Synthesis, 5-hydroxytryptamine1A receptor affinity and docking studies of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives

Article abstract of DOI:10.1248/cpb.60.632

A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-h) was synthesized and evaluated for binding affinity at the human 5-hydroxytryptamine_1A receptor (5-HT_1AR) compounds (12b) and (12h) showed the highest 5-HT_1A receptor affinity (IC ₅₀-=15 nM). Molecular docking studies with all the compounds in a homology model of 5-HT_1A showed that the main interaction anchoring the ligand in the receptor was a charge-reinforced bond between the protonated nitrogen atom (N-4) of the piperazine ring and Aspartate^3.32.

Full text of DOI:10.1248/cpb.60.632

632
Regular Article
Chem. Pharm. Bull. 60(5) 632–638 (2012)
Vol. 60, No. 5
Synthesis, 5-Hydroxytryptamine1A Receptor Affinity and Docking
Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1H-Indole Derivatives
,a
Hernán Pessoa-Mahana,* Catalina Ugarte Núñez,a Ramiro Araya-Maturana,a
Claudio Saitz Barría,a Gerald Zapata-Torres,b,c Carlos David Pessoa-Mahana,d
Patricio Iturriaga-Vasquez,c,e Jaime Mella-Raipán,d Miguel Reyes-Parada,c,f,g and
Cristian Celis-Barrosb
a Department of Organic and Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University
b
of Chile; Department of Analytical and Inorganic Chemistry, Faculty of Chemical and Pharmaceutical Sciences,
c
University of Chile; Casilla 233, Santiago 1, Chile: Millennium Institute for Cell Dynamics and Biotechnology; San-
d
tiago, Chile: Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile; Casilla 306,
e
f
Santiago 22, Chile: Department of Chemistry, Faculty of Sciences, University of Chile; Santiago, Chile: School of
g
Medicine, Faculty of Medical Sciences, University of Santiago de Chile; Santiago, Chile: and Facultad de Ciencias
de la Salud, Universidad Autónoma de Chile; Santiago, Chile.
Received December 26, 2011; accepted February 14, 2012; published online March 1, 2012
A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a–h) was synthesized and evalu-
ated for binding affinity at the human 5-hydroxytryptamine1A receptor (5-HT1AR) compounds (12b) and (12h)
showed the highest 5-HT1A receptor affinity (IC50=15nM). Molecular docking studies with all the compounds
in a homology model of 5-HT1A showed that the main interaction anchoring the ligand in the receptor was a
charge-reinforced bond between the protonated nitrogen atom (N-4) of the piperazine ring and Aspartate3.32
.
Key words indolylalkylarylpiperazine; 5-hydroxytryptamine1A receptor; docking; binding; synthesis
Serotonin (5-hydroxytryptamine, 5-HT) is an important also show high selectivity for 5-HT1A over other receptors.14)
neurotransmitter that mediates various physiological and Structure–activity relationship (SAR) studies, performed
pathological processes in the peripheral and central nervous with numerous generations of arylpiperazine derivatives,
system (CNS) by interacting with several different recep- showed that CNS activity and both, receptor affinity and se-
tors.1–3) The 5-HT1A receptor sub-population has attracted con- lectivity depend basically on the N-1-aryl substituent and a
siderable attention in the drug discovery field.4–7) It is assumed terminal fragment bound to the N-4 atom of the piperazine
that anxiolytic drugs such as buspirone (1), tandospirone (2), moiety by an alkyl chain. In these studies, this alkyl spacer is
gepirone (3) or ipsapirone (4) (Fig. 1), exert their pharmaco- frequently composed of two to four methylene units.15,16)
logical activity through the activation of the 5-HT1A receptor,
On the other hand, the indole substructure is the basic
where they act as partial agonists.8–10) The 5-HT1A receptor is element in a large number of biologically active natural and
also implicated in many other physiopathological CNS pro- synthetic products. In fact, until this day, the indole motif is
cesses and conditions such as neuroprotection, schizophrenia, present in more than 400 drugs and 3000 patents.17) The range
’
’
Parkinson s and Alzheimer s diseases, acting alone or associ- of applications for these therapeutically relevant compounds
ated with other neurotransmitter receptors, especially dopa- includes anti-inflammatory drugs, protein kinase C inhibitors,
mine receptors.
5-HT agonists and antagonists, melatonin agonists and gluco-
Long-chain arylpiperazine derivatives are one of the most corticoid receptor modulators.18) Studies on structural modifi-
important classes of 5-HT1A ligands. In general, the arylpi- cations of indolylalkylarylpiperazines carried out by Heinrich
perazine moiety is a good template for drugs acting on many et al.14,19) reported a high-affinity pattern for 5-HT1A agonism
different biological targets, especially CNS receptors.11–13) As a and succeeded in optimizing selectivity over dopamine D2
consequence, many compounds containing this scaffold bind receptors. This structural pattern considers a C5-substituted
with high affinity at 5-HT1A receptors, but only a few of them indole ring bearing different functional groups and a para-
substituted arylpiperazine. In these studies, a four-carbon
atom chain was employed as a linker of both heterocyclic
moieties. On the other hand, a few studies on indolylalkyl-
arylpiperazines containing a propyl chain as a linker have
been reported regarding their 5-HT1B/1D receptor affinity.20,21)
However, the influence of a propylic connecting chain on the
affinity of this type of compounds for 5-HT1A receptor has
not been reported. The present work describes a convenient
synthetic route for the preparation of a series of 3-[3-(4-aryl-
1-piperazinyl)-propyl]-1H-Indole derivatives (12a–h) as well
as their affinity for the human 5-HT1A receptor. In addition,
a docking study using a homology model of this receptor was
performed in order to rationalize the pharmacological results
and to investigate ligand-receptor interactions that might be
Fig. 1. Chemical Structures of Buspirone (1), Tandospirone (2), Ge-
pirone (3) and Ipsapirone (4)
The authors declare no conflict of interest.
*To whom correspondence should be addressed. e-mail: hpessoa@ciq.uchile.cl
© 2012 The Pharmaceutical Society of Japan

May 2012
633
important for affinity.
about 5-fold lower than the parent compound. This result is
in agreement with those reported by Caliendo et al.,27) where
a 3–24-fold decrease was observed after ortho-fluorination of
Results and Discussion
Chemistry The synthesis of compounds (12a–h) was car-
ried out using a previously reported methodology,21) based on
the Fischer22) reaction between 4-substituted phenylhydrazine
°
hydrochlorides and dihydropyran in acid medium at 100 C for
2h, to provide 3-(3-indolyl)propanol 10 as shown in Chart 1.
The indole derivative (10) was purified by column chro-
matography (AcOEt), to give 74% of pure product. The IR
spectrum of the compound showed O–H and N–H stretching
Chart 1. Fischer Reaction to Obtain Indole 10
1
bands at 3417 (NH) and 3424–3250 (OH). The H-NMR spec-
trum displayed chemical shifts at δ 2.02, 2.87 and 3.72ppm
which were assigned to the three methylene groups of the
alkyl chain, along with the aromatic hydrogens of the indole
skeleton at δ 6.93–7.64ppm and a broad singlet at δ 8.17ppm
(N–H).
Chart 2. Preparation of Tosylate (11)
Compound (10), was then reacted with p-toluenesulfonyl
chloride in CH2Cl2 to afford the tosyl derivative (11) in
65% yield (Chart 2), in agreement with previous described
synthesis.22,23)
Subsequent reaction of 11 with commercially available aryl-
piperazines led to the expected displacement products 12a–h,
with yields between 53% and 98%.
Pharmacology The affinity of all compounds (12a–h) for
the human 5-HT1A receptor (IC50) was evaluated on the basis
of their ability to displace 8-hydroxy-2-(di-n-propylamino)-
tetralin, [3H]8-OH-DPAT. Results are summarized in Table 1.
Most of the compounds displayed high affinity for the hu-
man 5-HT1A receptor (ranging from 15 to 587nM), with the
best ligands being (12b) and (12h) (IC50=15nM). The unsub-
stituted indolepropylphenylpiperazine (12a) showed a marked
affinity for 5-HT1A, which increased after the introduction of a
methoxyl group in the ortho position (12b). This result agrees
with a number of previous studies11,14,24–26) in which the 2-me-
thoxyarylpiperazine derivative exhibited one of the highest
affinities of the series.
Table 1. IC50 Volume (mM) of Compounds (12a–h) towards 5-HT1A
R
Compound
R
IC50 (nM) S.D.
22
2
12a
Additionally, we found that the presence of a methoxyl
group either at the meta- (12c) or para- (12d) positions in-
duced a decrease of the 5-HT1A affinity as compared with the
parent compound. This observation differs from the results
reported by Heinrich et al.,14,19) where the para-methoxylated
derivative in their indolebutylphenylpiperazine series are al-
ways better ligands than the unsubstituted analogues. On the
other hand, our result agrees with those reported by Modica et
al.,24) where the presence of a para-methoxy group notably re-
duced the 5-HT1A affinity in a series of arylpiperazinylthieno-
pyrimidinones. Interestingly, in this last report the alkyl chain
connecting the arylpiperazine and the thienopyrimidinone
moieties was composed of 3 methylene units. This suggests
that the length of the (CH2)n spacer influences the effect of the
aromatic para-substituents on the affinity, being detrimental
when n=3, but incremental when n=4. This idea is further
supported by the result obtained with the para-fluoro deriva-
tive (12f). Thus, the affinity of compound (12f) was about ten-
fold lower than that of the unsubstituted ligand (12a), whereas
in the case of the analogues containing a four-methylene con-
necting chain,14) a marked increase of the 5-HT1A affinity was
observed when a fluorine atom was introduced at the para
position.
15
1
12b
113 12
12c
12d
12e
587 21
122 10
229 11
12f
70
15
3
1
12g
12h
The ortho-fluoro derivative (12e) displayed an affinity

634
Vol. 60, No. 5
benzotriazinarylpiperazine derivatives. This might be related modification can lead to an increase of selectivity for 5-HT1A
to the strong electronegativity of fluorine. It is worth pointing receptor, but at the expense of potency. The fact that (12b) and
out that the different affinities of compounds (12b) and (12e) (12h) showed virtually identical affinities suggests that the lat-
indicate that the nature of the substituent at the ortho position ter compound might serve as a lead for novel 5-HT1A ligands
is important for modulating the affinity. On the other hand, with high potency and improved selectivity.
the decreased affinity exhibited by the para-nitro derivative
Docking Simulations The ligand binding poses within
(12g) suggests that the effect observed after substituting this the 5-HT1A receptor for all the synthesized compounds were
position (see 12d, 12f, 12g) is less dependent on the nature of studied by molecular docking using a model based on the
the substituent.
crystal structure of the β2-adrenergic receptor.28) Results are
Finally, the 2-(1-piperazinyl)pyrimidine derivative (12h) summarized in Figs. 2–4, which show the most stable docking
showed high affinity for the human 5-HT1A receptor, similar poses for several drug-receptor complexes.
to that of the ortho-methoxylated compound (12b). Interest-
As illustrated with the most potent compounds (12b) and
ingly, previous studies24) showed that this type of structural (12h) (Fig. 2), our indolylpropylarylpiperazine derivatives in-
teract with the receptor at the binding site located within the
heptahelical bundle, with the ortho-methoxyaryl and pyrimi-
dyl moieties deeply buried in the binding site and the indole
moiety facing towards the extracellular side of the receptor.
In all cases, the main interaction anchoring the ligand to the
receptor was the well described charge-reinforced hydrogen
bond between the protonated nitrogen atom of the piperazine
ring (N-4) and Asp3.32 (numbering scheme according to Ball-
esteros and Weinstein).29) A second interaction between the
indole moiety and Phe6.52 was also observed. These docking
poses are highly consistent with the binding mode of long-
chain arylpiperazines proposed by Kołaczkowski et al. and
Nowack et al.30,31) Additionally, the indole moiety was oriented
towards helices I, II and VII, in a favorable position to estab-
lish a π–π interaction with the aromatic ring of Tyr2.54 at the
end of helix II.
The comparative analysis of the binding modes for the
unsubstituted indolylpropylphenylpiperazine (12a) with the
methoxylated derivatives (12b–d) (depicted in Figs. 3A, B),
Fig. 2. Docking Poses of the Indolylpropylarylpiperazine Derivatives
(12b) (Grey Sticks) and (12h) (Grey Sticks) at the 5HT1A Receptor
revealed that the ortho-methoxy group (12b) acts as a hy-
drogen-bond acceptor with Ser5.42 (Fig. 3A). This interaction,
Key aminoacids are depicted with residues highlighted in grey. The ligand bind-
which is not seen in the unsubstituted derivative (12a, Fig.
ing pocket is shown as viewed from the extracellular surface with the extracellular
loops removed for clarity.
3A), might explain the increased affinity of analogue (12b) as
Fig. 3. Docking Interactions of Indolylpropylarylpiperazine Derivatives at the Binding Site of the 5HT1A Receptor
The unsubstituted (12a) (grey sticks) and ortho-methoxylated (12b) (grey sticks) derivatives are shown in Fig. 3A, while the meta-(12c) (grey sticks) and para-methoxyl-
ated (12d) (grey sticks) derivatives are shown in Fig. 3B. Key residues are dark grey.

May 2012
635
on the binding modes of these compounds which allowed their
different potencies to be rationalized.
Our results further support the versatility of indolylalkylpi-
perazines as potent 5-HT1A ligands and highlight the impor-
tance of the length of the alkyl spacer for modulating their
receptor affinity.
Experimental
Chemistry Melting points were determined on a hot-stage
apparatus and are uncorrected. The IR spectra were recorded
in KBr discs on an Fourier transform (FT)-IR Bruker IFS 55
spectrophotometer and wavenumbers are reported in cm−1.
1
The H- and 13C-NMR spectra were obtained on a Bruker
DRX-300 spectrometer (300, 75MHz, respectively) in CDCl3
or DMSO-d6. Chemical shifts were recorded in ppm (δ)
relative to tetramethylsilane (TMS) as an internal standard. J
values are given in Hz. Microanalyses were carried out on a
Fisons EA 1108 analyzer. High resolution mass spectra were
recorded on a Thermo Finnigan MAT 95XP mass spectrom-
eter. Silica gel Merck 60 (70–230 mesh) and aluminium sheets
coated with silica gel 60 F254 were used for column and TLC
chromatography, respectively.
Fig. 4. Binding Interactions of ortho-Methoxy-(12b) (Grey Sticks)
and ortho-Fluoro-(12e) (Dark Grey Sticks) Indolylpropylarylpiperazine
Derivatives
3-(1H-3-Indolyl)-1-propanol (10) To a stirred solution
of commercial phenylhydrazine HCl (1.01g, 6.9mmol) in
N,N-dimethylacetamide (NN-DMA) (10mL) and H2SO4 4%
Key residues are dark grey. Grey dots indicate edge-to-face or face-to-face π–π
°
interactions.
p/p (10mL, 0.04mmol), heated to 100 C, 3,4-dihydro-2H-
pyran (0.63mL, 6.9mmol) was added. The mixture was kept
compared with its parent compound. On the other hand, the at reflux temperature for 2h. After this time the reaction
meta-methoxy derivative (12c) lacks such an interaction with was quenched with water (50mL) and extracted with AcOEt
Ser5.42, exhibiting instead a binding mode in which the indole (3×30mL). The organic layer was dried over anhydrous Na-
moiety remains far from Tyr2.54 as compared with the other 2SO4 and evaporated in vacuo. The crude product was purified
derivatives (Fig. 3B). In consequence, the π–π interactions are by column chromatography on silica gel (AcOEt) to furnish
not observed, which might explain the lower affinity of com- 889mg (74%) of a brown oil. IR cm−1: 3417 (N–H), 3329 (O–
1
pound (12c). Regarding the para-methoxy derivative (12d), H), 3055 (C–H arom), 2926 (C–H aliph.). H-NMR (CDCl3) δ:
which showed the lowest affinity of the series, the docking 2.02 (m, 2H, 2′-H), 2.87 (t, 2H, 1′-H, J=7.5Hz), 3.72 (t, 2H, 3′-
study revealed the impossibility of this compound to attain H, J=6.50Hz), 6.93 (m, 1H, 2-H), 7.14 (t, 1H, 6-H, J=7.0Hz),
the conformation found in the preceding compounds (Fig. 3B). 7.22 (td, 1H, 5-H, Jo=8.0Hz, Jm=1.1Hz), 7.34 (d, 1H, 7-H,
In fact, this analogue displayed an alternative docking pose, J=7.4Hz), 7.64 (d, 1H, 5-H, J=7.8Hz), 8.17 (s, 1H, N–H). 13C-
orientating its para-methoxyl group towards helices I and VII, NMR (DMSO-d6): 21.8, 33.3, 63.0, 111.6, 116.2, 119.3, 119.5,
while its protonated N-4 atom forms a hydrogen bond with 121.9, 122.3, 127.9, 136.8. Anal. Calcd for C11H13NO: C, 75.40;
Asp3.32 at a longer distance (3.44Å), which could explain its H, 7.48; N, 7.99. Found: C, 75.35; H, 7.35; N, 7.89.
decreased affinity.
3-(3-Indolyl)-propyl-4-methylbenzenesulfonate (11) To
In order to evaluate the role of the ortho-phenyl substituent, a stirred solution of 10 (0.89g, 5.10mmol) in dry CH2Cl2
we compared the binding modes of the two compounds bear- (30mL), tosyl chloride (1.17g, 6.1mmol), and triethylamine
ing this substitution, namely the ortho-methoxy (12b) and the (0.62g, 6.1mmol), was added. The mixture was stirred at
ortho-fluoro (12e) derivatives (Fig. 4). As can be seen, both room temperature for 25h. After this time, the mixture was
compounds exhibit similar binding modes, but in the case of concentrated under vacuum to afford a crude product in
the fluorinated derivative (12e), the halogen atom is in close quantitative yield. The crude was purified by column chroma-
contact (3.8Å) with the carboxylate oxygens of Asp3.32, lead- tography (hexane:AcOEt 2:1) to afford 1.08g (64%) of pure
−1
°
ing to repulsive interactions which might explain the lower product (11) mp.: 84–86 C. IR cm : 3386 (N–H), 3038 (C–H
affinity displayed by this compound.
1
arom), 2929–2903 (C–H aliph.). H-NMR (CDCl3) δ: 2.05 (m,
2H, 2′-H), 2.44 (s, 3H, Ar-CH3), 2.82 (t, 2H, 1′-H, J=7.3Hz),
4.09 (t, 2H, 3′-H, J=6.2Hz), 6.92 (d, 1H, 2-H, J=2.1Hz), 7.10
Conclusions
A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole (t, 1H, 6-H, J=7.0Hz), 7.19 (t, 1H, 5-H, J=7.5Hz), 7.32 (d, 2H,
derivatives was prepared in a three-step sequence, using the 3″-H, 5″-H, J=8.5Hz), 7.35 (d, 1H, 4-H, J=9.5Hz), 7.50 (d,1H,
highlighted and efficient synthesis of tryptophol homologues. 7-H, J=7.8Hz), 7.77 (d, 2H, 2″-H, 6″-H, J=8.5Hz), 7.87 (brs,
All compounds displayed nanomolar affinity for the human 1H, N–H). 13C-NMR (DMSO-d6): 21.3, 22.0, 29.5, 70.5, 111.6,
5-HT1A receptor, but showed a differing trend of SAR as 114.8, 119.0, 119.7, 122.2, 122.4, 127.6, 128.3 (2×), 130.2 (2×),
compared with derivatives containing longer alkyl chains con- 133.6, 136.8, 145.1. Anal. Calcd for C18H19N03S: C, 65.63; H,
necting the arylpiperazine and the indole moieties. Molecular 5.81; N, 4.25; S, 9.73. Found: C, 65.63; H, 5.88; N, 4.28; S,
docking performed using a 5-HT1A receptor model shed light 11.84.

636
Vol. 60, No. 5
1
Typical Procedure for 3-[3-(4-Aryl-1-piperazinyl)- (arom C=C), 1242 (C–O). H-NMR (DMSO-d6): 1.83 (m, 2H,
propyl]-1H-indol Derivatives. 3-[3-(4-Phenyl-1-pipera- 2′-H), 2.40 (t, 2H, 3′-H, J=6.7Hz), 2.52 (s, 4H, 2″-H, 6″-H),
zinyl)-propyl]-1H-indol (12a)32) as a Model A mixture of 2.72 (t, 2H, 1′-H, J=7.1Hz), 3.01 (m, 4H, 3″-H, 5″-H), 3.68 (s,
3-(3-indolyl)propyl-4-methylbenzenesulfonate (0.15mmol) in 3H, Ar-OMe), 6.80 (d, 2H, 3‴-H, 5‴-H, J=9.2Hz), 6.88 (d, 2H,
acetonitrile (30mL), anhydrous potassium carbonate (0.0231g, 2‴-H, 6‴-H, J=9.2Hz), 6.96 (t, 1H, 6-H, J=7.0Hz), 7.06 (t, 1H,
0.17mmol) and 4-phenyl-1-piperazine (0,0246g, 0.15mmol) 5-H, J=7.0Hz), 7.12 (d, 1H, 2-H, J=2.0Hz), 7.33 (d, 1H, 4-H,
was stirred under reflux for 10h. After this time water was J=8.0Hz), 7.5 (d, 1H, 7-H, J=7.8Hz), 10.80 (s, 1H, NH). 13C-
added (30mL) and extracted with AcOEt (3×30mL). The NMR (DMSO-d6): 22.5, 26.9, 49.5 (2×), 52.8 (2×), 55.2, 57.7,
combined organic layers were washed and dried over anhy- 111.3, 114.3 (2×), 114.4, 117.4 (2×), 118.2, 118.3, 120.9, 121.9,
drous Na2SO4. The organic portion was filtered and the sol- 127.1, 136.1, 145.4, 152.7. Anal. Calcd for C22H27N3O: C, 75.61;
vent evaporated to obtain a crude, that was purified by column H, 7.79; N, 12.02; Found: C, 75.32; H, 7.75; N, 11.87.
chromatography (AcOEt) and recrystallized (EtOH), to afford
3-{3-[4-(2-Fluorophenyl)-1-piperazinyl]-propyl}-1H-
−1
°
pure (12a) (0.0435g, 90%) mp 104–106 C. IR cm : 3416 indol (12e) Prepared from 3-(3-indolyl)propyl-4-methyl-
(N–H), 3040 (C–H arom), 2930–2820 (C–H aliph.), 1599 (C= benzenesulfonate (0.21g, 0.63mmol), anhydrous potassium
1
C arom). H-NMR (DMSO-d6): 1.87 (m, 2H, 2′-H), 2.42 (t, carbonate (0.19g, 1.4mmol) and 2-fluoro-1 phenylpiperazine
−1
°
2H, 3′-H, J=6.7Hz), 2.54 (s, 4H, 2″-H, 6″-H), 2.76 (t, 2H, 1′-H, (0.13g, 0.74mmol). 98.3% yield, mp 105–107 C. IR cm : 3414
J=6.9Hz), 3.16 (s, 4H, 3′-H, 5′-H), 6.5–7.5 (m, 10H, 2-H, 4-H, (N–H), 3078 (C–H arom), 2943–2828 (C–H aliph.), 1455 and
1
5-H, 6-H, 7-H and 2‴-H–6‴H), 10.8 (s,1H, NH). 13C-NMR 1496 (arom C=C). H-NMR (DMSO-d6): 1.83 (m, 2H, 2′-H),
(DMSO-d6): 22.5, 27.2, 48.3 (2×), 52.9 (2×), 57.7, 111.3, 114.4, 2.39 (t, 2H, 3′-H, J=7.2Hz), 2.50 (s, 4H, 2″-H, 6-″H), 2.71 (t,
115.3 (2×), 118.1, 118.3, 118.7, 120.8, 122.2, 127.3, 128.9 (2×), 2H, 1′-H, J=7.4Hz), 3.00 (s, 4H, 3″-H, 5″-H), 6.90–7.13 (m,
136.3, 151.1. Anal. Calcd for C21H25N3: C, 78.96; H, 7.89; N, 7H, 2-H, 5-H, 6-H, 3‴-H–6‴-H), 7.33 (d, 1H, 4-H, J=8.0Hz),
13.15. Found: C, 78.82; H, 7.78; N, 13.21.
3-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propyl}-1H- (DMSO-d6): 22.0, 26.7, 49.7 (2×), 52.4 (2×), 57.2, 110.9, 113.9,
7.52 (d, 1H, 7-H, J=7.8Hz), 10.78 (s, 1H, NH). 13C-NMR
2
3
indol (12b) Prepared from 3-(3-indolyl)propyl-4-methylben- 115.74 (d, J=20.0Hz), 117.6–117.8, 118.6 (d, J=3.0Hz), 120.3,
2′
4
zenesulfonate (0.207g, 0.63mmol), anhydrous potassium car- 121.7 (d, J=5.1Hz), 124.3 (d, J=3.4Hz), 126.8 (2×), 135.8,
3′
1
bonate (0.0956g, 0.69mmol) and 1-(2-methoxyphenyl)pipera- 139.5 (d, J=8.4Hz), 154.5 (d, J=244.2Hz). Anal. Calcd for
−1
°
zine (0.1333g, 0.63mmol). 55.2% yield, mp 90–92 C. IR cm : C21H24FN3: C, 74.75; H 7.17; N, 12.45. Found: C, 74.72; H,
3413 (N–H), 3056 (C–H arom), 2938–2879 (C–H aliph.), 1499 7.16; N, 12.50.
1
(C=C), 1241 (C–O). H-NMR (DMSO-d6): 1.84 (m, 2H, 2′-H),
3-{3-[4-(4-Fluorophenyl)-1-piperazinyl]-propyl}-1H-
2.40 (t, 2H, 3′-H, J=6.4Hz), 2.50 (s, 4H, 2″-H, 6″-H), 2.71 (t, indol (12f) Prepared from 3-(3-indolyl)propyl-4-methyl-
2H, 1′-H, J=6.7Hz), 2.96 (s, 4H, 3″-H, 5″-H), 3.76 (s, 3H, Ar- benzenesulfonate (0.26g, 0.79mmol) anhydrous potassium
OMe), 6.86–6.99 (m, 5H, 6-H and 3‴-H–6‴-H), 7.06 (t, 1H, carbonate (0.12g, 0.87mmol) and 4-fluoro-1 phenylpiperazine
°
5-H, J=7.4Hz), 7.12 (s, 1H, 2-H), 7.33 (d,1H, 4-H, J=7.8Hz), 98% (0.14g, 0.79mmol). 72.7% yield, mp 106–108 C. IR
7.5 (d, 1H, 6-H, J=7.6Hz), 10.77 (s, 1H, NH). 13C-NMR cm−1: 3416 (N–H), 3053 (C–H arom), 2936–2831 (C–H aliph.),
1
(DMSO-d6): 22.0, 26.7, 49.6 (2×), 52.7 (2×), 54.8, 57.3, 110.8, 1509 (arom C=C). H-NMR (DMSO-d6): 1.87 (m, 2H, 2′-H),
111.4, 113.9, 117.4, 117.6, 117.8, 120.4 (2×), 121.7, 121.8, 126.8, 2.50 (m, 2H, 3′-H), 2.59 (s, 4H, 2″-H, 6-″H), 2.72 (t, 2H, 1′-
135.8, 140.8, 151.5. Anal. Calcd for: C22H27N3O: C, 75.61; H, H, J=7.3Hz), 3.10 (s, 4H, 3″-H, 5″-H), 6.90–7.1 (m, 6H, 5-H,
7.79; N, 12.02. Found: C, 75.83; H, 7.83; N, 11.92.
6-H, 2‴-H, 3‴-H, 5‴-H, 6‴-H), 7.13 (brs, 1H, 2-H), 7.34 (d,
3-{3-[4-(3-Methoxyphenyl)-1-piperazinyl]-propyl}-1H- 1H, 4-H, J=8.0Hz), 7.52 (d, 1H, 7-H, J=7.5Hz), 10.77 (s, 1H,
indol (12c) Prepared from 3-(3-indolyl)propyl-4-methylben- NH). 13C-NMR (DMSO-d6): 21.9, 26.3, 48.1 (2×), 52.0 (2×),
2
zenesulfonate (0.24g, 0.73mmol), anhydrous potassium car- 56.8, 110.8, 113.7, 114.7 (2×) (d, J=22.0Hz), 116.6 (2×) (d,
bonate (0.11g, 0.79mmol) and 1-(3-methoxyphenyl)piperazine 3J=7.6Hz), 117.6, 117.7, 120.3, 121.7, 126.7, 135.8, 147.3 (d,
−1
1
(0.15g, 0.74mmol). 92.4% yield, mp 82–84 C. IR cm : 3408 4J=1.9Hz), 155.5 (d, J=236Hz). Anal. Calcd for C21H24FN3:
°
(N–H), 3076 (C–H arom), 2948–2786 (C–H aliph.), 1609 (arom C, 74.75; H, 7.17; N, 12.45. Found: C, 74.55; H, 7.21; N, 12.36.
C=C), 1575 (arom C=C), 1218 (C–O). H-NMR (DMSO-d6):
1
3-{3-[4-(4-Nitrophenyl)-1-piperazinyl]-propyl}-1H-Indol
1.84 (m, 2H, 2′-H), 2.38 (t, 2H, 3′-H, J=6.8Hz), 2.50 (s, 4H, (12g) Prepared from 3-(3-indolyl)propyl-4-methylbenzene-
2″-H, 6″-H), 2.72 (t, 2H, 1′-H, J=7.2Hz), 3.12 (s, 4H, 3″-H, 5″- sulfonate (0.106g, 0.32mmol), anhydrous potassium carbonate
H), 3.70 (s, 3H, Ar-OMe), 6.36 (d,1H, 6‴-H, J=8.0Hz), 6.44 (0.049g, 0.35mmol) and 4-nitrophenyl-1-piperazine (0.067g,
−1
°
(s, 1H, 2‴-H), 6.50 (d, 1H, 4‴-H, J=8.2Hz), 6.97 (t, 1H, 6-H, 0.32mmol). 53.2% yield, mp 158–160 C. IR cm : 3415
J=7.3Hz), 7.04–7.12 (m, 3H, 5‴-H, 2-H, 5-H), 7.34 (d, 1H, (N–H), 3049 (C–H arom), 2936–2843 (C–H aliph.), 1600 (NO2
1
4-H, J=8.0Hz), 7.52 (d, 1H, 7-H, J=7.7Hz), 10.75 (s, 1H, NH). asym.), 1331 (NO2, sym). H-NMR (DMSO-d6): 1.86 (m, 2H,
13C-NMR (DMSO-d6): 22.3, 26.8, 47.8 (2×), 52.5 (2×), 54.6, 2′-H), 2.41 (t, 2H, 3′-H, J=6.8Hz), 2.50 (s, 4H, 2″-H, 6″-H),
’
57.5, 101.1, 103.8, 107.8, 111.1, 114.2, 117.9, 118.1, 120.6, 121.7, 2.75 (t, 2H, 1 -H, J=7.2Hz), 3.44 (s, 4H, 3″-H, 5″-H), 6.71–6.76
126.9, 129.4, 135.9, 152.2, 159.9. Anal. Calcd for C22H27N3O: (m, 3H, 6-H, 2‴-H, 6‴-H), 7.09 (t, 1H, 5-H, J=7.3Hz), 7.17
C, 75.61; H, 7.79; N, 12.02. Found: C, 75.47; H, 7.82; N, 11.97. (s, 1H, 2-H), 7.38 (d, 1H, 4-H, J=8.0Hz), 7.56 (d, 1H, 7-H,
3-{3-[4-(4-Methoxyphenyl)-1-piperazinyl]-propyl}-1H- J=7.8Hz), 8.07 (d, 2H, 3‴-H, 5‴-H, J=9.3Hz), 10.84 (brs, 1H,
indol (12d) Prepared from 3-(3-indolyl)propyl-4-methyl- NH). 13C-NMR (DMSO-d6): 22.5, 27.0, 46.2 (2×), 52.3 (2×),
benzenesulfonate (0.30g, 0.91mmol), anhydrous potassium 57.4, 111.4, 112.5 (2×), 114.3, 118.1, 118.3, 120.8, 122.2, 125.7
carbonate (0.14g, 1.0mmol) and 1-(4-methoxyphenyl)pipera- (2×), 127.2, 136.3, 136.8, 154.7. Anal. Calcd for C21H24N4O2:
−1
°
zine (0.26g, 1.0mmol). 91.9% yield, mp 116–118 C. IR cm : C, 69.21; H, 6.64; N, 15.37. Found: C, 69.35; H, 6.55; N, 15.15.
3420 (N–H), 3037 (C–H arom), 2948–2806 (C–H aliph.), 1508
3-[3-(4-Pyrimidin-2-yl-1-piperazinyl)-propyl]-1H-indol

May 2012
637
(12h) Prepared from 3-(3-indolyl)propyl-4-methylbenzene- x, y, and z directions was built, centered on the carboxylate
sulfonate (0.20g, 0.61mmol) anhydrous potassium carbonate oxygen atom of Asp3.32 in the binding site of the receptor. A
(0.09g, 0.70mmol) and 1-(2-pyrimidyl)piperazine dihydrochlo- grid spacing of 0.375Å and a distance-dependent function of
−1
°
ride (0.16g, 0.70mmol). 70.8% yield, mp 95–97 C. IR cm : the dielectric constant were used to calculate the energy map.
3422 (N–H), 3057 (C–H arom), 2996–2826 (C–H aliph.), 1587 The default settings were used for all other parameters. At
1
(arom C=N), 1546 (arom C=C). H-NMR (DMSO-d6): 1.83 the end of each docking, ligand conformations displaying the
(m, 2H, 2′-H), 2.34–2.42 (m, 6H, 3′-H, and 2″-H, 6″-H), 2.71 most favorable free energies of binding were selected as the
(t, 2H, 1′-H, J=7.4Hz), 3.72 (t, 4H, 3″-H, 5″-H, J=4.8Hz), 6.60 resulting complex structures. All calculations were carried out
(t, 1H, 4‴-H, J=4.7Hz), 6.96 (t, 1H, 6-H, J=7.1Hz), 7.05 (t, on a PC Cluster running Linux ×86 as the operating system.
1H, 5-H, J=7.1Hz), 7.12 (d, 1H, 2-H, J=2.0Hz), 7.33 (d, 1H, The resulting structure files were analyzed using the Pymol39)
4-H, J=8.0Hz), 7.5 (d, 1H, 7-H, J=7.5Hz), 8.34 (d, 2H, 3‴-H, visualization program.
5‴-H J=4.7Hz), 10.80 (s, 1H, NH). 13C-NMR (DMSO-d6):
22.0, 26.7, 42.9 (2×), 52.2 (2×), 57.2, 109.6, 110.9, 113.9, 117.6,
Acknowledgements This work was supported by Grants
117.8, 120.3, 121.7, 126.7, 135.8, 157.4 (2×), 160.8. Anal. Calcd from FONDECYT 1090169 to HP-M and 1090037 to MR-P
for C19H23N5: C, 71.00; H, 7.21; N, 21.79. Found: C, 70.87; H, and ICM Grant P05-001-F.
7.26; N, 21.64.
5-HT1A Receptor Binding Assay 5-HT1A receptor bind-
ing assay was performed using membranes from human em-
bryonic kidney (HEK-293) cells expressing the human 5-HT1A
receptor (RBHS1AM400UA; PerkinElmer Life and Analytical
Sciences, Waltham, MA, U.S.A.). The 5-HT1A receptor mem-
branes were thawed and diluted in assay buffer (50mM Tris–
HCl, pH 7.4, 5mM MgSO4) to a concentration of 16µg/500µL.
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