Synthesis and preliminary screening of novel indole-3-methanamines as 5-HT4 receptor ligands

Article abstract of DOI:10.1016/j.ejmech.2009.01.015

Twenty-three indole-3-methanamines were designed, synthesized and evaluated as ligands for the 5-HT₄ receptor. Compounds I-d, I-j, I-o, I-q and I-u showed good affinity at 100 μM and I-o was found to be only 5-fold less potent than the agonists

Full text of DOI:10.1016/j.ejmech.2009.01.015

European Journal of Medicinal Chemistry 44 (2009) 2952–2959
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and preliminary screening of novel indole-3-methanamines as 5-HT4
receptor ligands
,
Amir Hanna-Elias a, David T. Manallack a, Isabelle Berque-Bestel b c, Helen R. Irving a,
,
Ian M. Coupar a, Magdy N. Iskander a
*
a Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3053, Australia
b
ˆ
Univ Paris-Sud, BioCIS UMR 8076, Laboratoire de Chimie The´rapeutique, Facult´e de Pharmacie, rue J.B. Cle´ment, F-92296 Chatenay-Malabry, France
c Inserm U869, Universite´ Victor Segalen, 146 rue le´o Saignat, F-33076 Bordeaux, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty-three indole-3-methanamines were designed, synthesized and evaluated as ligands for the 5-
Received 22 July 2008
Received in revised form
16 December 2008
Accepted 9 January 2009
Available online 24 January 2009
HT4 receptor. Compounds I-d, I-j, I-o, I-q and I-u showed good affinity at 100 mM and I-o was found to be
only 5-fold less potent than the agonists serotonin (1) and 5-methoxytryptamine (2). Substitution on the
3-methanamine nitrogen clearly influenced activity with docking experiments into a homology model of
the 5-HT4 receptor showing a range of interactions with these side chain substituents. This modelling
work together with the SAR determined in this study has provided promising ideas for future synthetic
work.
Keywords:
Indole analogues
5-HT4 ligands
Ó 2009 Elsevier Masson SAS. All rights reserved.
5-HT4 receptor model
1. Introduction
receptor [16] to gain insight into the interaction with Asp100 and
other residues near the alkylamine side chain.
Agonists that target 5-HT4 receptors influence the regulation of
smooth muscle tone and nerve activity in various parts of the gut as
well as the bladder [1–3]. These compounds are used clinically for
both gastroesophageal reflux disease [4] and irritable bowel
syndrome [5–7]. Notably, cisapride and tegaserod have been
restricted for use in humans due to the prevalence of cardiovascular
side effects [8–10]. Given these deficits there is a clear need for new
compounds with improved receptor selectivity and clinical profiles.
This present study has used a range of methods to influence our
design strategy. The use of pharmacophore models developed in
our laboratories [11,12] contributed towards our choice of scaffold
and side chain substituents. Existing structure–activity information
was also used employing an indole-3-methanamine scaffold
related to the alkaloid gramine which has shown activity at
different 5-HT receptors [13–15]. This series has been limited to the
5-methoxy derivative given the known agonist actions of 5-HT (1)
and 5-methoxytryptamine (2) [Fig. 1]. Primarily the designs seek to
determine the effect of shortening the alkylamine side chain and to
observe the effect of varying the nature of this side chain. Finally,
each compound was modelled into a homology model of the 5-HT4
2. Chemistry
The design of various structurally diverse 5-HT4 agonists
explored in this study was based on the indole moiety of compound
2 which is known to result in good recognition at 5-HT4 receptors
[11]. As the indole moiety (Scheme 1, general structure I) is found to
be an essential part of the structure of many 5-HT receptor ligands
[17], we chose this group as our template for the diverse library of
compounds. We varied the side chain to encompass a wide array of
groups possessing different electronic, steric, lipophilic and
hydrophilic properties. In some cases a second basic centre was also
included [11]. A key feature of these compounds was the use of
a methylamine side chain. This differs from classic 5-HT ligands
which usually possess an ethylamine group.
The general reaction used to prepare each compound (I-a to
I-w) is shown in Scheme 1. Initial nucleophilic attack by the
primary amine on the carbonyl carbon of 5-methoxy indole-3-
carboxaldehyde (3) spontaneously caused the formation of
a Schiff’s base (II). The unstable imine was reduced to the equiva-
lent secondary amine (I) with yields ranging from 30 to 90%. While
some of these yields were low it was not our aim to optimize the
reaction conditions but to generate numerous analogues for
screening purposes. The variation in yield may also be attributed to
* Corresponding author. Tel.: þ61 3 99039679; fax: þ61 3 99039545.
E-mail address: magdy.iskander@vcp.monash.edu.au (M.N. Iskander).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.01.015

A. Hanna-Elias et al. / European Journal of Medicinal Chemistry 44 (2009) 2952–2959
2953
NH2
a manner similar to that shown previously [16] demonstrating key
interactions between Ser197 and the indole oxygen substituent as
well as the alkylamine side chain with Asp100 (Fig. 2A). Ten poses
were generated for each docking run and within this set a binding
mode was found that corresponded to the configuration of the
indole moiety of compounds 1 and 2 (Fig. 2B and C). An alternative
orientation of the indole ring was also found where the indole
nitrogen was placed next to Ser197 (Fig. 2C). A correlation was not
found between the docking scores and the percentage displace-
ment data; a result that was not unexpected. It was instructive
however, to examine the location and nature of the interactions
between the side chains of each ligand and the receptor to stimu-
late further synthetic ideas.
From the docking studies it was apparent that compounds I-o, I-j
and I-d oriented their side chain aromatic/heterocyclic rings above
Leu99 making van der Waals contact with the terminal methyl
groups of this residue (Fig. 2B). The rings were placed adjacent to
and in the same plane as the guanidine group of Arg96 which was
located in a position that could form hydrogen bonds with the
morpholine, benzenesulphonamide or 3-methoxy-4-hydroxy rings.
NH2
HO
H3CO
N
H
N
H
1
2
Fig. 1. Structures of serotonin (5-HT, 1) and 5-methoxytryptamine (5-MeOT, 2).
the diversity of amino groups used and was influenced by their
differing nucleophilic strengths. Each compound was purified by
preparative TLC or HPLC. Compounds I-e [18] and I-w [19] have
been described previously.
Using a homology model of the human 5-HT4 receptor [16] each
molecule was docked into the protein using Glide (Schrodinger)
[20,21]. Docking used the standard precision (sp) protocol and
ionization states of the ligands and protein side chains were care-
fully checked (e.g. Asp100) [22]. Compounds 1 and 2 bound in
O
NHR
NR
H3CO
H3CO
H3CO
a
b
N
H
N
H
N
H
3
II
I
HN
N
OCH3
OH
N
NH
N
I-a
NO2
H
I-b
I-c
I-d
F
F
F
N
N
N
O
I-e
I-f
I-g
I-h
N
F
F
F
O
S
O
OH
H
NH2
O
I-i
I-j
O
I-l
I-k
N
N
H
N
O
H
I-p
I-m
I-n
I-o
O
N
O
N
O
I-q
I-r
I-s
I-t
O
O
I-u
I-v
I-w
Scheme 1. Synthesis of 5-methoxyindole compounds; (a) R-NH2, in acetonitrile or methanol, reflux 24 h, (b) NaBH4, 0 ꢀC warmed slowly to rt.

2954
A. Hanna-Elias et al. / European Journal of Medicinal Chemistry 44 (2009) 2952–2959
in exactly the same plane as the indole ring of compound 1 (Fig. 2A).
In addition, the methanamine nitrogen is able to form an ionic bond
with Asp100 as well as placing the morpholine ring adjacent to
Arg96 once again. Given the importance of interactions with
Asp100 this alternative mode will require further scrutiny and will
certainly influence our design strategy.
3. Screening
The compounds were subjected to preliminary radioligand
displacement screening using [3H]-GR113808 which is a high
affinity and selective 5-HT4 receptor antagonist [26]. All molecules
were screened at 100 mM and 1 mM on the human 5-HT4b (h5-HT4b)
receptor splice variant as it is the most commonly expressed 5-HT4
receptor splice variant [1,2]. Two standard compounds (1 the
endogenous ligand; and 2 a 5-HT4 preferring full agonist) were
screened with the target candidate molecules. The displacements
recorded for the standards at 100 mM, 1 and 2 were 99% and 100%,
respectively. Compounds I-d, I-j, I-l, I-m, I-o, I-q, I-r and I-u
exhibited high affinity with displacement values not significantly
different to the standard compounds (Fig. 3). Only compound I-o
showed displacement values not significantly different to either 1
or 2 at 1 mM (Fig. 3). Hence a full displacement curve was con-
structed for compound I-o (Fig. 4). The pKi values obtained were
7.53 ꢁ 0.07, 7.57 ꢁ 0.12 and 6.84 ꢁ 0.20 for 1, 2 and compound I-o
respectively. Comparable literature values of pKi for 5-HT and
5-MeOT at the 5-HT4b receptor are 6.96 ꢁ 0.28 and 6.61 ꢁ0.30
respectively [27].
4. Discussion
This study has sought to explore a scaffold that has not been
extensively used in 5-HT receptor research. Indeed, the choice of
the gramine-like backbone was intended to challenge the phar-
macophore models established for 5-HT4 receptors. Shortening the
alkylamine side chain of 1 and 2 is contrary to many design strat-
egies that have placed the ionizable nitrogen atom further from the
indole/aromatic group. Encouragingly, compounds I-d, I-j, I-o, I-q
and I-u showed good affinity at 100 mM clearly showing that the
shorter alkylamine side chain was tolerated within the binding site.
Even more encouraging was the finding that I-o was only 5-fold
less potent than the classic agonists 1 and 2. Given that this small
library of compounds represents the first foray with this scaffold
then it certainly needs to be followed up to narrow down the SAR.
An initial attempt to understand the SAR was not entirely clear
given that in some cases the biology results between compounds,
either at 1 or 100 mM, were very similar. The side chain of
compound I-o is a simple morpholine ring that is directly attached
to the 3-methanamine nitrogen through the morpholine nitrogen
atom. Within series I only two other compounds (I-m and I-r)
Fig. 2. (A) Compound 1 docked into the homology model of the 5-HT4 receptor. (B)
Compound I-j docked into the homology model of the 5-HT4 receptor. (C) Compound
I-d docked into the homology model of the 5-HT4 receptor.
attach a ring directly to the methanamine nitrogen. At 1 mM both
I-m and I-r are inactive which may suggest that the morpholine
oxygen of I-o has some role to play in binding to the receptor. Given
that docking suggests there is a close proximity of this side chain
group to Arg96 then it is easy to suggest that there may be
a hydrogen bond formed between the morpholine oxygen and the
guanidine group. Taking this theme one stage further would
suggest that the basic piperazine of I-m would not favourably
interact with Arg96 and that I-r would be unable to make any
specific interactions. Another question that arises with I-o is the
location of the basic centre given that the morpholine ring is
directly attached to the scaffold (I) (i.e. an N–N bond). Using the
ACD/Labs software [28] the pKa was predicted to be 6.2 and to
reside on the 3-methanamine nitrogen itself. As such, the activity
seen with I-o is not a consequence of moving the basic centre
Future studies need to investigate this binding mode which will no
doubt involve revising the homology model using the recently
described beta-adrenergic receptor structures [23–25]. Particular
focus can then be given to the interactions with the side chains of
the more active compounds I-d, I-j, I-o, I-q and I-u. Interestingly,
the pyrrolidine side chain of compound I-h was found to have
a slightly altered configuration in which this group was located
close to Ile157. This can be attributed to the longer propyl chain
linking the indole and pyrrolidine groups allowing interactions
deeper within the binding cavity. The alternative binding mode of
the indole group as shown in Fig. 2C illustrates the hydrogen bond
between the indole nitrogen and Ser197. Notably, the indole ring is

A. Hanna-Elias et al. / European Journal of Medicinal Chemistry 44 (2009) 2952–2959
2955
A 100
*
*
*
*
*
*
*
*
*
*
80
60
40
20
0
Compound number
B
100
*
*
80
60
40
20
0
*
Compound number
Fig. 3. (A) Percentage displacement of [3H]-GR113808 binding to the h5-HT4b receptor by compounds I-a to I-w screened at 100
m
M, together with the reference compounds 1 and
2. (B) Percentage displacement of [3H]-GR113808 by each compound at 1
mM. Asterisks indicate compounds with displacement values not significantly different (P > 0.05) to
5-MeOT.
where it would have the same registry as either 1 or 2. The alter-
native binding mode shown in Fig. 2C does however, allow I-o to
bind to Asp100 despite the shortening of the side chain. Potentially
this binding mode may explain the potency of I-o and further work
needs to be undertaken to assess the feasibility of this docking
orientation. The only other SAR worth discussing is a comparison of
compounds to I-q which had fair affinity at 1 M and possessed a
m
1-propyl-1H-imidazole side chain. Other compounds that shared
this same three-atom chain to a ring structure were I-b, 1-h and I-t.
Apart from I-t they all have a basic side chain (in addition to the 3-
methanamine nitrogen) with predicted pKa values of 2.4, 10.4 and
7.1 for I-b, I-h and I-q, respectively. Since I-b and I-t had the lowest
activity of these four compounds and that their side chain
substituents are essentially neutral at pH 7.4, it may suggest that
a second basic group is needed further from the 3-methanamine
nitrogen. Indeed our earlier work has shown that a second basic
group was well tolerated at 5-HT4 receptors (unpublished obser-
vations). This is certainly of interest and further molecules based on
the indole-3-methanamine scaffold are planned to explore the
optimal location of a second basic centre. While there are other
compounds with a second basic centre within the current series
there may be additional considerations for activity such as the
similar shape that both 1-h and I-q share.
This study has generated a new scaffold for 5-HT4 receptors
which contrasts to previously developed series of compounds. The
most potent compound emerging from this set was marginally
lower in potency than both 1 and 2 highlighting the utility of this
finding. While some SAR’s have been cautiously put forward there
is a clear need for further experiments to clarify the relative
activities of the current set of compounds. In addition, docking
experiments will benefit from the development of updated models
100
1
2
80
I-o
60
40
20
0
-12
-10
-8
log [compound]
-6
-4
-2
Fig. 4. Displacement curves of [3H]-GR113808 binding to the h5-HT4b receptor by
compounds 1 (B), 2 ( ) and I-o (-).
6

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A. Hanna-Elias et al. / European Journal of Medicinal Chemistry 44 (2009) 2952–2959
of the 5-HT4 receptors using the recent crystal structures of beta-
adrenergic receptors [23–25]. Future chemistry efforts are planned
that will explore the SAR around the more active compounds from
this study as well as integrating ideas that emerge from the
molecular modelling.
glass backed Silica Gel 60 F254 sheets. Isolated compounds were
analysed by TLC to ensure that only 1 spot was visible for high
purity. All pKa values were calculated using ACD/Labs pKa calculator
[28].
5.2.1. N-((5-Methoxy-1H-indol-3-yl)methyl)-2-(piperazin-1-
yl)ethanamine (I-a)
5. Experimental
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
5.1. Binding assay
and 1-(2-aminoethyl)piperazine (77 mL, 0.59 mmol) were heated to
reflux in anhydrous acetonitrile (20 mL). After 5 h, the mixture was
cooled to 0 ꢀC and 3 molar equivalents of NaBH4 were used to
complete the reductive amination. The reaction mixture was dried
under reduced pressure, and extracted with DCM. The organic
fractions were washed with water, and then dried over anhydrous
sodium sulphate. The residue obtained was purified by preparative
TLC. This yielded N-((5-methoxy-1H-indol-3-yl)methyl)-2-(piper-
azin-1-yl)ethanamine as a yellow crystalline solid; 4.4 mg, 2.5%
Membranes were isolated from COS-7 cells 3 days following
transient transfection with the 5-HT4b receptor splice variant
using LipofectamineÔ 2000 (Invitrogen, Mount Waverley, VIC,
Australia). Radioligand binding assays were performed in 96-well
plates with a total volume of 300 ml containing 20 mg protein,
0.25 nM [3H]-GR113808 (1-(2-(methylsulphonyl)amino)ethyl-4-
piperidinyl)methyl-1-methyl-1H-indole-3-carboxylate from GE
Healthcare (Little Chalfont, Buckinghamshire, UK) with or
without competing unlabelled ligand in phosphate buffered
saline (PBS). Incubations were performed at room temperature
(20–25 ꢀC) for 60 min and the membranes were harvested onto
GF/B UniFilter plates (Perkin–Elmer, Rowville, VIC, Australia) pre-
soaked overnight in 0.5% (v/v) polyethyleneimine (Sigma) using
a Filtermate cell harvester (Packard, Meridan, Connecticut, USA),
washed three times with PBS and counted using a Top-count
Microplate scintillation counter (Packard). For competition (full
displacement) assays, the data were fitted by least squares
analysis using the one site fit Ki model in GraphPad Prism 5
(GraphPad Software, San Diego, California, USA) and the radio-
ligand value of 0.25 nM and Kd value of 0.087 previously deter-
mined for the 5-HT4b receptor splice variant. The mean
displacement values of the compounds in the preliminary
screening exercise were determined from n ¼ 3–6 experiments
and the data were analysed by one-way ANOVA followed by the
Tukey–Kramer post-hoc test.
yield; 1H NMR (d6-DMSO)
d
10.75 (1H, s, NH), 7.22 (1H, d, J ¼ 4.2 Hz,
CH), 7.18 (1H, s, CH), 7.02 (1H, s, CH), 6.74 (1H, dd, J ¼ 2.4 Hz, CH),
3.74 (3H, s, OCH3), 3.64 (2H, m, CH2), 2.65 (4H, t, CH2), 2.50 (2H, t,
CH2), 2.39–2.35 (6H, m, CH2); high-resolution ESIMS, m/z (MHþ)
289.2023 (error 1.7 ppm).
Compounds 5–26 were synthesized and purified in a similar
way as in compound 4.
5.2.2. N1-((5-Methoxy-1H-indol-3-yl)methyl)-N2-
(5-nitropyridin-2-yl)ethane-1,2-diamine (I-b)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 2(2-aminoethylamino)-5-nitropyridine (107 mg, 0.59 mmol)
were heated to reflux in anhydrous methanol (20 mL) for 3 h.
This yielded N1-((5-methoxy-1H-indol-3-yl)methyl)-N2-(5-nitro-
pyridin-2-yl)ethane-1,2-diamine as a brown solid; 7.4 mg, 3.7%
yield; mp 112 ꢀC; 1H NMR (d6-DMSO)
d 10.80 (1H, s, NH), 8.60 (1H,
s, CH), 8.01 (1H, dd, J ¼ 2.4 Hz, CH), 7.65 (1H, s, NH), 7.31 (1H, d,
J ¼ 2.4 Hz, CH), 7.29 (1H, s, CH), 7.01 (1H, s, CH), 6.80 (1H, dd,
J ¼ 2.4 Hz, CH), 6.45 (1H, dd, J ¼ 2.4 Hz, CH), 3.85 (3H, s, OCH3), 3.67
(2H, m, CH2), 3.35 (2H, t, CH2), 2.53 (2H, t, CH2); high-resolution
ESIMS, m/z (MHþ) 342.1562 (error 1.2 ppm).
5.2. Materials and methods
All synthesized compounds were checked by ESI Mass Spec-
troscopy and 1H NMR. Nuclear magnetic resonance spectra were
recorded at room temperature on a Bruker Avance 300 MHz
NMR spectrometer. Chemical shifts are reported relative to tet-
ramethylsilane at 0 ppm. Low Resolution Mass Spectrometry
analyses were performed using a Micromass Platform II single
quadrupole mass spectrometer equipped with an atmospheric
pressure (ESI/APCI) ion source. Sample management was facili-
tated by an Agilent 1100 series HPLC system and the instrument
was controlled using MassLynx software version 3.5. High-
Resolution Mass Spectrometry analyses were collected on
a Waters Micromass LCT Premier XE Time Of Flight mass spec-
trometer fitted with either an electrospray (ESI) or Ion Sabre
(APCI) ion source and controlled with MassLynx software version
4.1. All compounds were named using Chemdraw Ultra 10.0 and
predicted 1H NMR shifts were also used for comparison with
experimental data. It was observed that in d6-DMSO as NMR
solvent the indole nitrogen proton was always observed at the
same chemical shift, whereas in CDCl3, it was consistently
absent.
5.2.3. 1-(5-Methoxy-1H-indol-3-yl)-N-
(piperidin-4-ylmethyl)methanamine (I-c)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 4-(aminomethyl)piperidine (70 mL, 0.59 mmol) were heated to
reflux in anhydrous methanol (20 mL) for 3 h. This yielded 1-(5-
methoxy-1H-indol-3-yl)-N-(piperidin-4-ylmethyl)methanamine
as a light-brown coloured solid; 19.1 mg, 11.8% yield; mp 127–
128 ꢀC; 1H NMR (d6-DMSO)
d 10.85 (1H, s, NH), 7.21 (1H, s, CH), 7.15
(1H, d, J ¼ 2.4 Hz, CH), 7.09 (1H, s, CH), 6.73 (1H, dd, J ¼ 2.4 Hz, CH),
3.80 (3H, s, OCH3), 3.76 (2H, s, CH2), 2.91–2.87 (4H, m, CH2), 2.51
(2H, s, CH2), 1.66–1.40 (4H, m, CH2); high-resolution ESIMS, m/z
(M þ H)þ 274.1912 (error 2.6 ppm).
5.2.4. 2-Methoxy-4-({[(5-methoxy-1H-indol-3-
yl)methyl]amino}methyl)phenol (I-d)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 4-hydroxy-3-methoxy benzylamine (111 mg, 0.59 mmol) were
heated to reflux in anhydrous methanol (20 mL) for 3 h.
This yielded 2-methoxy-4-({[(5-methoxy-1H-indol-3-yl)methyl]a-
Anhydrous sodium sulphate was used as the drying agent in
organic solutions. Concentration and evaporation of organic solu-
tions were performed using a Buchi rotary evaporator. All reactions
requiring reflux were conducted under inert nitrogen atmosphere
using oven dried glassware (120 ꢀC). Analytical Thin Layer Chro-
matography (TLC) was performed using 0.2 mm, aluminium backed
Silica Gel 60 F254 sheets. Preparative TLC was performed on 2 mm
mino}methyl)phenol as a maroon coloured solid; 1.2 mg, 0.6%
1
yield; H NMR (d6-DMSO)
d 10.25 (1H, s, NH), 9.8 (1H, s, OH), 7.28
(1H, d, J ¼ 3.0 Hz, CH), 7.25 (1H, s, CH), 7.11 (1H, s, CH), 6.99 (1H, s,
CH), 6.80 (1H, dd, J ¼ 2.4 Hz, CH), 6.75 (1H, d, J ¼ 2.1 Hz, CH), 6.72
(1H, d, J ¼ 3.3 Hz, CH), 3.91 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.76
(2H, s, CH2), 3.60 (2H, s, CH2); high-resolution ESIMS, m/z (MHþ)
313.1547 (error 1.6 ppm).

A. Hanna-Elias et al. / European Journal of Medicinal Chemistry 44 (2009) 2952–2959
2957
5.2.5. 1-(5-Methoxy-1H-indol-3-yl)-N-(3-
(trifluoromethyl)benzyl)methanamine (I-e)
5.2.10. 4-(2-{[(5-Methoxy-1H-indol-3-yl)
methyl]amino}ethyl)benzenesulfonamide (I-j)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 3-(trifluoromethyl) benzylamine (84 mL, 0.59 mmol) were
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 4(2-aminoethyl) benzenesulphonamide (118 mg, 0.59 mmol)
were heated to reflux in anhydrous acetonitrile (20 mL) for 3 h.
This yielded 4-(2-{[(5-methoxy-1H-indol-3-yl)methyl]amino}e-
thyl)benzenesulfonamide as a brown crystalline solid; 3.2 mg, 1.6%
heated to reflux in anhydrous acetonitrile (20 mL) for 5 h.
This yielded 1-(5-methoxy-1H-indol-3-yl)-N-(3-(trifluoromethyl)-
benzyl)methanamine as a pink crystalline solid; 6.3 mg, 3% yield;
1H NMR (d6-DMSO)
d
10.65 (1H, s, NH), 7.76 (1H, s, CH), 7.67 (1H, t,
yield; 1H NMR (d6-DMSO)
d 10.65 (1H, s, NH), 7.75 (2H, d, CH), 7.43
J ¼ 6.9 Hz, CH), 7.52 (1H, d, J ¼ 6.9 Hz, CH), 7.38 (1H, d, J ¼ 6.9 Hz,
CH), 7.35 (1H, d, J ¼ 6.9 Hz, CH), 7.20 (1H, s, CH), 7.11 (1H, s, CH), 6.76
(1H, dd, J ¼ 2.4 Hz, CH), 3.81 (3H, s, OCH3), 3.78 (2H, s, CH2), 3.68
(2H, s, CH2); high-resolution ESIMS, m/z (MHþ) 335.1362 (error
2.7 ppm).
(2H, d, CH), 7.21 (1H, d, J ¼ 3.3 Hz, CH), 7.16 (1H, s, CH), 7.02 (1H, s,
CH), 6.75 (1H, dd, J ¼ 4.5 Hz, CH), 3.71 (3H, s, OCH3), 3.50 (2H, s,
CH2), 2.83 (2H, t, CH2), 2.53 (2H, t, CH2); high-resolution ESIMS, m/z
(MHþ) 360.1376 (error 1.7 ppm).
5.2.11. 1-(5-Methoxy-1H-indol-3-yl)-N-
5.2.6. N-((5-Methoxy-1H-indol-3-yl)methyl)-2-
morpholinoethanamine (I-f)
(4-(trifluoromethoxy)benzyl)methanamine (I-k)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 4-(trifluoromethoxy)benzylamine (90 mL, 0.59 mmol) were
and N-(
b
-aminoethyl) morpholine (77
m
L, 0.59 mmol) were
heated to reflux in anhydrous methanol (20 mL) for 3 h.
This yielded 1-(5-methoxy-1H-indol-3-yl)-N-(4-(trifluoromethoxy)
benzyl)methanamine as a dark green solid; 20.8 mg, 10% yield; mp
heated to reflux in anhydrous acetonitrile (20 mL) for 8 h. This
yielded N-((5-methoxy-1H-indol-3-yl)methyl)-2-morpholinoe-
thanamine as a brown crystalline solid; 3.7 mg, 2.2% yield; 1H
94–95 ꢀC; 1H NMR (d6-DMSO)
d 10.85 (1H, s, NH), 7.55 (1H, d,
NMR (d6-DMSO)
d
10.85 (1H, s, NH), 7.27 (1H, d, J ¼ 3.0 Hz, CH),
J ¼ 8.1 Hz, CH), 7.41 (1H, s, CH), 7.27 (1H, s, CH), 7.14 (1H, s, CH), 6.97
(1H, dd, J ¼ 15.9 Hz, CH), 6.85 (1H, dd, J ¼ 11.7 Hz, CH), 3.87 (1H, s,
CH2), 3.77 (1H, s, CH3), 3.49 (1H, s, CH2); high-resolution ESIMS, m/z
(MHþ) 351.1317 (error 0.85 ppm).
7.19 (1H, s, CH), 7.10 (1H, s, CH), 6.80 (1H, dd, J ¼ 2.4 Hz,
CH), 3.82 (3H, s, OCH3), 3.60 (2H, s, CH2), 3.39 (4H, t, J ¼ 4.5 Hz,
CH2, CH2), 2.57 (2H, t, J ¼ 6.6 Hz, CH2), 2.30–2.20 (2H, m, CH2,
CH2, CH2); high-resolution ESIMS, m/z (MHþ) 290.1862 (error
2.4 ppm).
5.2.12. 4-(2-{[(5-Methoxy-1H-indol-3-
yl)methyl]amino}ethyl)phenol (I-l)
5.2.7. N-((5-Methoxy-1H-indol-3-yl)methyl)-2-
(pyrrolidin-1-yl)ethanamine (I-g)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and tyramine (81 mg, 0.59 mmol) were heated to reflux in anhy-
drous methanol (20 mL) for 3 h. This yielded 4-(2-{[(5-methoxy-
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 2-(2-aminoethyl)pyrrolidine (74
m
L, 0.59 mmol) were heated
1H-indol-3-yl)methyl]amino}ethyl)phenol as
powdery solid; 10 mg, 5.7% yield; mp 220 ꢀC with decomposition;
1H NMR (d6-DMSO)
7.21 (1H, s, CH), 7.14 (2H, d, J ¼ 2.4 Hz, CH), 7.01 (1H, s, CH), 6.71 (1H,
dd, J ¼ 6.0 Hz, CH), 6.67 (2H, d, J ¼ 2.4 Hz, CH), 3.82 (3H, s, CH3), 3.74
(2H, s, CH2), 2.75 (2H, t, CH2), 2.52 (2H, t, CH2); high-resolution
ESIMS, m/z (MHþ) 297.1594 (error 3.0 ppm).
a cream-coloured
to reflux in anhydrous methanol (20 mL) for 3 h. This yielded N-((5-
methoxy-1H-indol-3-yl)methyl)-2-(pyrrolidin-1-yl)ethanamine as
a brown solid; 7.9 mg, 4.9% yield; mp 115–116 ꢀC; 1H NMR (d6-
d
10.85 (1H, s, NH), 7.23 (1H, d, J ¼ 2.4 Hz, CH),
DMSO)
d
10.90 (1H, s, NH),7.30 (1H, d, J ¼ 2.4 Hz, CH), 7.15 (1H, s,
CH), 7.09 (1H, s, CH), 6.89 (1H, dd, J ¼ 2.7 Hz, CH), 3.91 (3H, s, OCH3),
3.62 (2H, s, CH2), 3.19–3.12 (2H, m, CH2, CH2, CH2), 2.85 (2H, t,
J ¼ 6.0 Hz, CH2), 1.35 (2H, m, CH2, CH2); high-resolution ESIMS, m/z
(MHþ) 274.1911 (error 2.9 ppm).
5.2.13. N-((5-Methoxy-1H-indol-3-yl)methyl)-4-methylpiperazin-
1-amine (I-m)
5.2.8. N-((5-Methoxy-1H-indol-3-yl)methyl)-3-
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
(pyrrolidin-1-yl)propan-1-amine (I-h)
and 1-amino-4-methyl piperazine (71 mL, 0.59 mmol) were heated
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 1-(3-aminopropyl)pyrrolidine (74 mg, 0.59 mmol) were heated
to reflux in anhydrous methanol (20 mL) for 3 h. This yielded
N-((5-methoxy-1H-indol-3-yl)methyl)-3-(pyrrolidin-1-yl)propan-1-
amine as an orange crystalline solid; 25 mg, 15% yield; mp 116–
to reflux in anhydrous acetonitrile (20 mL) for 3 h. This yielded
N-((5-methoxy-1H-indol-3-yl)methyl)-4-methylpiperazin-1-amine
as an orange solid; 17.3 mg, 10.7% yield; 1H NMR (d6-DMSO)
d 10.45
(1H, s, NH), 7.50 (1H, d, J ¼ 2.7 Hz, CH), 7.31, (1H, s, CH), 7.21 (1H, s,
CH), 6.82 (1H, dd, J ¼ 2.7 Hz, CH), 3.80 (3H, s, OCH3), 3.37 (2H, s,
CH2), 3.07 (4H, t, J ¼ 9.3 Hz, CH2, CH2), 2.52 (4H, t, J ¼ 9.3 Hz, CH2,
CH2), 2.24 (3H, s, CH3); high-resolution ESIMS, m/z (MHþ) 275.1872
(error 0 ppm).
117 ꢀC; 1H NMR (d6-DMSO)
d 10.85 (1H, s, NH), 7.50 (1H, d,
J ¼ 2.4 Hz, CH), 7.34 (1H, s, CH), 7.29 (1H, s, CH), 6.84 (1H, dd,
J ¼ 2.4 Hz, CH), 3.82 (3H, s, OCH3), 3.53 (2H, m, CH2), 2.55–2.46 (8H,
m, CH2), 1.91–1.80 (6H, m, CH2); high-resolution ESIMS, m/z (MHþ)
288.2065 (error 3.8 ppm).
5.2.14. 1-(5-Methoxy-1H-indol-3-yl)-N-
((5-methylfuran-2-yl)methyl)methanamine (I-n)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
5.2.9. 1-(5-Methoxy-1H-indol-3-yl)-N-
(pyridin-2-ylmethyl)methanamine (I-i)
and 5-methyl furfurylamine (65 mL, 0.59 mmol) were heated to
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 2-(aminomethyl)pyridine (61 mL, 0.59 mmol) were heated to
reflux in anhydrous methanol (20 mL) for 3 h. This yielded 1-(5-
methoxy-1H-indol-3-yl)-N-((5-methylfuran-2-yl)methyl)methan-
amine as a light-brown crystalline solid; 86.3 mg, 52.6% yield; mp
reflux in anhydrous methanol (20 mL) for 3 h. This yielded a brown
solid; 19.1 mg, 12.2% yield; mp 118–119 ꢀC; 1H NMR (d6-DMSO)
111 ꢀC; 1H NMR (d6-DMSO)
d 10.85 (1H, s, NH), 7.49 (1H, d,
d
10.85 (1H, s, NH), 8.51 (1H, d, J ¼ 4.5 Hz, CH), 7.77 (1H, t, J ¼ 7.5 Hz,
J ¼ 8.4 Hz, CH), 7.31 (1H, s, CH), 7.26 (1H, s, CH), 6.85 (1H, dd,
J ¼ 7.5 Hz, CH), 6.44 (1H, d, J ¼ 3 Hz, CH), 5.98 (1H, d, J ¼ 2.7 Hz,
CH), 3.94 (3H, s, CH3), 2.95 (2H, s, CH2), 2.88 (2H, s, CH2), 2.17 (3H,
s, CH3); high-resolution ESIMS, m/z (MHþ) 271.1447 (error
0 ppm).
CH), 7.47–7.27 (2H, m, CH), 7.26 (1H, s, CH), 7.22 (1H, d, J ¼ 2.7 Hz,
CH), 7.10 (1H, s, CH), 6.75 (1H, dd, J ¼ 2.4 Hz, CH), 3.88 (2H, s, CH2),
3.76 (3H, s, OCH3), 3.31 (2H, s, CH2); high-resolution ESIMS, m/z
(MHþ) 268.1444 (error 2.2 ppm).

2958
A. Hanna-Elias et al. / European Journal of Medicinal Chemistry 44 (2009) 2952–2959
5.2.15. N-((5-Methoxy-1H-indol-3-yl)methyl)morpholin
-4-amine (I-o)
5.2.20. N-((5-Methoxy-1H-indol-3-yl)methyl)-2-
phenoxyethanamine (I-t)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 4-aminomorpholine (57
m
L, 0.59 mmol) were heated to reflux
and 2-phenoxyethylamine (77 mL, 0.59 mmol) were heated to
in anhydrous acetonitrile (20 mL) for 3 h. This yielded N-((5-
methoxy-1H-indol-3-yl)methyl)morpholin-4-amine as a black oil;
reflux in anhydrous methanol (20 mL) for 3 h. This yielded N-((5-
methoxy-1H-indol-3-yl)methyl)-2-phenoxyethanamine as a light-
4.3 mg, 2.8% yield; 1H NMR (d6-DMSO)
d
10.55 (1H, s, NH), 7.46 (1H,
brown oil; 15 mg, 8.6% yield; 1H NMR (d6-DMSO)
d 10.85 (1H, s,
d, J ¼ 2.4 Hz, CH), 7.30 (1H, s, CH), 7.14 (1H, s, CH), 6.73 (1H, dd,
J ¼ 2.4 Hz, CH), 3.77 (3H, s, OCH3), 3.66 (2H, s, CH2), 3.53 (2H, t,
J ¼ 3.0 Hz, CH2), 2.99 (2H, t, J ¼ 4.8 Hz, CH2); high-resolution ESIMS,
m/z (MHþ) 262.1556 (error 0 ppm).
NH), 7.31 (2H, d, J ¼ 8.1 Hz, CH, CH), 7.26 (1H, d, J ¼ 3.0 Hz, CH), 7.15
(1H, s, CH), 7.04. (1H, s, CH), 6.91 (1H, s, CH), 6.89 (2H, d, J ¼ 8.4 Hz,
CH, CH), 6.72 (1H, dd, J ¼ 2.4 Hz, CH), 4.11 (2H, t, J ¼ 5.4 Hz, CH2),
3.76 (3H, s, OCH3), 3.52 (2H, s, CH2), 3.01 (2H, s, CH2); high-reso-
lution ESIMS, m/z (MHþ) 297.1599 (error 1.4 ppm).
5.2.16. 1-Adamantyl-N-((5-methoxy-1H-indol-3-yl)
methyl)methanamine
5.2.21. 1-(6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)-N-
5-Methoxyindole-3-carboxaldehyde (100 mg, 0.59 mmol) and
1-adamantylamine (89 mg, 0.59 mmol) were heated to reflux in
anhydrous methanol (20 mL) for 3 h. This yielded as a black semi-
((5-methoxy-1H-indol-3-yl)methyl)methanamine (I-u)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and cis-myrtanylamine (98 mL, 0.59 mmol) were heated to reflux in
anhydrous methanol (20 mL) overnight. This yielded 1-(6,6-dime-
thylbicyclo[3.1.1]heptan-2-yl)-N-((5-methoxy-1H-indol-3-yl)me-
thyl)methanamine as a white powder; 37 mg, 20% yield; mp 92–
solid; 32.4 mg, 18% yield; 1H NMR (d6-DMSO)
d
10.85 (1H, s, NH),
7.26 (1H, d, J ¼ 2.4 Hz, CH), 7.19 (1H, s, CH), 7.04 (1H, s, CH), 6.73
(1H, dd, J ¼ 2.4 Hz, CH), 3.78 (3H, s, OCH3), 3.62 (2H, s, CH2), 2.14–
2.07 (9H, m, CH2, CH2, CH2, CH, CH, CH), 1.65 (6H, m, CH2, CH2,
CH2); high-resolution ESIMS, m/z (MHþ) 311.2122 (error
0.32 ppm).
93 ꢀC; 1H NMR (d6-DMSO)
d
10.85 (1H, s, NH), 7.20 (1H, d, J ¼ 9.0 Hz,
CH), 7.17 (1H, s, CH), 7.10 (1H, s, CH), 6.86 (1H, dd, J ¼ 2.4 Hz, CH),
3.98 (3H, s, OCH3), 3.89 (2H, s, CH2), 2.91 (2H, m, CH2), 2.40 (2H, m,
CH2), 2.01–1.82 (9H, m, CH, CH, CH, CH2, CH2, CH2); high-resolution
ESIMS, m/z (MHþ) 313.2275 (error 0 ppm).
5.2.17. 3-(1H-Imidazol-1-yl)-N-((5-methoxy-1H-indol-3-yl)
methyl)propan-1-amine (I-q)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 1-(3-aminopropyl)imidazole (70 mL, 0.59 mmol) were heated
5.2.22. 1-(Benzo[d][1,3]dioxol-4-yl)-N-((5-methoxy-1H-indol-3-yl)
methyl)methanamine (I-v)
to reflux in anhydrous methanol (20 mL) for 3 h. This yielded 3-
(1H-imidazol-1-yl)-N-((5-methoxy-1H-indol-3-yl)methyl)propan-
1-amine as a yellow oil; 16.7 mg, 10% yield; 1H NMR (d6-DMSO)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and piperonylamine (73 mL, 0.59 mmol) were heated to reflux
in anhydrous methanol (20 mL) overnight. This yielded 1-(ben-
zo[d][1,3]dioxol-4-yl)-N-((5-methoxy-1H-indol-3-yl)methyl)me-
thanamine as a cream-coloured powder; 7.8 mg, 4.3% yield; mp
d
10.65 (1H, s, NH), 8.31 (1H, s, CH), 7.30 (1H, d, J ¼ 2.1 Hz, CH), 7.28
(1H, d, J ¼ 2.7 Hz, CH), 7.15 (1H, s, CH), 7.05 (1H, s, CH), 6.91 (1H, dd,
J ¼ 2.4 Hz, CH), 6.86 (1H, d, J ¼ 2.7 Hz, CH), 4.08 (2H, t, J ¼ 6.9 Hz,
CH2), 3.89 (3H, s, OCH3), 3.64 (2H, s, CH2), 2.70 (2H, t, J ¼ 6.6 Hz,
CH2), 1.98 (2H, t, J ¼ 4.2 Hz, CH2); high-resolution ESIMS, m/z
(MHþ) 285.1707 (error 2.8 ppm).
109 ꢀC; 1H NMR (d6-DMSO)
d
10.75 (1H, s, NH), 7.25 (1H, d, J ¼ 2.4 Hz,
CH), 7.22 (1H, s, CH), 6.97 (1H, s, CH), 6.82 (1H, dd, J ¼ 3.0 Hz, CH),
5.98 (2H, s, CH2), 3.77 (3H, s, OCH3), 3.75 (2H, s, CH2), 3.65 (2H, s,
CH2); high-resolution ESIMS, m/z (MHþ) 311.1391 (error 1.6 ppm).
5.2.18. (1R,2R,4R)-N-((5-Methoxy-1H-indol-3-yl)
methyl)bicyclo[2.2.1]heptan-2-amine (I-r)
5.2.23. N-Benzyl-1-(5-methoxy-1H-indol-3-yl)methanamine (I-w)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and benzylamine (64 mL, 0.59 mmol) were heated to reflux in
and Exo-2-aminonorbornane (70
m
L, 0.59 mmol) were heated
anhydrous acetonitrile (20 mL) for 3 h. This yielded N-benzyl-1-(5-
methoxy-1H-indol-3-yl)methanamine as a black oil; 24.6 mg, 16%
to reflux in anhydrous methanol (20 mL) for 3 h. This yielded
(1R,2R,4R)-N-((5-methoxy-1H-indol-3-yl)methyl)bicyclo[2.2.1]-
heptan-2-amine as a dark brown solid; 16.6 mg, 10% yield; mp
yield; 1H NMR (d6-DMSO)
d 10.75 (1H, s, NH), 7.43 (2H, m, CH, CH),
7.34 (1H, s, CH), 7.32 (2H, m, CH, CH), 7.24 (1H, d, J ¼ 2.4 Hz, CH),
7.14 (1H, s, CH), 7.02 (1H, s, CH), 6.88 (1H, dd, J ¼ 2.4 Hz, CH), 3.89
(3H, s, OCH3), 3.77 (2H, s, CH2), 3.69 (2H, s, CH2); high-resolution
ESIMS, m/z (MHþ) 267.1490 (error 2.6 ppm).
93–94 ꢀC; 1H NMR (d6-DMSO)
d 10.85 (1H, s, NH), 7.29 (1H, d,
J ¼ 2.4 Hz, CH), 7.26 (1H, s, CH), 7.16 (1H, s, CH), 6.78 (1H, dd,
J ¼ 2.4 Hz, CH), 3.97 (3H, s, OCH3), 3.78 (2H, s, CH2), 2.79–2.75
(1H, m, CH), 2.35 (1H, m, CH2), 2.21 (1H, m, CH2), 1.57–1.07 (8H,
m, CH2); high-resolution ESIMS, m/z (MHþ) 271.1804 (error
2.2 ppm).
Acknowledgements
This work was funded by a project grant from the National
Health and Medical Research Council of Australia (NHMRC) and
a scholarship to Mr. Hanna-Elias from the Faculty of Pharmacy and
Pharmaceutical Sciences, Monash University. We would like to
thank Marina Shapiro and Kenneth Chinkwo for their assistance in
cell biology. The mammalian expression vector pcDNA3.1/5-HT4b
was a gift from Dr. F.O. Levy (University of Oslo).
5.2.19. 1-(4,4-Dimethyl-1,3-dioxolan-2-yl)-N-((5-methoxy-1H-
indol-3-yl)methyl)methanamine (I-s)
5-Methoxyindole-3-carboxaldehyde (3) (100 mg, 0.59 mmol)
and 2,2-dimethyl-1,3-dioxolane-4-methanamine (76 mL, 0.59 mmol)
were heated to reflux in anhydrous methanol (20 mL) for 3 h.
This yielded 1-(4,4-dimethyl-1,3-dioxolan-2-yl)-N-((5-methoxy-
1H-indol-3-yl)methyl)methanamine as an orange semi-solid;
19.9 mg, 12% yield; 1H NMR (d6-DMSO)
d 10.85 (1H, s, NH), 7.31 (1H,
References
d, J ¼ 2.4 Hz, CH), 7.27 (1H, s, CH), 7.19 (1H, s, CH), 6.78 (1H, dd,
J ¼ 2.4 Hz, CH), 4.27 (1H, t, J ¼ 6.0 Hz, CH), 3.79 (3H, s, OCH3), 3.98
(1H, t, J ¼ 6.3 Hz, CH2), 3.66 (1H, t, J ¼ 6.0 Hz, CH2), 2.83 (1H, m, CH2),
2.51 (1H, m, CH2), 1.28 (6H, s, CH3, CH3); high-resolution ESIMS, m/z
(MHþ) 291.1702 (error 2.4 ppm).
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