelius, L.; Rosqvist, S.;
Nordvall, G.; Hacksell, U.; Johansson, A. J. Med. Chem.
2001, 44, 1337.
10. Forbes, I.; Dabbs, S.; Duckworth, D.; Jennings, A.; King,
F.; Lovell, P.; Brown, A.; Collin, L.; Hagan, J.; Middlemiss,
D.; Riley, G.; Thomas, D.; Upton, N. J. Med. Chem. 1998, 41,
655.
11. Kikuchi, C.; Nagaso, H.; Hiranuma, T.; Koyama, M. J.
Med. Chem. 1999, 42, 533.
12. Lovell, P.; Bromidge, S; Dabbs, S; Duckworth, D; Forbes,
I.; Jennings, A; King, F.; Middlemiss, D.; Rahman, S.; Saun-
ders, D.; Collin, L.; Hagan, J.; Riley, G.; Thomas, D. J. Med.
Chem. 2000, 43, 342.
13. Poss, M.; Purandare, A.; Mattson, R.; Sun, L. (Bristol-
Myers Squibb Co.) Patent WO-00185701, 2001.
14. Ki values in nM are given as the mean of at least two
independent determinations performed in triplicate with less
than 15% deviation.
15. 1HNMR (CDCl3) for compound 21 (a yellow oil): d 7.51
(s, 1H), 7.46 (d, 1H), 7.18 (d, 1H), 7.13 (d, 1H), 6.46 (d,1H),
4.13 (t, 2H), 2.88 (t, 2H), 2.83–1.16 (m, 17H).
led to 51 and 53 with Kis 9 and 10 nM, respectively
(Table 4). On the contrary, the corresponding N-neo-
pentyl (50) and N-phenyl (55) analogue reduced 5-HT7
receptor affinity.
The information gleaned from the N-methylhomopi-
perazinylethyl indole derivatives and the finding that
6,7-bicyclohomopiperazine 21 was very potent promp-
ted us to synthesize and evaluate the affinity of the 6-
chloro (56) and 6-trifluoromethyl (57) analogues of 21.
Both compound were found to be highly potent 5-HT7
receptor ligands (56, Ki=10 nM and 57, Ki=7 nM,
respectively, Fig. 2).
For the most potent compound 2115 (Ki=3 nM), the
binding affinities at other serotonin receptors, dopamine
receptors and muscarinic receptors were measured
(Table 5). It can be seen that 21 possesses very good
selectivity over the battery of receptors examined.