Novel potent anticonvulsant agent containing a tetrahydroisoquinoline skeleton

Article abstract of DOI:10.1021/jm060411b

In our studies on the development of new anticonvulsants, we planned the synthesis of N-substituted 1,2,3,4-tetrahydroisoquinolines to explore the structure-activity relationships. All derivatives were evaluated against audiogenic seizures in DBA/2 mice,

Full text of DOI:10.1021/jm060411b

5618
J. Med. Chem. 2006, 49, 5618-5622
Brief Articles
Novel Potent Anticonvulsant Agent Containing a Tetrahydroisoquinoline Skeleton
Rosaria Gitto,*,† Roberta Caruso,† Benedetta Pagano,† Laura De Luca,† Rita Citraro,‡ Emilio Russo,‡
Giovambattista De Sarro,‡ and Alba Chimirri†
Dipartimento Farmaco-Chimico, UniVersita` di Messina, Viale Annunziata, 98168 Messina, Italy, and Dipartimento di Medicina
Sperimentale e Clinica, UniVersita` Magna Græcia, Via T. Campanella, 88100 Catanzaro, Italy
ReceiVed April 7, 2006
In our studies on the development of new anticonvulsants, we planned the synthesis of N-substituted 1,2,3,4-
tetrahydroisoquinolines to explore the structure-activity relationships. All derivatives were evaluated against
audiogenic seizures in DBA/2 mice, and the 1-(4′-bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl)
derivative (26) showed the highest activity with a potency comparable to that of talampanel, the only
noncompetitive R-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist in clinical trials
as an anticonvulsant agent. Electrophysiological experiments indicated that 26 acts as noncompetitive AMPA
receptor modulator.
Chart 1. Noncompetitive AMPA Receptor Antagonists
Introduction
Epilepsy affects approximatively 1% of the world’s popula-
tion according to epidemiological studies, and often, therapeutic
regimens for epileptic patients will involve a change of first-
line and/or add-on antiepileptic drugs. The efficacy of many of
the marketed anticonvulsant drugs is greatly compromised by
notable adverse effects, and about 30% of patients have
uncontrolled seizures.1 Therefore, the continued search for safer
and more effective new antiepileptic drugs (AEDs) is necessary.
Currently available clinically effective antiepileptics act by
inducing prolonged inactivation of the Na+ channel, blocking
Ca2+ channel currents, or enhancing inhibitory GABAergic
neurotransmission or via antagonism of glutamatergic neuro-
transmission. Glutamate (Glu) interacts with two distinct classes
of receptors named ionotropic (iGluRs) and metabotropic
(mGluRs) receptors.2 The iGluRs are involved in many different
physiological processes such as neuronal development, learning,
and memory,3 whereas their excessive activation is held
responsible for the destruction of neuronal cells that occurs in
several neurological diseases. Mammalian iGluRs are encoded
by 18 genes that assemble to form four major families: the
R-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA),
kainate, N-methyl-D-aspartate (NMDA), and δ receptors.4,5
Extensive studies have demonstrated that competitive and
noncompetitive antagonists of the AMPA receptor (AMPAR)
subtype show promise in terms of their therapeutic potential
for the prevention and treatment of a broad range of acute6 and
chronic disorders such as epilepsy.7,8
By employing a 3D-pharmacophore model, we recently found
that 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines might also
satisfy pharmacophore requirements of noncompetitive receptor
site antagonists.15 This study led to the discovery of the 2-acetyl-
1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (4, Chart 1), which showed better pharmacological effects
when compared using in vivo and in vitro tests with other current
AMPAR antagonists (1-3).16,17 Compound 4 demonstrated high
affinity for available AMPA receptors and good uptake in brain
and metabolic stability,18 and for these reasons it was selected
as a potential ligand for in vivo imaging of AMPA receptors
using PET.19-21 In previous studies we also evaluated the effects
of various modifications on the tetrahydroisoquinoline skeleton
and observed different degrees of potency as a function of C1
and N2 substitutions.22 We specifically confirmed the impor-
tance of some chemical features such as one aromatic region
and one hydrogen bond acceptor moiety linked to the N2
position of tetrahydroisoquinoline system.
As part of our efforts to design new anticonvulsant agents,
we identified some 2,3-benzodiazepines (e.g., 1, Chart 1) as
potent antiepileptic agents in various seizure models interacting
with AMPAR in a selective and noncompetitive fashion.9-12
Compound 1 (CFM-2) is closely related to 2 (GYKI 52466)
and 3 (talampanel)13 and has shown positive results in clinical
III trials.14
Following these results, in this paper we describe a simple
synthesis of new N-substituted 1,2,3,4-tetrahydroisoquinolines
to gain more insights into the structure-activity relationships
(SARs) and to explore if the presence of a basic nitrogen atom
could be an additional feature that is able to improve the
pharmacological profile of this class of compounds.
* To whom correspondence should be addressed. Phone: 00390906766413.
Fax: 0039090355613. E-mail: rgitto@pharma.unime.it.
† Universita` di Messina.
‡ Universita` Magna Græcia.
10.1021/jm060411b CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/29/2006

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5619
Scheme 1a
Table 1. Anticonvulsant Activity of Tetrahydroisoquinolines 17-40
Against Audiogenic Seizures in DBA/2 Mice and Prediction of Their
log D7.4 Values
ED50,a µmol/kg
b
compd
clonus
tonus
log D7.4
1
2
3
4
15.0 (9.01-24.0)
35.8 (24.4-52.4)
13.4 (10.1-17.8)
4.18 (2.23-7.84)
49.1 (36.9-65.5)
50.5 (37.5-68.6)
24.7 (13.2-46.2)
44.5 (26.7-74.2)
>100
38.6 (20.1-74.1)
80.2 (65.3-98.5)
111 (83.9-148)
>100
12.6 (8.01-19.0)
25.3 (16.0-40.0)
9.70 (7.00-13.4)
2.39 (1.30-4.40)
34.8 (19.6-61.6)
24.7 (14.9-40.8)
11.8 (8.10-17.0)
33.0 (19.8-55.0)
>100
16.7 (6.77-41.1)
49.0 (35.6-67.5)
50.5 (33.1-76.9)
>100
1.24
0.55
1.30
3.40
3.96
4.73
4.56
4.01
3.69
3.69
2.68
2.68
4.16
4.93
4.76
4.21
3.89
3.89
2.88
2.88
2.84
3.62
3.44
2.90
2.57
2.57
1.56
1.56
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
a Reagents: (i) ClCH2COCl, CHCl3, room temp, 90 min; (ii) N,N-
diethylamine or cycloalkylamines, toluene, K2CO3, ∆, 90 min; (iii) H2/5%
Pd/C, MeOH, room temp, 60 min.
12.7 (6.09-26.3)
39.8 (24.8-63.8)
82.8 (54.1-126)
>100
8.17 (4.03-16.6)
17.0 (7.58-38.1)
63.0 (32.8-101)
>100
Results and Discussion
The synthetic route to 1-aryl-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinolines (5-10) has previously been reported.16
Starting from these compounds, several N-substituted derivatives
(17-40) were obtained as outlined in Scheme 1. The reaction
of chloroacetyl chloride with 1-aryl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolines (5-10) gave the intermediates 1-aryl-
(2-chloroacetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
lines 11-16, and these were further subjected to reaction in an
alkaline medium with various amines giving N-alkylamino-2-
acetyl substituted derivatives 17-40 in good yields. The
structures of the compounds obtained were supported by
>100
>100
84.9 (64.7-111)
70.2 (57.9-85.0)
>100
45.3 (32.2-63.6)
47.3 (32.5-68.9)
>100
>100
>100
83.8 (42.5-165)
82.8 (34.1-200)
46.9 (21.3-103)
56.5 (38.1-84.0)
>100
63.4 (48.9-82.1)
34.3 (21.4-54.8)
71.7 (64.6-110)
>100
>100
87.5 (66.1-115)
63.4 (48.9-82.1)
a All data were calculated according to the method of Litchfield and
Wilcoxon. At least 32 animals were used to calculate each ED50. The 95%
confidence limits are given in parentheses. b The log D data at pH 7.4 are
predicted from a commercially available program (ACD/Lab).29
1
elemental analyses and H NMR measurements.
The anticonvulsant effects of N-acetylalkylamino-1-aryl-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolines (17-40) were evalu-
ated against audiogenic seizures in DBA/2 mice. This is
considered an excellent animal model for generalized epilepsy
and for screening new anticonvulsant drugs.23 The results were
compared with those of other well-known AMPA receptor
antagonists (1-4).16
The biological results presented in Table 1 show that several
compounds protect DBA/2 mice in audiogenic test after
intraperitoneal administration. The ED50 ) 12.7 µmol/kg (clonic
phase) of derivative 26 is comparable to the value of 3 and
better than the ones for 1 and 2. Derivatives 19, 22, and 27
were also particularly active and showed a potency comparable
to that of 2 in the same test. The different anticonvulsant
potencies of the derivatives synthesized are not directly cor-
related to their relative lipophilicity (log D7.4, Table 1), thus
suggesting the influence of other parameters. Considering that
the molecules bearing piperidin-1-ylacetyl or diethylaminoacetyl
moiety on N2 are generally more active than the less basic
morpholin-4-ylacetyl derivatives, we postulated that the different
rate of basicity might play a role in the anticonvulsant efficacy
of the title compounds.
To demonstrate the mechanism of action, we investigated the
inhibitory effects of the most active compound 26 on membrane
currents evoked by AMPA in single rat olfactory cortical brain
slice neurons in vitro, under voltage clamp conditions. In the
initial trial experiments, application of 26 alone (50 or 10 µM;
N ) 2 cells at each concentration) had no effect on baseline
holding current or input conductance at -70 mV; however, in
the presence of 26, 1 or 2 µM AMPA responses were
consistently abolished, suggesting that this compound is effective
as an AMPA current antagonist. Following a 10 min pre-
incubation period with a lower fixed concentration (1 µM)
of 26 (N ) 7 experiments), the mean peak amplitude of the
AMPA-evoked inward currents was suppressed by ∼6-53%
over the AMPA dose range of 0.25-5 µM. At 0.5, 1, 2, and 5
µM AMPA (see Supporting Information), this depression of
mean currents was significantly different from that of the control
(P < 0.05, t-test); a full recovery of AMPA responses has been
observed after 10-20 min washout of antagonist. We also
compared the potency of 26 against 4 using the same fixed
dose (0.5 µM) for both derivatives. At this dose, 26 suppressed
the mean peak amplitude of the AMPA-evoked current by
∼6-30% and 4 by ∼7-52% (Figure 1), indicating that the latter
is more potent than 26, thus confirming the results obtained in
vivo against audiogenic seizures in DBA/2 mice. The clear
depression of the apparent maximum of the AMPA dose
response relation indicates that 26 was acting via a non-
competitive-type blocking mechanism at the AMPA receptor/
ion channel complex. Moreover, competitive binding of 26 to
glutamate receptors, i.e., AMPA, NMDA, and kainate competi-
tive sites, was inhibited by less than 6% at 0.5 µM.
Finally, 26 was also part of a training set for the generation
of a quantitative pharmacophore model for tetrahydroisoquino-
line derivatives using the HypoGen algorithm implemented in
the Catalyst molecular modeling software.24 The model obtained
consisting of five chemical features (two hydrogen bond regions,
one aromatic hydrophobic feature, and two hydrophobic sites)
was able to predict the pharmacological profile of this class of
compounds. As shown in Figure 2, the derivative 26 fulfills all
chemical functionalities of the 3D pharmacophore model; the
two hydrogen bond regions were occupied by the carbonyl
oxygen and the oxygen atom of the methoxy group at C6 (the
aryl group filled the aromatic hydrophobic feature), whereas
the 7-methoxy group and 4′-substituent overlapped with the two
hydrophobic sites.

5620 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18
Brief Articles
concentrated in vacuo. Crystallization of the crude product from
diethyl ether gave 1-aryl-2-(chloroacetyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline derivative. Experimental data for compounds
11 and 15 are in line with the literature.25
2-(Chloroacetyl)-1-(4′-bromophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (12). Mp 134-138 °C. Yield 62%.
2-(Chloroacetyl)-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (13). Mp 148-151 °C. Yield 64%.
2-(Chloroacetyl)-6,7-dimethoxy-1-(4′-fluorophenyl)-1,2,3,4-
tetrahydroisoquinoline (14). Mp 163-165 °C. Yield 59%.
2-(Chloroacetyl)-6,7-dimethoxy-1-(3′-nitrophenyl)-1,2,3,4-tet-
rahydroisoquinoline (16). Mp 153-155 °C. Yield 65%.
General Procedure for the Synthesis of 1-Aryl-2-(alkylamino-
acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydrohydroisoquinolines (17-
40). A mixture of 1-aryl-2-(chloroacetyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (1 mmol), a suitable alkyl- or cycloalkylamine
(1 mmol), and a catalytic amount of K2CO3 in toluene (10 mL)
was refluxed for 90 min. K2CO3 was then removed by filtration,
and the filtrate was concentrated in vacuo. The crude product was
crystallized by adding a small amount of an appropriate solvent to
give the desired product. The nitro compounds (0.36 mmol) were
hydrogenated in vacuo by adding 5% Pd/C as catalyst to a methanol
solution (30 mL), and the mixture was stirred at room temperature
for 1 h to give the corresponding amine derivatives. The Pd/C was
filtered out, and the solvent was removed in vacuo. The resulting
residue was crystallized from the suitable solvent.
2-(Diethylaminoacetyl)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetra-
hydroisoquinoline (17). Mp 75-79 °C (cyclohexane). Yield 45%.
1-(4′-Bromophenyl)-2-(diethylaminoacetyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (18). Mp 120-125 °C (diethyl
ether). Yield 55%.
Figure 1. Noncompetitive-type depression of AMPA dose response
relation in the presence of 1,2,3,4-tetrahydroisoquinoline derivatives 4
and 26. Peak inward membrane currents induced by AMPA were
measured in rat olfactory cortical brain slice neurons, with voltage
clamped at -70 mV, in the presence of 1 µM TTX. Points represent
the pooled mean values ((SEM) (nA) plotted against applied AMPA
concentration (0.25-5 µM, log scale) in the absence (O, N ) 7) and
presence of 0.5 µM 4 (b, N ) 7) and 26 (2, N ) 7) (curves were
fitted by eye).
1-(4′-Chlorophenyl)-2-(diethylaminoacetyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (19). Mp 123-126 °C (diethyl
ether). Yield 62%.
2-(Diethylaminoacetyl)-6,7-dimethoxy-1-(4′-fluorophenyl)-
1,2,3,4-tetrahydroisoquinoline (20). Mp 125-129 °C (diethyl
ether). Yield 41%.
2-(Diethylaminoacetyl)-6,7-dimethoxy-1-(4′-nitrophenyl)-1,2,3,4-
tetrahydroisoquinoline (21). Mp 98-101 °C (diethyl ether). Yield
60%.
2-(Diethylaminoacetyl)-6,7-dimethoxy-1-(3′-nitrophenyl)-1,2,3,4-
tetrahydroisoquinoline (22). Mp 137-140 °C (diethyl ether). Yield
58%.
1-(4′-Aminophenyl)-2-(diethylaminoacetyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (23). Mp 165-170 °C (diethyl
ether). Yield 52%.
1-(3′-Aminophenyl)-2-(diethylaminoacetyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (24). Mp 162-165 °C (diethyl
ether). Yield 32%.
6,7-Dimethoxy-1-phenyl-2-(piperidin-1-y1acetyl)-1,2,3,4-tetra-
hydroisoquinoline (25). Mp 117-120 °C (cyclohexane).
1-(4′-Bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (26). Mp 123-126 °C (diethyl
ether). Yield 51%.
Figure 2. Best HypoGen pharmacophore hypothesis aligned to 26.
The pharmacophore features are color-coded as follows: green,
hydrogen bond acceptors (HBA1 and HBA2); blue, hydrophobic
aromatic region (HYAr); cyan, hydrophobic groups (HY1 and HY2).
In conclusion the synthesis of the herein reported compounds
has allowed us to further explore the SAR of this class of 1-aryl-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines. However, the
most significant result of this work is the finding of a new potent
anticonvulsant agent acting at the AMPA receptor in a non-
competitive fashion.
Experimental Section
Chemistry Melting points were determined on a Stuart SMP10
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 analytical TLC; column chroma-
tography was performed on Merck silica gel 60 (70-230 mesh).
1H NMR spectra were measured in CDCl3 with a Varian Gemini
300 spectrometer; chemical shifts are expressed in δ (ppm) relative
to TMS as internal standard and coupling constants (J) in Hz. All
exchangeable protons were confirmed by addition of D2O.
General Procedure for the Synthesis of 1-Aryl-2-(chloro-
acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (11-16).
A solution of suitable 1,2,3,4-tetrahydroisoquinoline (1 mmol),
chloroacetyl chloride (1 mmol), and Et3N (1 mmol) in CHCl3 (10
mL) was stirred at room temperature for 90 min. The reaction
mixture was washed with H2O, dried over Na2SO4, and then
1-(4′-Chlorophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (27). Mp 121-122 °C (diethyl
ether). Yield 55%.
6,7-Dimethoxy-1-(4′-fluorophenyl)-2-(piperidin-1-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (28). Mp 85-88 °C (diethyl ether).
Yield 35%.
6,7-Dimethoxy-1-(4′-nitrophenyl)-2-(piperidin-1-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (29). Mp 110-114 °C (diethyl
ether). Yield 56%.
6,7-Dimethoxy-1-(3′-nitrophenyl)-2-(piperidin-1-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (30). Mp 131-136 °C (diethyl
ether). Yield 52%.
1-(4′-Aminophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (31). Mp 90-96 °C (diethyl ether).
Yield 42%.

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5621
1-(3′-Aminophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (32). Mp 130-136 °C (diethyl
ether). Yield 45%.
depicting electrophysiological experiment. This material is available
free of charge via the Internet at http://pubs.acs.org.
6,7-Dimethoxy-1-phenyl-2-(morpholin-4-ylacetyl)-1,2,3,4-tetra-
hydroisoquinoline (33). Mp 102-105 °C (cyclohexane). Yield
38%.
1-(4′-Bromophenyl)-6,7-dimethoxy-2-(morpholin-4-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (34). Mp 124-129 °C (diethyl
ether). Yield 45%.
1-(4′-Chlorophenyl)-6,7-dimethoxy-2-(morpholin-4-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (35). Mp 133-135 °C (diethyl
ether). Yield 48%.
6,7-Dimethoxy-1-(4′-fluorophenyl)-2-(morpholin-4-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (36). Mp 91-95 °C (diethyl ether).
Yield 35%.
6,7-Dimethoxy-2-(morpholin-4-ylacetyl)-1-(4′-nitrophenyl)-
1,2,3,4-tetrahydroisoquinoline (37). Mp 111-15 °C (diethyl
ether). Yield 55%.
6,7-Dimethoxy-2-(morpholin-4-ylacetyl)-1-(3′-nitrophenyl)-
1,2,3,4-tetrahydroisoquinoline (38). Mp 126-130 °C (diethyl
ether). Yield 54%.
1-(4′-Aminophenyl)-6,7-dimethoxy-2-(morpholin-4-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (39). Mp 90-95 °C (diethyl ether).
Yield 48%.
1-(3′-Aminophenyl)-6,7-dimethoxy-2-(morpholin-4-ylacetyl)-
1,2,3,4-tetrahydroisoquinoline (40). Mp 100-105 °C (diethyl
ether). Yield 54%.
Pharmacology. Testing of Anticonvulsant Activity. All experi-
ments were performed with DBA/2 mice that are genetically
susceptible to sound-induced seizures.9 DBA/2 mice (8-12 g, 22-
25 days old) were purchased from Harlan Italy (Corezzano, Italy).
Groups of 10 mice of either sex were exposed to auditory
stimulation for 30 min following administration of vehicle or each
dose of drugs studied.23
Electrophysiology. Transverse slices of olfactory cortex were
obtained from male Wistar rats as previously described26 and stored
in oxygenated Krebs solution before being transferred to an
immersion chamber for recordings. AMPA, 4, and 26 were tested.
In addition, slices were continuously superfused with 1 µM TTX
to block voltage-activated sodium currents and induced repetitive
firing at the peak of AMPA responses. AMPA and TTX were
freshly prepared in Krebs solution, whereas 4 and 26 were
predissolved in dimethyl sulfoxide (DMSO) to give 1 mM stock
solutions and subsequently diluted in Krebs solution (containing
0.1-1% v/v DMSO), immediately prior to use. These concentra-
tions of DMSO had no deleterious effects on neuronal membrane
properties or AMPA-induced inward currents. All measurements
were performed before, during, and after bath application of
pharmacological agents so that each neuron served as its own
control.
Ionotropic Glutamate Receptor Binding Studies. The radio-
ligand binding studies were carried out at 0.5 µM using the specific
ligands [3H]AMPA, [3H]CGP 39653, and [3H]kainic acid.27
Statistical Analysis Statistical comparisons between groups of
control and drug-treated animals were made using Fisher’s exact
probability 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 the Litchfield and Wilcoxon method via a computer pro-
gram.28
References
(1) Nadkarni, S.; LaJoie, J.; Devinsky, O. Current treatments of epilepsy.
Neurology 2005, 64, S2-S11.
(2) Kew, J. N.; Kemp, J. A. Ionotropic and metabotropic glutamate
receptor structure and pharmacology. Psychopharmacology (Berlin)
2005, 179, 4-29.
(3) Mayer, M. L. Glutamate receptor ion channels. Curr. Opin. Neurobiol.
2005, 15, 282-288.
(4) Wollmuth, L. P.; Sobolevsky, A. I. Structure and gating of the
glutamate receptor ion channel. Trends Neurosci. 2004, 27, 321-
328.
(5) Palmer, C. L.; Cotton, L.; Henley, J. M. The molecular pharmacology
and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepro-
pionic acid receptors. Pharmacol. ReV. 2005, 57, 253-277.
(6) Weiser, T. AMPA receptor antagonists for the treatment of stroke.
Curr. Drug Targets: CNS Neurol. Disord. 2005, 4, 153-159.
(7) De Sarro, G.; Gitto, R.; Russo, E.; Ferreri Ibbadu, G.; Barreca, M.
L.; De Luca, L.; Chimirri, A. AMPA receptor antagonists as potential
anticonvulsant drugs. Curr. Top. Med. Chem. 2005, 5, 31-42.
(8) Lees, G. J. Pharmacology of AMPA/kainate receptor ligands and
their therapeutic potential in neurological and psychiatric disorders.
Drugs 2000, 59, 33-78.
(9) Chimirri, A.; De Sarro, G.; De Sarro, A.; Gitto, R.; Grasso, S.;
Quartarone, S.; Zappala, M.; Giusti, P.; Libri, V.; Constanti, A.;
Chapman, A. G. 1-Aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones:
novel AMPA receptor antagonists. J. Med. Chem. 1997, 40, 1258-
1269.
(10) Chimirri, A.; De Sarro, G.; De Sarro, A.; Gitto, R.; Quartarone, S.;
Zappala, M.; Constanti, A.; Libri, V. 3,5-Dihydro-4H-2,3-benzodi-
azepine-4-thiones: a new class of AMPA receptor antagonists. J.
Med. Chem. 1998, 41, 3409-3416.
(11) Zappala`, M.; Gitto, R.; Bevacqua, F.; Quartarone, S.; Chimirri, A.;
Rizzo, M.; De Sarro, G.; De Sarro, A. Synthesis and evaluation of
pharmacological and pharmacokinetic properties of 11H-[1,2,4]-
triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones. J. Med. Chem. 2000,
43, 4834-4839.
(12) Gitto, R.; Orlando, V.; Quartarone, S.; De Sarro, G.; De Sarro, A.;
Russo, E.; Ferreri, G.; Chimirri, A. Synthesis and evaluation of
pharmacological properties of novel annelated 2,3-benzodiazepine
derivatives. J. Med. Chem. 2003, 46, 3758-3761.
(13) Langan, Y. M.; Lucas, R.; Jewell, H.; Toublanc, N.; Schaefer, H.;
Sander, J. W.; Patsalos, P. N. Talampanel, a new antiepileptic drug:
single- and multiple-dose pharmacokinetics and initial 1-week
experience in patients with chronic intractable epilepsy. Epilepsia
2003, 44, 46-53.
(14) Bialer, M.; Johannessen, S. I.; Kupferberg, H. J.; Levy, R. H.; Perucca,
E.; Tomson, T. Progress report on new antiepileptic drugs:
summary of the Seventh Eilat Conference (EILAT VII). Epilepsy
Res. 2004, 61, 1-48.
a
(15) Barreca, M. L.; Gitto, R.; Quartarone, S.; De Luca, L.; De Sarro,
G.; Chimirri, A. Pharmacophore modeling as an efficient tool in the
discovery of novel noncompetitive AMPA receptor antagonists. J.
Chem. Inf. Comput. Sci. 2003, 43, 651-655.
(16) Gitto, R.; Barreca, M. L.; De Luca, L.; De Sarro, G.; Ferreri, G.;
Quartarone, S.; Russo, E.; Constanti, A.; Chimirri, A. Discovery of
a novel and highly potent noncompetitive AMPA receptor antagonist.
J. Med. Chem. 2003, 46, 197-200.
(17) Ferreri, G.; Chimirri, A.; Russo, E.; Gitto, R.; Gareri, P.; De Sarro,
A.; De Sarro, G. Comparative anticonvulsant activity of N-acetyl-
1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives in
rodents. Pharmacol. Biochem. BehaV. 2004, 77, 85-94.
(18) Rizzo, M.; Ventrice, D.; De Sarro, G.; Gitto, R.; Caruso, R.; Chimirri,
A. SPE-HPLC determination of new tetrahydroisoquinoline deriva-
tives in rat plasma. J. Chromatogr., B: Anal. Technol. Biomed. Life
Sci. 2005, 821, 15-21.
(19) Gao, M.; Kong, D.; Clearfield, A.; Zheng, Q. H. Synthesis of carbon-
11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline derivatives as new potential PET AMPA
receptor ligands. Bioorg. Med. Chem. Lett. 2006, 16, 2229-2233.
(20) Arstad, E. Closing in on the AMPA receptor: Synthesis and
Evaluation of 2-Acetyl-1-(p-chlorophenyl)-6-methoxy-7-[11C]methoxy-
1,2,3,4-tetrahydroisoquinoline as a Novel PET Ligand. Presented at
the Asia-Pacific Symposium on Radiochemistry (APSORC-05),
Beijing, China, October 17-21, 2005.
Acknowledgment. Financial support for this research by
Italian Ministry of Education, University and Research (Grants
FIRB2003, COFIN 2003, 2004, 2005) is gratefully acknowl-
edged.
(21) Arstad, E.; Gitto, R.; Chimirri, A.; Caruso, R.; Constanti, A.; Turton,
D.; Hume, S. P.; Ahmad, R.; Pilowsky, L.; Luthra, S. K. Closing in
on the AMPA receptor: Synthesis and evaluation of 2-acetyl-1-(4′-
chlorophenyl)-6-methoxy-7-[11C]methoxy-1,2,3,4-tetrahydroisoquino-
Supporting Information Available: Elemental analysis data
for 11-40, H NMR assignments for new intermediates and final
products, procedure for electrophysiological study, and figure
1

5622 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18
Brief Articles
line as a potential PET tracer. Bioorg. Med. Chem. 2006, 14, 4712-
4717.
(22) Gitto, R.; Caruso, R.; Orlando, V.; Quartarone, S.; Barreca, M. L.;
Ferreri, G.; Russo, E.; De Sarro, G.; Chimirri, A. Synthesis and
anticonvulsant properties of tetrahydroisoquinoline derivatives.
Farmaco 2004, 59, 7-12.
(23) Chapman, A. G.; Croucher, M. J.; Meldrum, B. S. Evaluation of
anticonvulsant drugs in DBA/2 mice with sound-induced seizures.
Arzneimittelforschung 1984, 34, 1261-1264.
(24) De Luca, L.; Gitto, R.; Barreca, M. L.; Caruso, R.; Quartarone, S.;
Citraro, R.; De Sarro, G.; Chimirri, A. 3D pharmacophore models
for 1,2,3,4-tetrahydroisoquinoline derivatives acting as anticonvulsant
agents. Arch. Pharm. Chem. Life Sci. 2006, 339, 388-400.
(25) Venkov, A. P.; Lukanov, L. K. Improved methods for the synthesis
of N-acyltetrahydroisoquinolines. Synth. Commun. 1992, 22, 3235-
3242.
(26) Constanti, A.; Bagetta, G.; Libri, V. Persistent muscarinic excitation
in guinea-pig olfactory cortex neurons: involvement of a slow post-
stimulus after depolarizing current. Neuroscience 1993, 56, 887-
904.
(27) MDS Pharma Services. http://www.mdsps.com.
(28) Litchfield, J. T., Jr. A method for rapid graphic solution of time-
per cent effect curves. J. Pharmacol. Exp. Ther. 1949, 97, 399-
408.
(29) Advanced Chemistry Development ACD/Lab 2004. www.acdlabs.com.
JM060411B