January 2011 Evaluation of 1-Arylpiperazine Derivative of Hydroxybenzamides as 5-HT1A and 5-HT7
Serotonin Receptor Ligands: An Experimental and Molecular Modeling Approach
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CH2ANApip, 2CH2-pip), 3.00–3.25 (m, 8H, 2CH2-pip, 2CH2-
piperid), 3.85 (s, 3H, OCH3), 4.06 (t, 2H, CH2AO), 6.86–7.31
(m, 8H, ArH). MS: (ESI-MSþ) m/z 438 [MH]þ. Anal. Calcd.
for C26H35N3O3ꢃHCl (474.03): C, 65.88; H, 7.65; N, 8.86.
Found: C, 65.65; H, 7.61; N, 8.83.
cal bundle of b2-adrenergic receptor (PDB code 2rh1) was
used as a template [19]. The latest studies show the usefulness
of this structure for homology modeling of GPCRs [20,21].
Aminoacid sequences of the receptors (P08908 for 5-HT1A and
P34969 for 5-HT7) were downloaded from the Uniprot data-
meta2). The starting homology models of each receptor were
generated using the SwissModel server (accessible from the
program DeepView/SwissPdb-Viewer). Further modifications
N-Phenyl-2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}-
benzamide (6). Base; IR: 724, 1080, 1349, 1394, 1711, 2934,
1
3046, 3460 cmꢂ1. H-NMR: d 2.22–2.46 (m, 2H, CH2), 2.71–
2.93 (m, 6H, CH2ANApip, 2CH2-pip), 3.13–3.28 (m, 4H,
2CH2-pip), 3.83 (s, 3H, OCH3), 4.27 (t, 2H, CH2AO), 5.80 (s,
1H, NH), 6.79–7.79 (m, 12H, ArH), 8.16 (dd, 1H, ArH).
MS: (ESI-MSþ) m/z 446 [MH]þ. Anal. Calcd. for
C27H31N3O3ꢃHClꢃH2O (500.03): C, 64.85; H, 6.85; N, 8.40.
Found: C, 64.97; H, 7.02; N, 8.14.
¨
of the models were performed using components of Schro-
dinger Suite 2008. The models were initially optimized in Pro-
tein Preparation Wizard and the extracellular loops were
refined using Prime. In the next step, induced fit docking
(IFD) was involved for ligand-based optimization of the recep-
tors [22,23]. For this purpose, a group of possibly the most
rigid compounds with high affinity for given receptors was
chosen. Receptor models found in the top-scored complexes
(12 structures for 5-HT1A and six structures for 5-HT7 recep-
tor) were selected to serve as molecular targets in further
docking studies.
The docking of novel compounds (1–10) was carried out
using Glide with XP precision mode. An interaction constraint
on a hydrogen bond between Asp3.32 and the protonated nitro-
gens of the ligands was applied, since that interaction was con-
sidered crucial for the monoaminergic GPCRs [24].
2-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethoxy}benzamide
(7). Base; IR: 751, 1148, 1239, 1455, 1597, 1670, 2820, 2946,
3168, 3361 cmꢂ1 1H-NMR: d 2.60–2.82 (m, 4H, 2CH2-pip),
.
2.89 (t, 2H, CH2ANApip), 2.94–3.15 (m, 4H, 2CH2-pip), 3.86
(s, 3H, OCH3), 4.26 (t, 2H, CH2AO), 5.85 (s, 1H, NH2), 6.83–
7.48 (m, 7H, ArH), 8.20 (dd, 1H, ArH), 8.66 (s, 1H, NH2).
MS: (ESI-MSþ) m/z 356 [MH]þ. Anal. Calcd. for
C20H25N3O3ꢃ2HCl (428.35): C, 56.08; H, 6.35; N, 9.81.
Found: C, 56.34; H, 6.44; N, 9.65.
2-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy}benzamide
(8). Base; IR: 755, 1015, 1233, 1456, 1597, 1677, 2342, 2938,
3171, 3451 cmꢂ1 1H-NMR: d 1.76–1.97 (m, 4H, CH2), 2.51
.
Glide, IFD, Prime and Protein Preparation Wizard are
¨
implemented in Schrodinger Suite 2008, licensed for Jagiello-
nian University Collegium Medicum.
(t, 2H, CH2ANApip), 2.61–2.74 (m, 4H, 2CH2-pip), 3.04–3.18
(m, 4H, 2CH2-pip), 3.86 (s, 3H, OCH3), 4.18 (t, 2H, CH2AO),
6.10 (s, 1H, NH2), 6.87–7.48 (m, 7H, ArH), 7.80 (s, 1H, NH2),
8.20 (dd, 1H, ArH). MS: (ESI-MSþ) m/z 384 [MH]þ. Anal.
Calcd. for C22H29N3O3ꢃHCl (419.94): C, 62.92; H, 7.20; N,
10.01. Found: C, 62.88; H, 7.40; N, 9.93.
REFERENCES AND NOTES
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Res 1999, 52, 103.
2-{5-[4-(2-Methoxyphenyl)piperazin-1-yl]pentoxy}benzamide
(9). Base; IR: 755, 1150, 1241, 1596, 1669, 2818, 2945, 3166,
1
3440 cmꢂ1. H-NMR: d 1.59–2.06 (m, 6H, CH2), 2.81 (t, 2H,
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CH2ANApip), 2.92–3.12 (m, 4H, 2CH2-pip), 3.28–3.42 (m,
4H, 2CH2-pip), 3.86 (s, 3H, OCH3), 4.17 (t, 2H, CH2AO),
6.05 (s, 1H, NH2), 6.83–7.59 (m, 7H, ArH), 7.72 (s, 1H, NH2),
8.18 (dd, 1H, ArH). MS: (ESI-MSþ) m/z 398 [MH]þ. Anal.
Calcd. for C23H31N3O3ꢃHClꢃH2O (451.99): C, 61.12; H, 7.58;
N, 9.30. Found: C, 61.00; H, 7.45; N, 9.46.
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2-{6-[4-(2-Methoxyphenyl)piperazin-1-yl]hexoxy}benzamide
(10). Base; IR: 751, 1148, 1239, 1455, 1597, 1670, 2820,
1
2946, 3157, 3361 cmꢂ1. H-NMR: d 1.40–1.65 (m, 6H, CH2),
1.78–1.96 (m, 2H, CH2), 2.44 (t, 2H, CH2ANApip), 2.62–2.75
(m, 4H, 2CH2-pip), 3.01–3.19 (m, 4H, 2CH2-pip), 3.86 (s, 3H,
OCH3), 4.13 (t, 2H, CH2AO), 5.95 (s, 1H, NH2), 6.90–7.47
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(ESI-MSþ) m/z 412 [MH]þ. Anal. Calcd. for C24H33N3O3ꢃHCl
(448.00): C, 64.34; H, 7.65; N, 9.38. Found: C, 64.57; H,
7.48; N, 9.30.
Biology. The activity of the compounds was tested in com-
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expressing human 5-HT7 receptors according to the previously
described procedures [7]. The results of those assays and the
previously published data on compound 1 from our laboratory
are displayed in Table 2.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet