Synthesis and anticonvulsant properties of tetrahydroisoquinoline derivatives

Article abstract of DOI:10.1016/j.farmac.2003.10.003

As a follow up of our previous structure-activity relationship and molecular modeling studies, we synthesized a novel series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as potential non-competitive AMPA receptor antagonists. When te

Full text of DOI:10.1016/j.farmac.2003.10.003

IL FARMACO 59 (2004) 7–12
www.elsevier.com/locate/farmac
Synthesis and anticonvulsant properties
of tetrahydroisoquinoline derivatives
Rosaria Gitto a,*, Roberta Caruso a, Valerie Orlando a, Silvana Quartarone a,
Maria Letizia Barreca a, Guido Ferreri b, Emilio Russo b,
Giovambattista De Sarro b, Alba Chimirri a
a Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, Messina 98168, Italy
b Dipartimento di Medicina Sperimentale e Clinica, Università “Magna Græcia” di Catanzaro, Via T. Campanella, 88100, Italy
Received 24 July 2003; accepted 24 October 2003
Abstract
As a follow up of our previous structure–activity relationship and molecular modeling studies, we synthesized a novel series of
1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as potential non-competitive AMPA receptor antagonists. When tested for
their ability to prevent sound-induced seizures in DBA/2 mice, some of these novel compounds showed high anticonvulsant potency.
© 2003 Elsevier SAS. All rights reserved.
Keywords: AMPA receptor antagonists; Anticonvulsant agents; Tetrahydroisoquinolines; DBA/2 mice
1. Introduction
[2,3]benzodiazepine (2, talampanel), which possesses potent
anticonvulsant properties and which is being submitted to
phase II clinical trial [13].
In our previous studies [14–24], we identified other 2,3-
benzodiazepine derivatives, such as 1-(4-aminophenyl)-3,5-
The excitatory neurotransmitter glutamate binds both me-
tabotropic (mGluRs) and ionotropic receptors (iGluRs) and
controls many fundamental processes. Ion channels repre-
sent important pharmacological targets for drug intervention
and treatment of disorders in the central nervous system
(CNS). Molecules that modulate ion channel activities have
been actively investigated as potential drugs for the treatment
of depression and anxiety, impairments in cognition and
memory, epilepsy and neuronal ischemia. [1–4].
In particular, it is well known that 2-amino-3-(3-hydroxy-
methylisoxazol-4-yl)propionic acid (AMPA) receptor (AM-
PAR) type of iGluRs plays a role in epileptogenesis and
several AMPAR antagonists show promise in terms of their
therapeutic potential for the prevention and treatment of
epilepsy [5–8]. In fact, a selective and non-competitive
blockade of AMPA receptor was shown by some 2,3-benzo-
diazepines [9–12], such as the 1-(4-aminophenyl)-4-methyl-
7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI
52466) (Chart 1) and in particular the (R)-7-acetyl-5-(p-
aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h]
dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one
(3,
CFM-2) [14], thiocarbonyl analog 4 (CFM-2S) [17] and
8,9-dimethoxy-6-(4-bromophenyl)-11H-[1,2,4]triazolo[4,5-
c][2,3]benzodiazepin-3(2H)-one [23] (5) (Chart 1) that
showed marked antiepileptic properties in various animal
models of convulsive epilepsy. Electrophysiological studies
confirmed that their anticonvulsant effects are mediated
through the AMPAR allosteric modulation.
We have recently developed [25] a pharmacophore 3D-
model of non-competitive AMPAR antagonists and found
that compounds containing 6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline skeleton satisfied the pharmacophore hy-
pothesis. The synthesis of a series of these derivatives was
carried out and the obtained compounds were tested for their
anticonvulsant properties [26]. The pharmacological screen-
ing put in evidence that some synthesized compounds proved
to be anticonvulsant agents acting as new non-competitive
AMPAR antagonists. In particular, the 2-acetyl-1-(4-chloro-
phenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 6c
(Chart 1) was characterized in vivo and in vitro tests by an
* Corresponding author.
E-mail address: rgitto@pharma.unime.it (R. Gitto).
© 2003 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2003.10.003

8
R. Gitto et al. / IL FARMACO 59 (2004) 7–12
Me
Me
X
MeO
MeO
O
O
Me
O
O
O
N
NH
N
N
N
N
H2N
H2N
2, Talampanel
H2N
1, GYKI 52466
3, X = O (CFM-2)
4, X = S (CFM-2S)
N
MeO
MeO
NH
MeO
MeO
N
Me
N
O
N
O
Cl
5
6c
Br
Chart 1. Non-competitive AMPA receptor antagonists.
improved pharmacological profile when compared with
other current AMPAR antagonists [26].
2.1.1. 2-Acetyl-6,7-dimethoxy-1-(3-nitrophenyl)-1,2,3,4-
tetrahydroisoquinoline (6f)
Melting point: 158–160 °C. Yield: 82%. 1H-NMR: d 2.19
(s, 3H, MeCO), 2.75–3.41 (m, 4H, CH2–CH2), 3.76 (s, 3H,
MeO-6), 3.90 (s, 3H, MeO-7), 6.48 (s, 1H, H-5), 6.70 (s, 1H,
H-8), 6.91 (s, 1H, H-1), 7.26–8.10 (m, 4H, Ar). Anal.
(C19H20N2O5) C, H, N.
Aiming at extending our knowledge in structure–activity
relationships (SAR) of this class ofAMPAR non-competitive
antagonists, we synthesized novel 6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolines and evaluated their anticonvulsant
properties. Since our previous studies suggested that both
4-chlorophenyl substituent and N-acetyl function positively
influenced the AMPAR recognition and anticonvulsant ef-
fects, herein we report the anticonvulsant screening carried
out on mono- or poly-halosubstituted derivatives (6) bringing
an N-acetyl group at 2-position in comparison with
N-unsubstituted compounds (10).
2.1.2. 2-. Acetyl-1-(3-aminophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (6h)
Melting point: 182–183 °C. Yield: 80%. 1H-NMR: d 2.17
(s, 3H, MeCO), 2.70–3.71 (m, 4H, CH2–CH2), 3.77 (s, 3H,
MeO-6), 3.89 (s, 3H, MeO-7), 6.54 (s, 1H, H-5), 6.56–6.62
(m, 3H, H-2′, H-4′, H-6′), 6.64 (s, 1H, H-8), 6.80 (s, 1H,
H-1), 7.04–7.19 (m, 1H, H-5′) Anal. (C19H22N2O3) C, H, N.
2.1.3. 2-Acetyl-(3-chlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (6j)
2. Experimental
Melting point: 200–203 °C. Yield: 70%. 1H-NMR: d 2.18
(s, 3H, MeCO), 2.76–3.74 (m, 4H, CH2–CH2), 3.77 (s, 3H,
MeO-6), 3.89 (s, 3H, MeO-7), 6.50 (s, 1H, H-5), 6.67 (s, 1H,
H-8), 6.84 (s, 1H, H-1), 7.16–7.26 (m, 4H, Ar) Anal.
(C19H20ClNO3) C, H, N.
2.1. Chemistry
Melting points were determined on a Kofler hot-stage
apparatus and are uncorrected. Elemental analyses (C, H, N)
were carried out on a Carlo Erba Model 1106 Elemental
Analyzer and the results are within 0.4% of the theoretical
values. Merck silica gel 60 F254 plates were used for analyti-
cal TLC; column chromatography was performed on Merck
2.1.4. 2-Acetyl-(2,3-difluorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (6l)
1
Melting point: 217–218 °C with dec. Yield: 58%. H-
1
silica gel 60 (70–230 mesh). H-NMR spectra were mea-
NMR: d 2.17 (s, 3H, MeCO), 2.73–3.57 (m, 4H, CH2–CH2),
3.75 (s, 3H, MeO-6), 3.89 (s, 3H, MeO-7), 6.51 (s, 1H, H-5),
6.64 (s, 1H, H-8), 6.91 (s, 1H, H-1), 6.85–7.15 (m, 3H, Ar).
Anal. (C19H19F2NO3) C, H, N.
sured in CDCl3 with a Varian Gemini 300 spectrometer;
chemical shifts are expressed in d (ppm) relative to TMS as
internal standard and coupling constants (J) in Hz. All ex-
changeable protons were confirmed by addition of D2O.
Compounds 6f, 6h–p and 10a–p were prepared according
to a previously described procedure [25]. Compounds 10b–f,
10j–k and 10o have also been obtained by other authors
using a different synthetic procedure [27,28].
2.1.5. 2-Acetyl-(3,4-difluorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (6m)
Melting point: 155–157 °C. Yield: 60%. 1H-NMR: d 2.17
(s, 3H, MeCO), 2.76–3.71 (m, 4H, CH2–CH2), 3.77 (s, 3H,

R. Gitto et al. / IL FARMACO 59 (2004) 7–12
9
MeO-6), 3.89 (s, 3H, MeO-7), 6.48 (s, 1H, H-5), 6.66 (s, 1H,
H-8), 6.80 (s, 1H, H-1), 6.90–7.10 (m, 3H, Ar). Anal.
(C19H19F2NO3) C, H, N.
3.90 (s, 3H, MeO-7), 5.22 (s, 1H, H-1), 6.18 (s, 1H, H-5),
6.66 (s, 1H, H-8), 7.18 (s, 2H, H-2′, H-6′), 7.34 (s, 1H, H-4′).
Anal. (C17H17Cl2NO2) C, H, N.
2.2. Pharmacology
2.1.6. 2-Acetyl-(2,3-dichlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (6n)
1
2.2.1. Testing of anticonvulsant activity
Melting point: 260–262 °C with dec. Yield: 65%. H-
All experiments were performed with DBA/2 mice, which
are genetically susceptible to sound-induced seizures [29].
DBA/2 mice (8–12 g; 22–25-d-old) were purchased from
Harlan Italy (Corezzano, Italy). Groups of 10 mice of either
sex were exposed to auditory stimulation 30 min following
administration of vehicle or each dose of drugs studied. The
compounds were given intraperitoneally (i.p.) (0.1 ml/10 g of
body weight of the mouse) as a freshly prepared solution in
50% dimethylsulfoxide (DMSO) and 50% sterile saline
(0.9% NaCl). Individual mice were placed under a hemi-
spheric perspex dome (diameter 58 cm), and 60 s were
allowed for habituation and assessment of locomotor activ-
ity. Auditory stimulation (12–16 kHz, 109 dB) was applied
for 60 s or until tonic extension occurred, and induced a
sequential seizure response in control DBA/2 mice, consist-
ing of an early wild running phase, followed by generalized
myoclonus and tonic flexion and extension sometimes fol-
lowed by respiratory arrest. The control and drug-treated
mice were scored for latency to and incidence of the different
phases of the seizures [30].
NMR: d 2.18 (s, 3H, MeCO), 2.72–3.49 (m, 4H, CH2–CH2),
3.75 (s, 3H, MeO-6), 3.88 (s, 3H, MeO-7), 6.49 (s, 1H, H-5),
6.64 (s, 1H, H-8), 6.76 (s, 1H, H-1), 7.01–7.40 (m, 3H, Ar).
Anal. (C19H19Cl2NO3) C, H, N.
2.1.7. 2-Acetyl-(3,4-dichlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (6o)
Melting point: 130–132 °C. Yield: 56%. 1H-NMR: d 2.17
(s, 3H, MeCO), 2.78–3.71 (m, 4H, CH2–CH2), 3.77 (s, 3H,
MeO-6), 3.89 (s, 3H, MeO-7), 6.46 (s, 1H, H-5), 6.67 (s, 1H,
H-8), 6.80 (s, 1H, H-1), 7.11 (d, J5′,6′ = 1.9 Hz, 1H, H-6′),
7.29 (s, 1H, H-2′), 7.34 (d, J5′,6′ = 1.9 Hz, 1H, H-5′). Anal.
(C19H19Cl2NO3) C, H, N.
2.1.8. 2-Acetyl-(3,5-dichlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (6p)
Melting point: 179–181 °C. Yield: 59%. 1H-NMR: d 2.19
(s, 3H, MeCO), 2.73–3.71 (m, 4H, CH2–CH2), 3.79 (s, 3H,
MeO-6), 3.90 (s, 3H, MeO-7), 6.47 (s, 1H, H-5), 6.68 (s, 1H,
H-8), 6.79 (s, 1H, H-1), 7.12 (s, 2H, H-2′, H-6′), 7.26 (s, 1H,
H-4′). Anal. (C19H19Cl2NO3) C, H, N.
The experimental protocol and all the procedures involv-
ing animals and their care were conducted in conformity with
the institutional guidelines and the European Council Direc-
tive of laws and policies.
2.1.9. 1-(3-Aminophenyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (10h)
Melting point: 121–123 °C. Yield: 65%. 1H-NMR: d
2.75–3.30 (m, 5H, CH2–CH2 + NH), 3.40 (bs, 2H, NH2) 3.65
(s, 3H, MeO-6), 3.85 (s, 3H, MeO-7), 4.94 (s, 1H, H-1), 6.30
(s, 1H, H-5), 6.53–7.08 (m, 5H, H-8 e Ar). Anal.
(C17H20N2O2) C, H, N.
2.2.2. Statistical analysis
Statistical comparisons between groups of control and
drug-treated animals were made using Fisher’s exact prob-
ability test (incidence of the seizure phases). The ED50 values
of each phase of audiogenic seizures were determined for
each dose of compound administered, and dose–response
curves were fitted using a computer program by Litchfield
and Wilcoxon’s method [31].
2.1.10. 1-(2,3-Difluorophenyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (10l)
Melting point: 108–110 °C. Yield: 68%. 1H-NMR: d
3.04–3.35 (m, 5H, CH2–CH2 + NH), 3.67 (s, 3H, MeO-6),
3.88 (s, 3H, MeO-7), 5.86 (s, 1H, H-1), 6.18 (s, 1H, H-5),
6.82 (s, 1H, H-8), 6.82–7.23 (m, 3H, Ar). Anal.
(C17H17F2NO2) C, H, N.
3. Results and discussion
1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines
(10) were prepared via the Pictet-Spengler synthetic ap-
proach as depicted in Scheme 1. The condensation of the
2-(3′,4′-dimethoxyphenyl)ethylamine (7) with suitable aro-
matic aldehydes 8 gave the benziliden[2-(3′,4′-dime-
thoxyphenyl)ethyl]amines 9 that under acid catalysis condi-
tions cyclized into the corresponding racemic mixture of
1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (10).
The isoquinoline derivatives 10 were further subjected to
reaction with acetic anhydride to afford N-acetyl derivatives
6. The structures of the compounds obtained were supported
by elemental analyses and spectroscopic measurements (1H-
NMR).
2.1.11. 1-(3,4-Difluorophenyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (10m)
Melting point: 90–92 °C. Yield: 62%. 1H-NMR: d 2.76–
3.20 (m, 5H, CH2–CH2 + NH), 3.67 (s, 3H, MeO-6), 3.88 (s,
3H, MeO-7), 5.01 (s, 1H, H-1), 6.20 (s, 1H, H-5), 6.63 (s, 1H,
H-8), 7.02–7.13 (m, 3H, Ar). Anal. (C17H17F2NO2) C, H, N.
2.1.12. 1-(3,5-Dichlorophenyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (10p)
Melting point: 176–178 °C. Yield: 71%. 1H-NMR: d
2.88–3.20 (m, 5H, CH2–CH2 + NH), 3.69 (s, 3H, MeO-6),

10
R. Gitto et al. / IL FARMACO 59 (2004) 7–12
Table 1
Anticonvulsant activity of GYKI 52466 (1), Talampanel (2), CFM-2 (3) and
1,2,3,4-tetrahydroisoquinolines 6 and 10 against audiogenic seizures in
DBA/2 mice
Compound R1
R2 ED50, µmol/kga ( 95% confidence limits)
Clonic phase
44.8 (23.9–84.0)
57.8 (25.0–133)
20.1 (9.65–41.9)
30.6 (19.4–48.2)
101 (52.0–194)
19.3 (6.10–61.2)
46.6 (28.0–77.4)
40.4 (21.8–74.7)
96.9 (60.5–155)
>100
Tonic phase
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
6ab
6bb
6cb
6db
6eb
6f
6gb
6h
6i
6j
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
19.3 (9.05–41.3)
26.4 (15.5–44.9)
19.3 (11.8–31.5)
12.5 (6.90–22.6)
56.1 (26.9–117)
7.20 (2.45–21.2)
28.6 (14.4–56.8)
18.2 (7.76–41.8)
53.5 (38.3–73.8)
>100
4-F
4-Cl
4-Br
4-NO2
3-NO2
4-NH2
3-NH2
3-F
3-Cl
3-Br
>100
>100
2,3-F2
3,4-F2
2,3-Cl2
3,4-Cl2
3,5-Cl2
H
>100
>100
>100
>100
71.6 (53.2–96.3)
>100
53.2 (36.9–76.5)
44.9 (26.6–75.8)
80.3 (47.9–135)
37.7 (21.2–67.0)
18.0 (7.76–41.8)
2.39 (1.30–4.40)
16.5 (7.77–34.9)
107 (45.9–252)
12.8 (7.76–21.0)
21.1 (11.0–40.4)
17.6 (10.4–29.7)
82.5 (58.6–116)
>100
>100
Ac 53.5 (37.6–76.2)
Ac 36.8 (20.6–65.8)
Ac 4.18 (2.23–7.84)
Ac 43.1 (21.9–84.6)
Ac >100
4-F
4-Cl
4-Br
4-NO2
3-NO2
4-NH2
3-NH2
3-F
Ac 37.2 (18.9–73.4)
Ac 32.1 (17.7–58.3)
Ac 29.9 (17.5–50.9)
Ac >100
3-Cl
Ac >100
6k
6l
6m
6n
6o
6p
GYKI 52466
Talampanel
CFM-2
3-Br
Ac 79.3 (44.8–140)
Ac >100
49.6 (32.1–76.8)
48.1 (25.4–91.2)
19.3 (11.5–32.3)
32.8 (17.5–61.5)
21.4 (13.0–35.1)
56.9 (40.9–79.2)
25.3 (16.0–40.0)
9.70 (7.00–13.4)
12.6 (8.01–19.0)
2,3-F2
3,4-F2
2,3-Cl2
3,4-Cl2
3,5-Cl2
Ac 45.5 (27.4–74.3)
Ac 63.3 (35.8–111)
Ac 77.7 (44.7–135)
Ac 63.8 (45.1–90.2)
35.8 (24.4–52.4)
13.4 (10.1–17.8)
15.0 (9.01–24.0)
a All data were calculated according to the method of Litchfield and
Wilcoxon. 95% confidence limits are given in parentheses. At least 32 ani-
mals were used to calculate each ED50
.
a
b See Ref. [26].
Scheme 1. Reagents: (i) dry toluene, D, 180 min; (ii) TFA, D, 90 min; (iii)
Ac2O, D, 90 min; (iv) Pd–C/H2 5%, MeOH, r.t.
some of them (10a, 10d and 10f–h) were able to antagonize
audiogenic seizures in DBA/2 mice at doses comparable to
those of GYKI 52466.
The anticonvulsant effects of 1-aryl-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolines (6a–p and 10a–p) were
evaluated after i.p. administration against audiogenic sei-
zures in DBA/2 mice (Table 1), which are considered an
excellent animal model for generalized epilepsy and for
screening new anticonvulsant drugs [29].
The results were compared with those of well-known
non-competitive AMPA receptor antagonists such as GYKI
52466 (1), talampanel (2) and CFM-2 (3) as well as 1-aryl-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (6a–e and
6g) already studied [26].
The occurrence of high efficacy for N-deacetylated com-
pounds could be due to the fact that the acetyl function is
important but not essential for anticonvulsant activity and
that the other structural features are able to drive AMPAR
recognition. In fact, compounds 10 map three of the four
requirements of our pharmacophore hypothesis, that is, two
hydrophobic groups and one aromatic region in a specific
three-dimensional arrangement [26]. The higher potency of
compound 10f could be explained considering that this mol-
ecule assumes a spatial disposition so that the nitro group in
3′-position, likewise the acetyl function in derivatives 6,
maps the hydrogen bond acceptor region (Fig. 1).
As shown in Table 1, the N-unsubstituted derivatives 10
were generally less active than the corresponding N-acetyl-
1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 6, but

R. Gitto et al. / IL FARMACO 59 (2004) 7–12
11
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Fig. 1. The alignment of compound 10f with the pharmacophore hypothesis
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[19] R. Gitto, M. Zappalà, G. De Sarro, A. Chimirri, Design and develop-
ment of 2,3-benzodiazepine (CFM) noncompetitive AMPA receptor
antagonists, Il Farmaco 57 (2002) 129–134.
Other structural considerations suggest that the shift of
halogen atom or amino group from 4′-position to 3′-position
and the polyhalogen substitution are detrimental to anticon-
vulsant effects perhaps for the lipophilic and steric features,
which could influence their pharmacokinetic and/or pharma-
codynamic properties.
In brief, we obtained new 1-aryl-6,7-dimethoxytetra-
hydroisoquinoline derivatives able to prevent audiogenic sei-
zures in DBA/2 mice and observed that a suitable pattern of
substitution can optimize their pharmacological profile. Fur-
thermore, this study has confirmed the main structural fea-
tures involved in engagement of AMPAR binding thus sup-
porting the goodness of our pharmacophore hypothesis.
[20] G. De Sarro, G. Ferreri, P. Gareri, E. Russo, A. De Sarro,
R. Gitto, et al., Comparative anticonvulsant activity of some 2,3-
benzodiazepines in rodents, Pharmacol. Biochem. Behav. 74 (2003)
595–602.
Acknowledgements
[21] A. Chimirri, F. Bevacqua, R. Gitto, S. Quartarone, M. Zappalà, A. De
Sarro, et al., Synthesis and anticonvulsant activity of new 11H-
triazolo[4,5-c][2,3]benzodiazepines, Med. Chem. Res. 9 (1999) 203–
212.
[22] M. Zappalà, R. Gitto, F. Bevacqua, S. Quartarone, A. Chimirri,
M. Rizzo, et al., Synthesis and evaluation of pharmacological and
pharmacokinetic properties of 11H-[1,2,4]triazolo[4,5-c][2,3]benzo-
diazepin-3(2H)-ones, J. Med. Chem. 43 (2000) 4834–4839.
[23] R. Gitto, V. Orlando, S. Quartarone, G. De Sarro, A. De Sarro,
E. Russo, et al., Synthesis and evaluation of pharmacological proper-
ties of novel annelated 2,3-benzodiazepine derivatives, J. Med. Chem.
46 (2003) (web release July 10, 2003).
[24] A. Chimirri, R. Gitto, S. Quartarone, V. Orlando, A. De Sarro, G. De
Sarro, Synthesis and pharmacological properties of new
3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines, Il
Farmaco 57 (2002) 759–763.
[25] M.L. Barreca, R. Gitto, S. Quartarone, L. De Luca, G. De Sarro,
A. Chimirri, Pharmacophore modeling as an efficient tool in the
discovery of novel noncompetitive AMPA receptor antagonists, J.
Chem. Inf. Comp. Sci. 43 (2003) 651–655.
Financial support for this research by Fondo diAteneo per
la Ricerca (2002, Messina, Italy) and Ministero
dell’Università e della Ricerca Scientifica (COFIN 2002).
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