N-[4-(arylpiperazin-1-yl)butyl]bicyclo[2.2.1]hept-5-ene-endo-2, endo-3-dicarboximides and Their Epoxy Derivatives. Synthesis and affinity for 5-HT1a receptors

Article abstract of DOI:10.1134/S1070363209020212

New ligands for 5-HT_1A serotonin receptors, N-[4-(4- arylpiperazin-1-yl)butyl]bicyclo[2.2.1]hept-5-ene-endo-2,endo-3-dicarboximides and their epoxy derivatives, were synthesized, and their affinity for 5-HT _1A receptors was estimated at 16.2 ± 2.0 to 0.60 ± 0.08 nM.

Full text of DOI:10.1134/S1070363209020212

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 2, pp. 292–296. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © S.Yu. Makan, D.I. Tsymbal, S.G. Soboleva, I.N. Tarabara, L.I. Kas’yan, S.A. Andronati, 2009, published in Zhurnal Obshchei
Khimii, 2009, Vol. 79, No. 2, pp. 303–307.
N-[4-(Arylpiperazin-1-yl)butyl]bicyclo[2.2.1]hept-5-ene-
endo-2,endo-3-dicarboximides and Their Epoxy Derivatives.
Synthesis and Affinity for 5-HT1a Receptors
S. Yu. Makan† a, D. I. Tsymbala, S. G. Sobolevab, I. N. Tarabarac,
L. I. Kas’yanc, and S. A. Andronatia
a Bogatskii Physicochemical Institute, National Academy of Sciences of Ukraine,
Lyustdorfskaya dor. 86, Odessa, 65080 Ukraine
e-mail: tsymbal@te.net.ua
b Mechnikov Odessa National University, Odessa, Ukraine
c Dnepropetrovsk National University, Dnepropetrovsk, Ukraine
Received August 15, 2008
Abstract—New ligands for 5-HT1A serotonin receptors, N-[4-(4-arylpiperazin-1-yl)butyl]bicyclo[2.2.1]hept-5-
ene-endo-2,endo-3-dicarboximides and their epoxy derivatives, were synthesized, and their affinity for 5-HT1A
receptors was estimated at 16.2±2.0 to 0.60±0.08 nM.
DOI: 10.1134/S1070363209020212
Ligands for serotonin and dopamine receptors were
found among aryl(hetaryl)piperazine derivatives like I,
and they showed anxiolytic, antidepressant, and neuro-
leptic properties [1–3].
Neuropharmacological action of arylpiperazines I
originates from formation of a supramolecular ligand
I–5-HT1AR complex. On the basis of QSAR analysis
and molecular docking studies, hypothetical models
have been proposed for the ligand–receptor interact-
tions. It is believed that the ligand–receptor binding is
determined by the ability of protonated N4 atom in the
piperazine ring to form hydrogen bond (whose strength
approaches the strength of a ionic bond) with the aspartic
acid residue which is located in the third transmem-
brane domain of the receptor (Asp 3.32) [11–15]. The
second important structural fragment of the ligand,
which is directly involved in ligand–receptor interact-
tion, is aromatic ring R2; it is responsible for CH–π
interaction with the phenylalanine residue in the sixth
domain of the receptor (Phe 6.52) [15]. An important
role in ligand I binding to 5-HT1AR is played by the
terminal fragment R1 which is capable of forming
hydrogen bonds with the amino acid residues in the
second and seventh domains of 5-HT1AR [14, 15].
4
N
R1 (CH2)n
R2
N
I
R1 is imide or amide terminal fragment; n = 2–6; R2 is
aryl or getaryl fragment.
Buspirone (II) and related compounds, in particular
gepirone (III), tandospirone (IV), ipsapirone (V), and
flesinoxan (VI), exhibit high affinity for 5-HT1A
serotonin receptors (5-HT1AR) and were the subjects of
numerous studies in the field of medicinal chemistry,
neuropharmacology, and clinical testing of neurotropic
agents [4–7]. Buspirone and tandospirone are used in
the treatment of anxiety and depressions [8, 9].
Arylpiperazine derivatives VII containing a norbor-
nenedicarboximide moiety as terminal fragment were
shown to be highly selective and potent ligands for 5-
HT1AR [10].
With a view to examine the structure–molecular
mechanism of action–pharmacological properties relation-
ships for ligands selective for 5-HT1A receptors we
synthesized new arylpiperazine derivatives of type I,
which contained bicyclo[2.2.1]hept-5-ene- or 5,6-epoxy-
bicyclo[2.2.1]heptane-endo-2,endo-3-dicarboximide
† Deceased.
292

N-[4-(ARYLPIPERAZIN-1-YL)BUTYL]BICYCLO[2.2.1]HEPT-5-ENE-...
293
N
O
N
O
N
N
N
II
N
N
N
O
N
N
O
N
O
N
N
H
H
H
H
N
H3C
H3C
N
O
IV
III
HO
N
O
N
N
O
N
S
O
O
N
O
F
N
N
O
HN
V
VI
O
O
Ar
N
(CH2)n
N
N
O
VII
n = 2, 3.
moiety as terminal fragment (R1), and determined their
affinity for 5-HT1AR. The synthesized compounds
seem to be also interesting as new derivatives of cage-
like systems exhibiting versatile pharmacological
activity [16–21].
situ from 98% formic acid and 50% aqueous hydrogen
peroxide according to the procedure reported in [23]
gave epoxide X.
The product structure was confirmed by their IR,
1H NMR, and mass spectra. The IR spectra of XI and
XII contained strong absorption bands due to
symmetric and asymmetric stretching vibrations of the
C=O bonds (1680–1699 and 1760–1763 cm–1), C–H
bonds in the methylene groups (2830–3000 cm–1), and
C–H bonds in unsaturated fragments (3054–3062 cm–1).
In addition, epoxynorbornane derivatives XII character-
istically displayed absorption bands belonging to the
oxirane fragment (850, 852 cm–1). In the mass spectra
of hydrochlorides XI and XII we observed molecular
ion peaks of the corresponding bases, while the most
abundant ions were those resulting from elimination of
the arylpiperazine fragment from the molecular ion
By reaction of endic acid imide IX or its epoxy
derivative X with 1-aryl-4-(4-bromobutyl)piperazine in
boiling anhydrous toluene in the presence of potassium
carbonate we obtained 4-{4-[4-(4-arylpiperazin-1-yl]-
butyl}-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-diones XI
and 4-{4-[4-(arylpiperazin-1-yl]butyl}-exo-8,9-epoxy-
4-azatricyclo[5.2.1.02,6]decane-3,5-diones XII, respect-
ively (Table 1), which were isolated as the correspond-
ing hydrochlorides. As starting compound we used
endic anhydride (VIII, bicyclo[2.2.1]hept-5-ene-endo-
2,endo-3-dicarboxylic anhydride). Imide IX was syn-
thesized by reaction of anhydride VIII with aqueous
ammonia, followed by heating in glacial acetic acid
according to the procedure described in [22]. Oxida-
tion of imide IX with peroxyformic acid generated in
1
(Table 2). The H NMR spectra of these compounds
were consistent with the assumed structures (Table 2).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 2 2009

294
MAKAN et al.
O
O
NH3
O
NH
R
Br(CH2)4
N
N
O
O
VIII
IX
O
N
N
N
HCO3H
O
R
XI
XIa, R = H; XIb, R = o-Cl;
XIc, R = m-Cl; XId, R = o-Me;
XIe, R = m-Me
R
O
O
Br(CH2)4
N
N
N
O
NH
O
N
N
O
O
R
XII
X
XIIa, R = o-Cl; XIIv, R = o-Me
Table 1. Yields, melting points, elemental analyses, and affinities for 5-HT1A receptors of N-[4-(4-arylpiperazin-1-yl)butyl]
endic and -epoxyendic acid imides XIa–XIe, XIIa, and XIIb
O
3
O
1
2
6
9
8
β
4
δ
N
N
O
N
N
5
α
γ
7
N
N
O
O
R
R
XI
XII
Calculated, %
H
Found, %
H
Comp.
no.
mp,
°C
Yield,
%
R
Formula
Ki, nM
C
N
C
N
H
190–192 66.0
250–252 80.6
198–200 53.4
66.4
61.3
61.3
67.0
67.0
59.2
64.6
7.0
6.3
6.3
7.3
7.3
6.1
7.0
10.1
9.3
9.3
9.8
9.8
9.0
9.4
C23H29N3O2·HCl
66.5
7.1 10.1
16.2±2.0
0.60±0.08
3.5±0.5
XIа
XIb
XIc
о-Cl
C23H28ClN3O2·HCl 61.4
C23H28ClN3O2·HCl 61.4
6.3
6.4
7.3
7.4
6.1
7.1
9.4
9.4
9.7
9.8
9.1
9.4
m-Cl
o-CH3 252–255 87.6
m-CH3 195–198 62.8
C24H31N3O2·HCl
C24H31N3O2·HCl
67.0
67.1
8.3±0.9
XId
XIe
3.6±0.5
о-Cl
259–262 88.8
C24H28ClN3O3·HCl 59.3
C24H31N3O3·HCl 64.7
0.70±0.08
8.9±1.0
XIIa
o-CH3 257–258 65.8
XIIb
Buspirone 15.0±1.5
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 2 2009

N-[4-(ARYLPIPERAZIN-1-YL)BUTYL]BICYCLO[2.2.1]HEPT-5-ENE-...
Table 2. Mass and 1H NMR spectra of compounds XIa–XIe, XIIa, and XIIb
295
Mass
spectrum,a
m/z
Comp.
no.
1Н NMR spectrum, δ, ppm
379
1.38 m (2Н, β-СН2); 1.54 m (2Н, Н10s, H10a); 1.65 m (2Н, γ-СН2); 3.06 m (6Н, Н1, Н7, 2СН2piper); 3.24 t (4Н,
2СН2piper); 3.34 m (2Н, Н2, Н6); 3.48 d (2Н, δ-СН2); 3.78 d (2Н, α-СН2); 6.11 m (2Н, Н8, Н9); 6.84–7.29 m (5Нarom);
11.24 br.s (1Н, +NH)
ХIа
413
1.39 m (2Н, β-СН2); 1.53 m (2Н, Н10s, H10a); 1.65 m (2Н, γ-СН2); 3.06–3.20 m (6Н, Н1, Н7, 2СН2piper); 3.24 m (4Н, Н2,
XIb
6
Н
,
δ-СН2); 3.36–3.42 m (4Н, 2СН2piper); 3.51 d (2Н, α-СН2); 6.12 m (2Н, Н8, Н9); 7.09–7.46 m (4Нarom); 11.09 br.s (1Н,
NH)
1.39 m (2Н, β-СН2); 1.56 m (2Н, Н10s, H10a); 1.65 m (2Н, γ-СН2); 3.07 m (6Н, Н1, Н7, 2СН2piper); 3.24 m (6Н, Н2, Н6,
2СН2piper); 3.47 d (2Н, δ-СН2); 3.86 d (2Н, α-СН2); 6.12 m (2Н, Н8, Н9); 6.86–7.26 m (4Нarom.); 11.02 br.s (1Н, +NH)
1.39 m (2Н, β-СН2); 1.55 m (2Н, Н10s, H10a); 1.66 m (2Н, γ-СН2); 2.25 с (3Н, СН3); 3.09 m (2Н, Н1, Н7); 3.14 br.s
(8Н, 4СН2piper); 3.25 m (4Н, Н2, Н6, δ-СН2); 3.46 t (2Н, α-СН2); 6.12 m (2Н, Н8, Н9); 6.99–7.20 m (4Нarom); 11.09 br.s
(1Н, +NH)
413
393
XIc
XId
1.40 m (2Н, β-СН2); 1.55 m (2Н, Н10s, H10a); 1.66 m (2Н, γ-СН2); 2.27 с (3Н, СН3); 3.06 m (6Н, Н1, Н7, 2СН2piper);
3.24 m (6Н, Н2, Н6, 2СН2piper); 3.47 d (2Н, δ-СН2); 3.75 d (2Н, α-СН2); 6.11 m (2Н, Н8, Н9); 6.86–7.16 m (4Нarom);
11.32 br.s (1Н, +NH)
393
429
409
XIe
2
1.07 d (1Н, H10a); 1.36 d (1Н, Н10s, J10s,10a 9.9 Hz); 1.49 m (2Н, β-СН2); 1.69 m (2Н, γ-СН2); 2.88 m (2Н, Н1, Н7);
ХIIа
XIIb
3.12 c (6Н, Н8, Н9, 2СН2piper); 3.26 m (2Н, Н2, Н6); 3.36 t (6Н, δ-СН2, 2-СН2piper); 3.51 br.s (2Н, α-СН2); 7.11–
7.44 m (4Нarom); 11.14 br.s (1Н, +NH)
1.07 d (1Н, H10a); 1.36 d (1Н, Н10s, 2J10s,10a 9.9 Hz); 1.50 m (2Н, β-СН2); 1.71 m (2Н, γ-СН2); 2.88 s (3Н, 3СН3); 2.88 s
(2Н, Н1, Н7); 3.12 m (8Н, Н8, Н9, δ-СН2, 2СН2piper); 3.26 m (2Н, Н2, Н6); 3.36 t (2Н, α-СН2); 3.47 s (4Н, 2СН2piper);
6.98–7.20 m (4Нarom); 10.95 br.s (1Н, +NH)
a
Given are m/z values for the free bases.
The affinity of compounds XI and XII for 5-HT1A
preciable change of the affinity for 5-HT1AR in com-
serotonin receptors were determined in vitro by
radioligand assay. The ability of XI and XII to form
supramolecular complexes with 5-HT1AR was
characterized by Ki values according to [24] (Table 1).
As follows from the obtained data, all compounds XI
and XII show high affinity for 5-HT1AR. For example,
the affinity of XIa approaches that typical of buspirone
parison with XIb and XId.
EXPERIMENTAL
The purity of the synthesized compounds was
checked by TLC on Silufol UV-254 plates using
butanol–acetic acid–water (3:1:1) and chloroform–
acetone (9:1) as eluent; spots were visualized under
UV light or by treatment with a solution of potassium
permanganate. The IR spectra were recorded in KBr
on a Specord 75IR spectrometer. The mass spectra
(electron impact, 70 eV) were obtained on an MKh-
1321 instrument (ion source temperature 200°C). The
1H NMR spectra were measured on a Varian WXP-300
spectrometer (299.95 MHz) from solutions in DMSO-
d6 using tetramethylsilane as internal reference.
(K = 16.2±2.0 and 15.0±1.5 nM, respectively). Introduc-
i
tion of a chlorine atom into the ortho position of the
benzene ring (compound XIb) gave rise to a subnano-
molar affinity for 5 HT1AR (Ki = 0.60±0.08 nM). o-
Tolyl analog XId showed slightly lower affinity. En-
hanced affinity was also found for m-chloro and m-
methyl derivatives XIc and XIe as compared to
unsubstituted ligand XIa. Our results are consistent
with the conclusions drawn in [10], according to which
high affinity for 5-HT1A receptors is inherent to
compounds containing an endic acid imide moiety as
terminal fragment. As followed from the Ki values for
compounds XIIa and XIIb, replacement of norbornene
fragment by epoxynorbornane did not result in ap-
4-[4-(4-Phenylpiperazin-1-yl)butyl]-4-azatricyclo
[5.2.1.02,6]dec-8-ene-3,5-dione hydrochloride (XIa).
A mixture of 0.247 g of imide IX, 0.446 g of 1-(4-
bromobutyl)-1-phenylpiperazine, and 0.42 g of anhyd-
rous potassium carbonate in 8 ml of anhydrous toluene
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 2 2009

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MAKAN et al.
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was heated for 30 h under reflux. The mixture was
filtered while hot, and the precipitate of potassium
carbonate was washed with boiling toluene. The
filtrate was combined with the washings, the solvent
was distilled off under reduced pressure, the residue
was dissolved in anhydrous acetone, and the solution
was acidified with a saturated solution of hydrogen
chloride in alcohol. The precipitate was filtered off and
washed with anhydrous acetone and diethyl ether.
Yield 0.41g (66%).
Compounds XIb–XIe, XIIa, and XIIb were
synthesized in a similar way.
13. Lopez-Rodriguez, M.L., Vicente, B., Deupi, X.,
Barrondo, S., Olivella, M., Morcillo, M.J., Behamu, B.,
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The affinity of compounds XI and XII for 5-HT1A
receptors was determined according to the procedure
described in [24] with the use of [3H]-8-ON-DPAT as
radioligand (Amersham, specific radioactivity
8470 TBq mol–1). The assays were performed in
outbred male rats with a weight of 180–200 g, which
were maintained under standard vivarium conditions.
All experimental procedures in animals were in com-
pliance with the European Communities Council
Directive of 24 November 1986 (86/609/EEC). The
bound radioactivity was quantitated with the aid of a
RackBeta-1219 (LKB) scintillation counter. The
inhibitory concentration IC50 was determined by
graphical method, and Ki values were calculated using
the Cheng–Prusoff equation [25]. The results were
processed using Statistica program.
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