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W06:ZPHAR610XA
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Original Paper
Pharmacology 1998;57:233–241
Department of Pharmacology,
Faculty of Pharmaceutical
Sciences, Okayama University,
Okayama, Japan
Anticonvulsant Properties of
1,4-Benzodiazepine Derivatives in
Amygdaloid-Kindled Seizures and
Their Chemical Structure-Related
Anticonvulsant Action
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Key Words
Kindling
Amygdala
1,4-Benzodiazepines
Structure-activity
relationships
Prophylactic effect
Abstract
The effects of 14 different 1,4-benzodiazepines on amygdaloid-kindled seizures and their chemical structure-related anticonvulsive actions were studied. The prophylactic effects of
1,4-benzodiazepines on amygdaloid-kindled seizures were
also examined. Male Wistar strain rats were used in this study.
Rats were anesthetized with pentobarbital sodium (35 mg/kg
i.p.) and bipolar electrodes were implanted into the right
amygdala. The stimulating parameters were 1 ms pulse duration, 60 Hz frequency and a 1 s duration at an intensity just
sufficient to induce afterdischarge (AD). All the 1,4-benzodiazepines depressed both seizure stage and AD duration of
amygdaloid-kindled seizures. Of the 1,4-benzodiazepines,
prazepam, flutoprazepam and flurazepam with a long alkyl
chain at position 1 were less effective than the drugs having a
hydrogen or methyl group at the same position. Nitrazepam,
nimetazepam, flunitrazepam and clonazepam which have a
nitro group at position 7 showed more potent antiepileptic
activity than the drugs with a chloro group. Certain 1,4-benzodiazepines caused inhibition of the development of amygdaloid-kindled seizures. The existence of a hydrogen or methyl
group at position 1 and a nitro group at position 7 is important
for exhibiting potent anticonvulsant activity in amygdaloidkindled seizures. Introduction of an oxygen group at position 2
is also necessary for high activity. 1,4-benzodiazepines had not
only therapeutic but also prophylactic effects on amygdaloidkindled seizures.
ABC
© 1998 S. Karger AG, Basel
0031–7012/98/0575–0233$15.00/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
Accessible online at:
http://BioMedNet.com/karger
Dr. Chiaki Kamei, Department of Pharmacology
Faculty of Pharmaceutical Sciences, Okayama University
Okayama 700-8530 (Japan)
Tel./Fax +81 86 251 7939
E-Mail kamei@pheasant.pharm.okayama-u.ac.jp
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Masafumi Fukinaga
Keisuke Ishizawa
Chiaki Kamei
Received: December 18, 1997
Accepted: March 28, 1998
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Since its demonstration by Goddard et al.
[1], the kindling preparation has frequently
been used as a model for the evaluation of
antiepileptic drugs. In particular, amygdaloid-kindled rats are widely used for this purpose. The kindling model has the merit that
the efficacy of the drugs on the progressive
process leading to epileptogenesis as well as
on the fully kindled state can be measured [2].
On the other hand, a number of 1,4-benzodiazepines have been synthesized and used in
clinical settings. It is well known that 1,4-benzodiazepines have more or less anticonvulsant activities besides anxiolytic, sedativehypnotic and muscle relaxant activities. The
neuropharmacological effects of 1,4-benzodiazepines have been reported to be mediated
by their interaction with a specific benzodiazepine recognition site within the GABA
receptor complex [3]. GABA is well known to
be an inhibitory neurotransmitter in the
mammalian CNS, and GABA-mediated inhibition is believed to control the neuronal hyperexcitability state leading to epilepsy [4].
Considerable literature exists concerning the
effects of 1,4-benzodiazepines such as diazepam, clonazepam, clobazam, bromazepam,
lorazepam and nitrazepam [5–10] on amygdaloid-kindled seizures. However, we have as
yet very little information about the structureactivity relationship of 1,4-benzodiazepines
on amygdaloid-kindled seizures.
Therefore, the present study was carried
out to clarify the effects of 14 different 1,4benzodiazepines on fully amygdaloid-kindled
rats as well as their structure-activity relationships. In addition, the effects of certain 1,4benzodiazepines on the development of
amygdaloid-kindled seizures were also studied.
Materials and Methods
Animals
Male Wistar strain rats, 7–8 weeks old and weighing 200–250 g, were used (Oriental Bioservice). All animals were maintained in an air-conditioned room controlled for temperature (24–25 ° C) and humidity (50–
60%). They were housed in aluminium cages with
wood shavings and were kept on a constant (07.00–
19.00 h) light-dark schedule. The animals were allowed
free access to food and tap water, except during the
experiment.
Surgery
Under pentobarbital sodium anesthesia (35 mg/kg
i.p., Dainippon), the animals were placed on a stereotaxic apparatus and bipolar electrodes were implanted
into the right amygdala (A 5.0, L 5.0, H –2.5) according to the atlas of de Groot [11]. The electrodes were
bipolar twisted stainless steel wires 200 Ìm in diameter (tip distance of 0.5–1.0 mm) and insulated except
for 0.5 mm at the tip. Electrodes were connected to a
miniature receptacle, which was embedded in the skull
with dental cement. At least 2 weeks were allowed to
elapse after surgery and experiments.
Experimental Procedure in Kindled Seizures
The procedure to cause kindled seizures was similar to that described in a previous paper [6]. The animals were placed in a plexiglas observation chamber
(20 ! 35 ! 25 cm). An EEG was recorded bipolarly
prior to and following stimulation with an electroencephalograph (San-ei, 1A74). Electrical stimulation was
applied bipolarly every day by a contrast current stimulator (Nihon Kohden, SEN-3301), equipped with a
stimulus isolation unit (Nihon Kohden, SS-102J) and
continued until a generalized convulsion was obtained.
The stimulating parameters were 1.0 ms pulse duration, 60 Hz frequency and a 1.0 s duration at an intensity just sufficient to induce afterdischarge (AD, 200–
250 ÌA). The developmental patterns of the clinical
manifestations of amygdaloid kindling were classified
using the method described by Racine [12] as follows:
stage 1, jaw movement; stage 2, head nodding; stage 3,
forelimb clonus; stage 4, kangaroo posture; stage 5,
kangaroo posture and falling back. After the animals
developed the final stage of generalized seizure, they
were subjected to the stimulation for 5 more days and
then used for the drug study.
Drugs
The drugs used were diazepam (Takeda), nitrazepam (Wako), clonazepam (Roche), clorazepate dipo-
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tassium (Dainippon), fludiazepam (Sumitomo), medazepam (Shionogi), prazepam (Kowa), flutoprazepam
(Kanebo), oxazepam (Banyu), lorazepam (Yamanouchi), flurazepam (Roche), nimetazepam (Sumitomo),
flunitrazepam (Roche) and lormetazepam (Yamanouchi). All drugs were suspended in 0.4% carboxymethylcellulose sodium solution. These drugs were administered per os at a volume of 1.0 ml/kg of body weight.
The doses of drugs were expressed in terms of the free
base. In this experiment for testing of drug effects,
brain stimulation was performed before and 0.5, 1, 2,
4, 6, 8 and 24 h after administration of the drugs.
Histological Examinations
After the experiments, the animals were sacrificed,
and localization of the electrodes in the brain was histologically verified.
Statistical Analysis
ED50 values were determined by the probit method. The ED50 values represent the dose of drug required to produce a 50% protection of the seizure stage
or AD duration. The Mann-Whitney U test and
ANOVA with Dunnett’s test were used to calculate the
statistical difference between the means of the test and
control groups.
Results
Effects of 1,4-Benzodiazepines on
Amygdaloid-Kindled Seizures
The results obtained at 1 h (maximal effect) after oral administration of 1,4-benzodiazepines are shown in tables 1–3. Diazepam
at doses of 1, 2 and 5 mg/kg caused a significant inhibition of the seizure stage and AD
duration in amygdaloid-kindled seizures.
Clonazepam used for seizure disorders in
clinical therapy was the most effective in depressing amygdaloid-kindled seizures, and a
significant effect was observed on both seizure stage and AD duration at a dose of 0.5
mg/kg (table 1). On the other hand, high doses
of 10–20 mg/kg were required to inhibit kindled seizures when prazepam and flutoprazepam, for anxiety disorders, were used, though
the effects of fludiazepam, oxazepam and lo-
1,4-Benzodiazepines and Kindling
Table 1. Effects of 1,4-benzodiazepines used for
seizure disorders on amygdaloid-kindled seizures
Drugs
Dose
mg/kg
Seizure
stage
AD
duration, s
Control
–
5.0B0.0
55.8B3.5
Diazepam
0.5
1
2
5
4.2B0.3
2.7B1.3**
1.5B0.2**
0.8B0.3**
47.5B3.6
30.1B5.6**
22.4B6.6**
16.8B4.2**
Clonazepam
0.1
0.5
1
2
4.3B0.4
1.8B0.4**
0.8B0.2**
0.5B0.2**
51.3B4.5
25.3B4.4**
14.2B3.7**
7.3B3.3**
4.7B0.2
4.2B0.3
3.7B0.3**
1.5B0.3**
54.1B2.6
47.4B3.3
27.5B3.5**
17.0B3.9**
Clorazepate
1
2
5
10
Each value represents mean B SEM (n = 6).
Significantly different from control group: * p !
0.05, ** p ! 0.01.
razepam were relatively potent (table 2).
Among the 1,4-benzodiazepines used for insomnia, the effects of nitrazepam, nimetazepam and flunitrazepam were remarkable (table 3). There were no great differences between seizure stage and AD duration for the
inhibition of kindled seizures by each drug.
ED50 Values of 1,4-Benzodiazepines on the
Amygdaloid-Kindled Seizures and Their
Chemical Structures
Figure 1 shows the ED50 values of 1,4-benzodiazepines on both seizure stage and AD
duration of amygdaloid-kindled seizures. The
ED50 values for seizure stage and AD duration of diazepam were 1.50 (1.17–1.93) and
1.30 (0.70–2.15) mg/kg, respectively. The
same potency was observed with fludiazepam, suggesting that the existence of a fluoro
group at position 2) makes a relatively small
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Table 2. Effects of 1,4-benzodiazepines used for
anxiety disorders on amygdaloid-kindled seizures
Table 3. Effects of 1,4-benzodiazepines used for
insomnia on amygdaloid-kindled seizures
Drugs
Dose
mg/kg
Seizure
stage
AD
duration, s
Drugs
Control
–
5.0B0.0
54.5B4.0
Control
Fludiazepam
0.5
1
2
5
4.8B0.2
3.3B0.4*
1.5B0.6**
0.8B0.3**
51.3B3.6
40.2B5.2
18.8B4.3**
14.3B4.9**
Flurazepam
Dose
mg/kg
–
5
10
20
50
Seizure
stage
AD
duration, s
5.0B0.0
56.5B3.4
4.8B0.2
3.5B0.3*
1.8B0.5**
0.7B0.2**
50.5B3.0
37.7B4.9*
23.5B6.4**
6.2B1.6**
Medazepam
2
5
10
20
4.2B0.5
2.5B0.3**
1.0B0.3**
0.7B0.2**
53.0B5.4
33.0B4.7**
12.3B2.8**
8.0B2.8**
Nitrazepam
0.1
0.5
1
2
4.2B0.3
2.0B0.3**
1.0B0.4**
0.2B0.2**
40.3B4.8
20.7B5.0**
11.5B4.1**
4.3B1.5**
Prazepam
5
10
20
50
5.0B0.0
4.0B0.5
1.7B0.4**
0.7B0.3**
54.2B2.1
45.2B3.6
20.2B3.5**
13.8B5.0**
Nimetazepam
0.5
1
2
5
4.7B0.2
4.0B0.5
0.8B0.3**
0.5B0.2**
52.5B3.7
39.3B5.1*
16.7B4.5**
13.0B4.3**
Flutoprazepam
5
10
20
50
4.3B0.4
3.8B0.4
2.7B0.5**
1.3B0.3**
46.8B2.5
35.3B5.4*
19.5B6.5**
15.3B5.4**
Flunitrazepam
0.5
1
2
5
4.7B0.2
2.0B0.4**
0.7B0.2**
0.3B0.2**
43.7B3.8
25.0B2.6**
9.2B3.3**
6.5B4.3**
Oxazepam
1
2
5
10
4.0B0.5
3.2B0.4**
0.7B0.3**
0.3B0.2**
49.7B6.6
40.0B4.3**
17.3B6.3**
6.2B4.0**
Lormetazepam
4.0B0.6
2.7B0.3**
2.0B0.4**
1.0B0.3**
45.8B2.9
39.7B5.9**
29.5B3.1**
11.2B4.2**
Lorazepam
1
2
5
10
4.7B0.3
2.8B0.4**
1.5B0.2**
0.5B0.2**
52.8B4.3
42.7B6.0*
19.8B2.6**
11.5B3.6**
2
5
10
20
Each value represents mean B SEM (n = 6).
Significantly different from control group: * p !
0.05, ** p ! 0.01.
Each value represents mean B SEM (n = 6).
Significantly different from control group: * p !
0.05, ** p ! 0.01.
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contribution to inhibiting amygdaloid-kindled seizures. The potency of medazepam was
less than that of diazepam. Of 1,4-benzodiazepines, prazepam, flutoprazepam and flurazepam with a long alkyl chain at position 1
were less effective than the drugs having a
methyl group (prazepam vs. diazepam; flutoprazepam, flurazepam vs. fludiazepam). The
effect of nitrazepam was about 4 times more
potent compared with that of nimetazepam,
suggesting that the replacement of a methyl
group by a hydrogen group at position 1 is
effective in increasing the anticonvulsant activity. The same relation was observed with
lorazepam and lormetazepam. Nimetazepam
and flunitrazepam, which have a nitro group
at position 7, showed more potent antiepileptic activities than the drugs having a chloro
group (nimetazepam vs. diazepam, flunitrazepam vs. fludiazepam). The ED50 values for
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Fig. 1. ED50 values (mg/kg) for 14 different 1,4-benzodiazepines on amygdaloid-kindled
seizures (seizure stage and AD duration) and their chemical structures.
Effects of Diazepam, Medazepam,
Prazepam and Nitrazepam on the
Development of Amygdaloid-Kindled
Seizures
Four compounds having different chemical structures, namely diazepam, medazepam, prazepam and nitrazepam, were chosen
to study their effects on the development of
amygdaloid-kindled seizures. The results are
shown in figures 2 and 3. In this experiment,
all animals were subjected to amygdala stimulation 1 h after each drug administration
(p.o.). Control animals developed fully kin-
1,4-Benzodiazepines and Kindling
dled (i.e., developed full stage 5) seizures by
the 15th day after initial stimulation. Drugs
were administered every day at doses which
were shown to be the ED50 for seizure inhibition in amygdaloid-kindled rats. All the drugs
used inhibited the evolution of the fully kindled seizure activity. When drug administration was stopped at day 15 (animals exhibited
stage 1 or 2 at this time), seizure stage and AD
duration gradually increased, and at day 30,
fully kindled seizures comparable to those observed in control rats were observed.
Discussion
In the present study, it was found that all
the 1,4-benzodiazepine derivatives used depressed both the seizure stage and AD dura-
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clorazepate for both parameters were 5.24
(3.78–8.50) and 4.59 (3.44–6.69) mg/kg, respectively. Oxazepam and lorazepam were
about 2 times more effective than clorazepate.
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Fig. 2. Effects of diazepam, medazepam, prazepam and nitrazepam on the development
of amygdaloid-kindled seizures (seizure stage). a [ = Control, P = diazepam 1.50 mg/kg
(p.o.). b [ = Control, P = medazepam 4.17 mg/kg (p.o.). c [ = Control, P = prazepam 15.3
mg/kg (p.o.). d [ = Control, P = nitrazepam 0.29 mg/kg (p.o.). Significantly different from
control group: * p ! 0.05, ** p ! 0.01.
Fig. 3. Effects of diazepam, nitrazepam, prazepam and nimetazepam on the development
of amygdaloid-kindled seizures (AD duration). For further explanation, see legend to figure 2.
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tion of amygdaloid-kindled seizures in a doserelated manner. In particular, clonazepam
and diazepam, which are widely used in the
treatment of epilepsy, had a potent effect on
amygdaloid-kindled seizures. On the other
hand, the effects of prazepam, flutoprazepam
and flurazepam, which are applied as anxielytic or sedative-hypnotic drugs, were less potent. Löscher and Schmidt [13] reported that
information obtained from experiments on
amygdaloid-kindled seizures is essentially
consistent with the clinical data. Our present
results support the views of Löscher and
Schmidt [13] exactly.
It is generally recognized that prazepam
and flutoprazepam have a very slow onset and
are very long acting in humans [14, 15]. However, as shown in this study, the peak effects
for both prazepam and flutoprazepam were
observed 1 h after administration. Therefore,
it seems likely that large differences would be
found between human beings and rats for
Tmax and T½.
In this study, it was revealed that when a
long alkyl chain was introduced to position 1
of the 1,4-benzodiazepines, the anticonvulsant effect was extremely reduced. The same
finding was reported by Babbini et al. [16] in
an anti-pentetrazol test, where introduction of
a longer side chain to position 1 reduced the
potency. Babbini et al. [16] also demonstrated
that there was no remarkable difference between a hydrogen group and methyl group at
position 1 for anti-pentetrazol activity. However, in the present amygdaloid-kindled seizures, the compounds having a hydrogen
group at position 1 had a more potent effect
than the compounds with a methyl group at
the same position (lorazepam vs. lormetazepam; nitrazepam vs. nimetazepam). Loew et
al. [17] reported that the existence of hydrogen and methyl groups is important for receptor affinity.
It is clear from the present findings that
medazepam is less effective than diazepam.
The same finding was reported by Loew et al.
[17] in a mouse anti-pentetrazol test. They
demonstrated that medazepam has a very low
receptor activity, indicating that an oxygen
group at position 2 is the most important condition for high affinity. Comparing the activity of clorazepate with that of oxazepam, clorazepate was found to exhibit a less potent anticonvulsant activity than that of oxazepam.
Oxazepam has a hydroxy group at position 3,
whereas clorazepate has a carboxyl group at
the same position.
It can be seen that nimetazepam and flunitrazepam were more potent than diazepam
and fludiazepam, respectively. Sternbach et
al. [18] reported that variation of the substituents at position 7 does not have a consistent effect on potency from the findings
that similar effects were found for 7-chloro-,
7-bromo-, 7-trifluoromethyl-, or 7-nitro-substituted compounds on anti-pentetrazol activity. On the contrary, Loew et al. [17] described that 1,4-benzodiazepines with a nitro
group at position 7 had a more potent anticonvulsant activity than the compounds having a chloro group at the same position. The
reason for the necessity of the existence of a
nitro group at position 7 is obscure, but it
seems likely that the presence of these groups
enhances receptor binding.
Babbini et al. [19] reported that halogen
substitution at position 2) always enhances
the potency of the anxielytic effects. Sternbach et al. [18] also described in a mouse antipentetrazol test that compounds having a
fluoro group at position 2) were generally
more potent than those having a hydrogen or
chloro group at the same position. As shown
in the present study, however, introduction of
a fluoro or chloro group was ineffective in
causing a high anticonvulsant activity in
amygdaloid-kindled seizures (diazepam vs.
1,4-Benzodiazepines and Kindling
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fludiazepam; prazepam vs. flutoprazepam;
nimetazepam vs. flunitrazepam; oxazepam
vs. lorazepam).
However, diazepam, clorazepate, medazepam, prazepam, flunitrazepam, nimetazepam
and flurazepam are easily metabolized and
these metabolites are also active. Therefore, it
seems likely that in the whole animal study,
the structure activity relationships may not be
so simple.
As shown in figures 2 and 3, amygdaloid
kindling was markedly delayed by certain 1,4benzodiazepines, suggesting that these drugs
have a prophylactic effect. In addition, it was
found that when drug administration was
stopped, rats required an almost equal
amount of stimulation to produce fully kindled seizures as control animals. The prophylactic effect of diazepam against amygdaloid
kindling in the rat has been reported previously by Schwark and Haluska [20], i.e., chronic
treatment with diazepam (2 mg/kg i.p.) markedly inhibits kindling-induced epileptogenesis. Racine et al. [21] also found a definite
retardation of kindling by diazepam at doses
of 0.5 and 1.0 mg/kg. In this study, it was
revealed that prazepam also possessed a prophylactic effect, though its inhibitory effect on
fully kindled seizures was extremely weak.
Therefore, it seems likely that the prophylactic effects observed in certain 1,4-benzodiazepines used in the present study are applicable
to all 1,4-benzodiazepine derivatives.
In conclusion, the existence of a hydrogen
or methyl group at position 1 and a nitro
group at position 7 are important for exhibiting a potent anticonvulsant activity in amygdaloid-kindled seizures. Introduction of an
oxygen group at position 2 is also essential for
high activity. 1,4-Benzodiazepines had not
only therapeutic but also prophylactic effects
on amygdaloid-kindled seizures.
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References
240
5 Albertson TE, Peterson SL, Stark
LG: Anticonvulsant drugs and their
antagonism of kindled amygdaloid
seizures in rats. Neuropharmacology 1980;19:643–652.
6 Kamei C, Oka M, Masuda Y, Yoshida K, Shimizu M: Effects of 3-sulfamoylmethyl-1,2-benzisoxazole (AD810) and some antiepileptics on the
kindled seizures in the neocortex,
hippocampus and amygdala in rat.
Arch Int Pharmacodyn Thér 1981;
249:164–176.
7 Löscher W, Hönach D, Hashem A:
Anticonvulsant efficacy of clonazepam and the ß-carboline ZK93423
during chronic treatment in amygdala-kindled rats. Eur J Pharmacol
1987;143:403–414.
Pharmacology 1998;57:233–241
8 Tietz EI, Rosenberg HC, Chin TH:
A comparison of the anticonvulsant
effect of 1,4- and 1,5-benzodiazepines in the amygdala-kindled rats
and their effect on motor function.
Epilepsy Res 1989;3:31–40.
9 Wise RA, Chinerman J: Effects of
diazepam and phenobarbital on
electrically induced amygdaloid seizures and seizure development. Exp
Neurol 1974;45:355–363.
10 Morita Y, Shinkuma D, Shibagaki
N, Miyoshi K: Effect of benzodiazepine derivatives on amygdaloid-kindled convulsion. Folia Psychiatr
Neurol 1982;36:391–399.
11 de Groot J: The rat forebrain in stereotaxic coordinates. Trans R Neth
Acad Sci 1959;52:1–40.
12 Racine RJ: Modification of seizure
activity by electrical stimulation. II.
Motor seizure. Electroencephalogr
Clin Neurophysiol 1972;32:281–
294.
Fukinaga/Ishizawa/Kamei
Downloaded by:
University of Florida, Gainesville and Jacksonville
128.227.24.141 - 10/28/2017 10:31:42 PM
1 Goddard GV, McIntyre DC, Leech
CK: A permanent change in brain
function resulting from daily electrical stimulation. Exp Neurol 1969;
25:295–330.
2 Sato M, Racine RJ, McIntyre DC:
Kindling: Basic mechanisms and
clinical validity. Electroencephalogr
Clin Neurophysiol 1990;76:459–
472.
3 Sieghart W: Structure and pharmacology of Á-aminobutyric acid a receptor subtypes. Pharmacol Rev
1995;47:181–234.
4 Morimoto K, Sanei T, Sato K: Comparative study of the anticonvulsant
effect of Á-aminobutyric acid agonists in the feline kindling model of
epilepsy. Epilepsia 1993;34:1123–
1129.
SIBY
13 Löscher W, Schmidt D: Which animal models should be used in the
search for new antiepileptic drugs?
A proposal based on experimental
and clinical considerations. Epilepsy
Res 1988;2:145–181.
14 Breimer DD, Jochemsen R, von Albert HH: Pharmacokinetics of benzodiazepines. Short-acting versus
long-acting. Arzneimittelforschung
1980;30:875–881.
15 Barzaghi N, Leone L, Monteleone
M, Tomasini G, Perucca E: Pharmacokinetics of flutoprazepam, a novel
benzodiazepine drug, in normal
subjects. Eur J Drug Metab Pharmacokinet 1989;14:293–298.
1,4-Benzodiazepines and Kindling
16 Babbini M, Torrielli MV, Gaiardi
M, Bartoletti M, de Marchi F: Central effects of three fluorinated benzodiazepines in comparison with
diazepam. Pharmacology 1974;12:
74–83.
17 Loew GH, Nienow JR, Poulsen M:
Theoretical structure-activity studies of benzodiazepine analogues requirement for receptor affinity and
activity. Mol Pharmacol 1984;26:
19–34.
18 Sternbach LH, Archer GA, Earley
JV, Fryer RI, Reeder E, Wasyliw N:
Quinazolines and 1,4-benzodiazepines. XXV. Structure-activity relationships of amino alkyl-substituted
1,4-benzodiazepin-2-ones. J Med
Chem 1965;8:815–821.
19 Babbini M, Gaiardi M, Bartoletti
M: Anxiolytic versus sedative properties in the benzodiazepines series:
Differences in structure-activity relationships. Life Sci 1979;25:15–22.
20 Schwark WS, Haluska M: Prophylaxis of amygdala kindling-induced
epileptogenesis: Comparison of a
GABA uptake inhibitor and diazepam. Epilepsy Res 1987;1:63–69.
21 Racine RJ, Livingston K, Joaquin
A: Effects of procaine hydrochloride, diazepam, and diphenylhydantoin on seizure development in cortical and subcortical structures in
rats. Electroencephalogr Clin Neurophysiol 1975;38:355–365.
Pharmacology 1998;57:233–241
241
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