Discovery of a novel and highly potent noncompetitive AMPA receptor antagonist

Article abstract of DOI:10.1021/jm0210008

N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class o

Full text of DOI:10.1021/jm0210008

J . Med. Chem. 2003, 46, 197-200
197
Discover y of a Novel a n d High ly P oten t Non com p etitive AMP A Recep tor
An ta gon ist
†
†
†
‡
‡
Rosaria Gitto, Maria Letizia Barreca, Laura De Luca, Giovambattista De Sarro, Guido Ferreri,
†
§
§
,†
Silvana Quartarone, Emilio Russo, Andrew Constanti, and Alba Chimirri*
Dipartimento Farmaco-Chimico, Universit a` di Messina, Viale Annunziata, 98168 Messina, Italy, Dipartimento di Medicina
Sperimentale e Clinica, Universit a` Magna Græcia, Via T. Campanella, 88100 Catanzaro, Italy, and Department of
Pharmacology, School of Pharmacy, University of London, 29/ 39, Brunswick Square, London, WC1N 1AX, U.K.
Received J uly 30, 2002
N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and
synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular
modeling studies. Sound-induced seizure testing showed that this class of compounds possessed
anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a
noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as
an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly
effective noncompetitive-type modulator of the AMPA receptor.
In tr od u ction
Ch a r t 1. Noncompetitive AMPA Receptor Antagonists
The ionotropic glutamate receptors (iGluRs) are
divided into N-methyl-D-aspartic acid (NMDA), 2-
amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid
(
AMPA), and kainate (KA) receptors, on the basis of
1
their pharmacology and structural properties. AMPA
receptor (AMPAR) subtypes are involved in learning and
memory but can also mediate neuronal degeneration
and even cell death. For this reason, particular attention
has been devoted to selective AMPA receptor antago-
nists as potential neuroprotective agents against neu-
rological diseases such as epilepsy, ischemia, Parkin-
son’s disease, and multiple sclerosis.2
-4
There is extensive literature on derivatives able to
inhibit glutamatergic transmission in a competitive
fashion, whereas only a few classes of selective non-
competitive AMPAR antagonists have been developed,
i.e., 2,3-benzodiazepines, phthalazines, and quinazolines
5
(Chart 1).
The 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-
H-2,3-benzodiazepine hydrochloride (1, GYKI 52466)
antagonists and potent anticonvulsant agents.1
0-14
More-
5
over, taking the 2,3-benzodiazepine derivatives as a
mold, different arylphthalazines (e.g., 4, SYM-2207)
have been synthesized, leading to potent neuroprotec-
tive derivatives with the same mechanism of action.1
Finally, a series of quinazolinone noncompetitive AM-
PAR antagonists were recently described by Pfizer
was the prototype of noncompetitive AMPAR antago-
nists.6 With this molecule as a template, the R-(-)
enantiomer of 3-N-acetyl-1-(4-aminophenyl)-4-methyl-
5-18
7
,8-methylenedioxy-4,5-dihydro-2,3-benzodiazepine (2,
talampanel) has been identified as a selective ligand for
AMPAR.7
-9
Phase II clinical trials with talampanel in
1
8
researchers, the 3-(2-chlorophenyl)-2-[2-(6-diethylami-
nomethylpyridinyl)vinyl]-6-fluoro-3H-quinazolinone de-
rivative (5, CP-465022) being the lead compound, char-
acterized by excellent in vivo and in vitro pharmacological
patients with severe epilepsy not responsive to other
drugs have shown positive results, and phase III trials
in epilepsy are underway to confirm and expand these
results.
Our research group has previously reported chemical
and biological studies of a large series of 7,8-dimethoxy-
1
9-20
profiles as well as aqueous solubility.
On the basis of these encouraging results, the devel-
opment of new and potent noncompetitive AMPAR
antagonists continues to be important as a feasible
therapeutic strategy in the treatment of neurological
diseases involving glutamate receptors, particularly
epilepsy. Unfortunately, target-structure-based design
of noncompetitive AMPAR antagonists is currently
hampered by the fact that no structural information is
available on the location and composition of this ligand
2
,3-benzodiazepines (e.g., 3, CFM-2) that have also been
shown to be specific noncompetitive AMPA receptor
*
To whom correspondence should be addressed. Phone: (++39)
90-6766412. Fax: (++39) 090-355613. Email: chimirri@
pharma.unime.it.
0
†
Universit a` di Messina.
Universit a` Magna Græcia.
University of London.
‡
§
1
0.1021/jm0210008 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/27/2002

1
98 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Brief Articles
Ta ble 1. Anticonvulsant Activity of GYKI 52466 (1),
Talampanel (2), CFM-2 (3), and Compounds 10a -f against
Audiogenic Seizures in DBA/2 Mice 30 min after
Intraperitoneal Administration
Sch em e 1a
a
ED50, µmol/kg
compound
clonic phase
tonic phase
GYKI 52466b
talampanel
CFM-2b
35.8 (24.4-52.4)
13.4 (10.1-17.8)
15.0 (9.01-24.0)
53.5 (37.6-76.2)
43.1 (21.9-84.6)
4.20 (2.23-7.84)
36.8 (20.6-65.8)
>100
25.3 (16.0-40.0)
9.70 (7.00-13.4)
12.6 (8.01-19.0)
37.7 (21.2-67.0)
16.5 (7.77-34.9)
2.40 (1.30-4.40)
18.0 (7.76-41.8)
>100
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
32.1 (17.7-58.3)
21.1 (11.0-40.4)
a
All data were calculated according to the method of Litchfield
and Wilcoxon.25 95% confidence limits are given in parentheses.
At least 32 animals were used to calculate each ED50. Reference
b
1
1.
with those of GYKI 52466 (1), talampanel (2), and
CFM-2 (3).
As shown in Table 1, compound 10c proved to be in
vivo more potent than GYKI 52466, talampanel, and
CFM-2. In fact, this derivative demonstrated anticon-
vulsant activity with ED50 values an order of magnitude
less than those of GYKI 52466. Furthermore, 10c was
∼3-fold more active than talampanel and CFM-2.
a
Reagents: (i) dry toluene, ∆, 180 min; (ii) TFA, ∆, 90 min;
iii) Ac2O, ∆, 90 min; (iv) Pd-C/H2 5%, MeOH, room temp.
(
binding region. For this reason, we have recently
generated ligand-based pharmacophore models of nega-
tive allosteric modulators of AMPAR in order to develop
new potential ligands for this receptor.21 This study has
suggested that N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolines (type 10) might satisfy the
structural requirements for AMPAR binding (unpub-
lished results). Consequently, the synthesis of the most
promising derivatives has been realized and their
pharmacological profiles were evaluated.
Compounds 10d and 10f also displayed anticonvul-
sant potencies comparable to that of GYKI 52466. In
addition, to define the mechanism of action and confirm
the hypothesis suggested by molecular modeling studies,
electrophysiological experiments were carried out on
compound 10c (Figure 1), the most potent anticonvul-
sant compound of the current series. We investigated
its effects on membrane currents evoked by AMPA in
single rat olfactory cortical brain slice neurons in vitro,
Ch em istr y
27
under voltage clamp conditions
(1 µM TTX was
N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinolines (10a -f) were synthesized via the Pictet-
Spengler approach as shown in Scheme 1, according to
previously reported procedures.22 The first step of the
synthetic pathway was the formation of benziliden[2-
routinely included in the bathing medium to block fast
sodium spike generation). Short (1 min) bath superfu-
sions of AMPA (0.25-5 µM; N ) 7 experiments) to
neurons voltage-clamped at a -70 mV holding potential
produced slow, dose-dependent, and reproducible mem-
brane currents (mean response measured at peak
amplitude for 1 µM AMPA ) 1.44 ( 0.32 nA) that
decayed slowly to control baseline level over a 5-15 min
washout period, depending on the current response
magnitude. A prominent outward “rebound” current (up
to ∼0.5 nA) was also usually seen during the agonist
washout period, particularly following the larger AMPA
responses, most likely due to activation of electrogenic
Na -K pump activity. In initial trial experiments,
application of 10c alone (50 or 1 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 this compound, 1 or 2 µM AMPA responses
were consistently abolished.
In particular, after a 10 min preincubation period
with a lower fixed concentration (0.5 µM) of 10c (N ) 7
experiments), the mean peak amplitude of the AMPA-
evoked inward currents was suppressed by ∼7-52%
over the AMPA dose range of 0.25-5 µM respectively
(Figure 1A). An example of such an experiment carried
out on a single neuron is shown in Figure 1B. At 1, 2,
and 5 µM AMPA, this depression of mean currents was
significantly different from the control (P < 0.05; t test);
(3′,4′-dimethoxyphenyl)ethyl]amines 8a -e obtained by
condensation of the 2-(3′,4′-dimethoxyphenyl)ethyl-
amine (6) with appropriate aromatic aldehydes 7a -e
in refluxing anhydrous toluene. Under conditions of acid
catalysis with trifluoroacetic acid (TFA), the intermedi-
ate azomethines 8 underwent intramolecular cyclization
into the corresponding racemic mixture of 1-aryl-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolines (9a -e) with
good yields. The isoquinoline derivatives 9 were further
subjected to reaction with acetic anhydride to afford
N-acetyl derivatives 10a -e. Moreover, the aminophen-
yl-substituted derivative 10f was prepared by reduction
of the corresponding nitro analogues 10e. The structures
of the compounds obtained were supported by elemental
+
+
26
1
analyses and spectroscopic measurements ( H NMR).
Biologica l Resu lts a n d Discu ssion
The anticonvulsant effects of N-acetyl-1-aryl-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolines (10) were
evaluated against audiogenic seizures in DBA/2 mice
(
Table 1),23 which has been considered an excellent
animal model for generalized epilepsy and for screening
new anticonvulsant drugs.24 The results were compared

Brief Articles
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 199
Exp er im en ta l Section
Ch em istr y. 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
1
for analytical TLC. H NMR spectra were measured in CDCl
3
with a Varian Gemini 300 spectrometer; chemical shifts are
expressed in δ (ppm) relative to TMS as the internal standard
and coupling constants (J ) are in hertz. All exchangeable
2
protons were confirmed by addition of D O.
Gen er a l P r oced u r e for th e Syn th esis of 1-Ar yl-6,7-
d im eth oxy-1,2,3,4-tetr a h yd r oisoqu in olin es (9a -e). A mix-
ture of 2-(3′,4′-dimethoxyphenyl)ethylamine (6) (1.8 g, 10
mmol) and suitable aldehyde derivative 7a -e (12 mmol) in
anhydrous toluene (50 mL) was refluxed for 3 h and then
cooled and evaporated in vacuo. The oil residue was treated
with diethyl ether to give a solid residue, which was crystal-
lized from ethanol to afford the desired imine 8a -e. Trifluo-
roacetic acid (10 mL) was added to a solution of benziliden[2-
(3′,4′-dimethoxyphenyl)ethyl]amine 8a -e (3.2 mmol), and the
mixture was refluxed for 90 min. The reaction was quenched
by adding water, and the mixture was basified (pH ∼8-9) with
sodium hydroxide to give the isoquinoline derivative as a solid.
The crude product was collected by filtration and purified by
crystallization with MeOH to afford compounds 9a -e.
Gen er a l P r oced u r e for th e Syn th esis of 2-Acetyl-1-
ar yl-6,7-dim eth oxy-1,2,3,4-tetr ah ydr oisoqu in olin es (10a-
f). A solution of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (9a -e) (1.3 mmol) in acetic anhydride (10 mL) was
refluxed for 90 min and then cooled, the reaction was quenched
by adding water, and the organic layer was extracted with
2 4
chloroform. The organic layer was dried over Na SO , and the
solvent was removed until dryness under reduced pressure.
The oil residue was washed with diethyl ether, and the crude
product was crystallized with EtOH to afford compounds 10a -
e. To the methanolic solution of the nitroderivative 10e was
added 5% Pd-C as catalyst; the reaction mixture was hydro-
genated and stirred at room temperature for 120 min. The
Pd-C was filtered out, and the solvent was removed in vacuo;
the resulting residue was crystallized from EtOH to give
compound 10f.
F igu r e 1. (A) Noncompetitive-type depression of AMPA dose-
response relation in the presence of the derivative 10c. Peak
inward membrane currents induced by AMPA were measured
in rat olfactory cortical brain slice neurons 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 )
Compounds 10a , 10c, and 10e have also been obtained by
2
8
other authors using a different synthetic procedure.
7
) and presence (b; N ) 7) of 0.5 µM compound 10c (curves
2-Acetyl-1-(4′-br om op h en yl)-6,7-d im eth oxy-1,2,3,4-tet-
1
were fitted by eye). (B) Chart recordings from a single cortical
neuron clamped at -70 mV (in TTX), showing inward currents
evoked by 0.5, 1, and 2 µM AMPA (1 min bath applications)
in control solution and after 15 min of preincubation with 0.5
µM compound 10c. Peak currents were depressed by 35%, 48%,
and 53% respectively. Note “rebound” outward currents seen
during washout period of larger AMPA currents (chart speed
unchanged). Scale bars apply to all traces.
r a h yd r oisoqu in olin e (10b). Mp 138-140 °C. Yield 68%. H
NMR: δ 2.16 (s, 3H, MeCO), 2.71-3.69 (m, 4H, CH
2
2
-CH ),
3.75 (s, 3H, MeO-6), 3.89 (s, 3H, MeO-7), 6.48 (s, 1H, H-5),
6.66 (s, 1H, H-8), 6.83 (s, 1H, H-1), 7.16-7.25 (m, 4H, ArH).
Anal. (C19H20BrNO ) C, H, N.
3
2-Acetyl-6,7-d im eth oxy-1-(4′-flu or op h en yl)-1,2,3,4-tet-
1
r a h yd r oisoqu in olin e (10d ). Mp 158-160 °C. Yield 79%. H
NMR: δ 2.15 (s, 3H, MeCO), 2.70-3.35 (m, 4H, CH
2
2
-CH ),
3
6
.74 (s, 3H, MeO-6), 3.85 (s, 3H, MeO-7), 6.44 (s, 1H, H-5),
.64 (s, 1H, H-8), 6.83 (s, 1H, H-1), 7.02-7.23 (m, 4H, ArH).
) C, H, N.
a full recovery of AMPA responses was observed after
a 10-20 min washout of antagonist. From the clear
depression of the apparent maximum of the AMPA
dose-response relation, it is likely that 10c was acting
via a noncompetitive-type blocking mechanism at the
AMPA receptor/ion channel complex.
Anal. (C19H20FNO
3
Acet yl-1-(4′-a m in op h en yl)-6,7-d im et h oxy-1,2,3,4-t et -
1
r a h yd r oisoqu in olin e (10f). Mp 182-183 °C. Yield 70%. H
NMR: δ 2.15 (s, 3H, MeCO), 2.70-3.70 (m, 4H, CH
2
2
-CH ),
3.75 (s, 3H, MeO-6), 3.89 (s, 3H, MeO-7), 6.51 (s, 1H, H-5),
6.64 (s, 1H, H-8), 6.64 (s, 1H, H-1), 6.58-7.02 (m, 4H, ArH).
Anal. (C19
22 2 3
H N O ) C, H, N.
It is worth noting that to obtain a similar response
in the same in vitro assay, it is necessary to use for
GYKI 52466 and some other 2,3-benzodiazepines doses
Testin g of An ticon vu lsa n t Activity. Au d iogen ic Sei-
zu r es in DBA/2 Mice. All experiments were performed with
DBA/2 mice that are genetically susceptible to sound-induced
seizures. DBA/2 mice (8-12 g, 22-25 days old) were purchased
from Charles River (Calco, Como, 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 ip (0.1 mL/10 g of body
weight of the mouse) as a freshly prepared solution in 50%
DMSO and 50% sterile saline (0.9% NaCl). Individual mice
were placed under a hemispheric Perspex dome (diameter 58
cm), and a period of 60 s was allowed for habituation and
1
1-12
1
00-fold higher than those of 10c, i.e., 50 vs 0.5 µM.
In conclusion, using molecular modeling studies, we
have discovered a novel class of potent noncompetitive
AMPAR antagonists. In particular, derivative 10c is
characterized by an improved pharmacological profile
when compared with other current antagonists and
might be a useful lead for developing novel, therapeuti-
cally promising compounds.

2
00 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Brief Articles
assessment of locomotor activity. Auditory stimulation (12-
6 kHz, 109 dB) was applied for 60 s or until tonic extension
(9) Lodge, D.; Bond, A.; O’Neill, M.; Hicks, C. A.; J ones, M. G.
Stereoselective Effects of 2,3-Benzodiazepines in Vivo: Electro-
physiology and Neuroprotection Studies. Neuropharmacology
1
occurred, and it induced a sequential seizure response in
control DBA/2 mice consisting of an early wild running phase
followed by generalized myoclonus and tonic flexion and
extension sometimes followed by respiratory arrest. The
control and drug-treated mice were scored for latency to and
incidence of the different phases of the seizures.
St a t ist ica l An a lysis. 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 the audiogenic seizure were
determined for each dose of compound administered, and
dose-response curves were fitted using a computer program
incorporating Litchfield and Wilcoxon’s method. The relative
anticonvulsant activities were determined by comparison of
respective ED50 values.
1
996, 35, 1681-1688.
(
10) De Sarro, G.; Chimirri, A.; De Sarro, A.; Gitto, R.; Grasso, S.;
Giusti, P.; Chapman, A. G. GYKI 52466 and Related 2,3-
Benzodiazepines as Anticonvulsant Agents in DBA/2 Mice. Eur.
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(
11) Chimirri, A.; De Sarro, G.; De Sarro, A.; Gitto, R.; Grasso, S.;
Quartarone, S.; Zappal a` , 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,
4
0, 1258-1269.
(
(
(
12) Chimirri, A.; De Sarro, G.; De Sarro, A.; Gitto, R.; Quartarone,
S.; Zappal a` , M.; Constanti, A.; Libri, V. 3,5-Dihydro-4H-2,3-
benzodiazepine-4-thiones: A New Class of AMPA Receptor
Antagonists. J . Med. Chem. 1998, 41, 3409-3416.
13) Chimirri, A.; Bevacqua, F.; Gitto, R.; Quartarone, S.; Zappal a` ,
M.; De Sarro, A.; Maciocco, L.; Biggio, G.; De Sarro, G. Synthesis
and Anticonvulsant Activity of New 11H-Triazolo[4,5-c][2,3]-
benzodiazepines. Med. Chem. Res. 1999, 9, 203-212.
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A.; Rizzo, M.; De Sarro, G.; De Sarro A. Synthesis and Evaluation
of Pharmacological and Pharmacokinetic Properties of 11H-
Electr op h ysiology. Transverse slices of olfactory (piriform)
cortex (∼450 µm thick) were prepared from 200-250 g male
Wistar rats as previously described and were maintained in
oxygenated Krebs solution at 32 °C for 30 min to 1 h before
being transferred to an immersion chamber for recording. The
composition of the Krebs solution was the following (mM):
[1,2,4]Triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones. J . Med. Chem.
2
000, 43, 4834-4839.
NaCl, 118; KCl, 3; CaCl
D-glucose, 11 (bubbled with 95%/5% O
2
, 1.5; NaHCO
3
, 25; MgCl
2
‚6H
2
O, 1;
(
15) Pelletier J . C.; Hesson, D. P.; J ones, K. A.; Costa, A. M.
Substituted 1,2-Dihydrophthalazines: Potent, Selective, and
Noncompetitive Inhibitors of the AMPA Receptor. J . Med. Chem.
1996, 39, 343-346.
2
/CO , pH 7.4). Intra-
2
cellular recordings were made from the periamygdaloid area
of the slices within the olfactory pyramidal cell layers II and
III, using glass microelectrodes filled with 4 M potassium
acetate (tip resistances of 40-60 MΩ). Voltage-clamp record-
ings were made at a holding membrane potential of -70 mV
with an Axoclamp 2 A sample-and-hold preamplifier (2-3 kHz
switching frequency, 30% duty cycle). Sampled membrane
currents (filtered at 30 Hz, low pass) and voltage were recorded
on a Gould 2400 ink-jet chart recorder. Data are presented as
the mean ( SEM, and statistical significance between data
groups was assessed by unpaired t test. The following com-
pounds were tested: AMPA and 10c. In addition, 1 µM TTX
was continually present in the bathing medium to eliminate
fast voltage-activated sodium currents and induced repetitive
firing at the peak of the AMPA responses. AMPA and TTX
were freshly prepared in Krebs solution immediately before
use, whereas compound 10c was predissolved in DMSO to give
a 1 mM stock solution that was subsequently diluted in Krebs
(16) Pei, X.; Sturgess, M. A.; Valenzuela, C. F.; Maccecchini, M. L.
Allosteric Modulators of AMPA Receptor: Novel 6-Substituted
Dihydrophthalazines. Bioorg. Med. Chem. Lett. 1999, 9, 539-
5
42.
(
17) Gitto, R.; Chimirri, A.; Zappal a` , M.; De Sarro, G.; De Sarro, A.;
Synthesis and Pharmacological Evaluation of 4-Aryl-6,7-dimeth-
oxyphthalazines as Anticonvulsant Agents. Med. Chem. Res.
2
000, 10, 1-10.
(18) Grasso, S.; De Sarro, G.; De Sarro, A.; Zappal a` , M.; Puja, G.;
Baraldi, M.; De Micheli, C. Synthesis and Anticonvulsant
Activity of Novel and Potent 6,7-Methylenedioxyphthalazin-
1
(2H)-ones. J . Med. Chem. 2000, 43, 2851-2859.
(
19) Welch, W. M.; Ewing, F. E.; Huang, J .; Menniti, F. S.; Pagnozzi,
M. J .; Kelly, K.; Seymour, P. A.; Guanowsky, W.; Guhan, S.;
Guinn, M. R.; Critchett, D.; Lazzaro, J .; Ganong, A. H.; Chenard,
B. L. Atropisomeric Quinazolin-4-ones Derivatives Are Potent
Noncompetitive R-Amino-3-hydroxy-5-methyl-4-isoxazolepropi-
onic Acid (AMPA) Receptor Antagonists. Bioorg. Med. Chem.
Lett. 2001, 11, 177-181.
(final DMSO concentration of 0.1-1% v/v) prior to use. These
concentrations of DMSO had no obvious deleterious effects on
neuronal membrane properties or on AMPA-induced mem-
brane currents. Measurements were routinely performed
before, during, and after bath superfusion of pharmacological
agents so that each neuron served as its own control.
(20) Lazzaro, J . T.; Paternain, A. V.; Lerma, J .; Chenard, B. L.;
Ewing, F. E.; Huang, J .; Welch, W. M.; Ganong, A. H.; Menniti,
F. S. Functional Characterization of CP-465,022, a Selective,
Noncompetitive AMPA Receptor Antagonist. Neuropharmacol-
ogy 2002, 42, 143-153.
(
21) Gitto, R.; De Sarro, G.; Quartarone, S.; Barreca, M. L.; De Luca,
L.; Chimirri, A. Noncompetitive AMPA Receptor Antagonists
and Proposed Pharmacophore Model. Presented at the Hungar-
ian-German-Italian-Polish J oint Meeting on Medicinal Chem-
istry, Budapest, Hungary, September 2-6, 2001.
Ack n ow led gm en t . We thank and acknowledge
funding for this work from Fondo Ateneo di Ricerca
(2000, Messina, Italy) and COFIN2000.
(
22) Yokoyama, A.; Ohwada, T.; Shudo, K. Prototype Pictet-Spengler
Reactions Catalyzed by Superacids, Involvement of Dicationic
Superelectrophiles. J . Org. Chem. 1999, 64, 611-617.
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