Faculty of Pharmaceutical Sciences, Kyushu University, Higashiku,
Fukuoka 812-8582, Japan
Recently, clinical cases of parkinsonism due to antiarrhythmics drugs
amiodarone and aprindine and a local anesthetic drug procaine have been
reported. We performed both in vivo and in vitro experiments to quantitatively predict the intensity of
catalepsy by these drugs and haloperidol in mice. Haloperidol showed
the most potent relative intensity of catalepsy, followed by aprindine, metoclopramide, tiapride, amiodarone and procaine, in that order. In vivo dopamine D1 and D2
receptor occupancies of the six drugs to the striatum were observed.
In vitro binding affinity
(Ki) of these drugs to the
D1 and D2 receptors in the striatum
synaptic membrane was within the range of 60 nM to 706 µM, 0.5 nM to
75 µM and 860 nM to 115 µM, respectively. A good correlation
between the relative intensity of drug-induced catalepsy and the
Ki values for the dopamine
D1 and D2 receptors was obtained
(r = .911 and r = .896, respectively; P < .05). The
partial tertiary structure of the tested drugs was well superimposed on
that of haloperidol. In conclusion, these drug-induced catalepsies were due to the blockade of the D1 and D2 receptors,
which was related to the analogous tertiary structures
(diethylaminoethyl side chain).
 |
Introduction |
It
is generally known that antipsychotic drugs, such as phenothiazine
derivatives and butyrophenone derivatives, induce the parkinsonism as a
serious side effect in clinical practice. It is very important to
predict the intensity of the drug-induced parkinsonism because its
progress is rapid and the patients' quality of life become worse.
Besides antipsychotic drugs, flunarizine and cinnarizine, used in the
treatment of cerebral blood flow disturbances, induce parkinsonism
(Chouza et al., 1986
; Kuzuhara et al., 1989;
Negrotti and Calzetti, 1997). Recently, it has been reported that
amiodarone (fig. 1) and aprindine,
antiarrhythmic drugs, and procaine, a local anesthetic, induced
parkinsonism (Dotti and Federico, 1995; Itou et al., 1996,
Marti Masso et al., 1993; Gjerris, 1971). The structures of
amiodarone, aprindine and procaine possess a highly similar in
diethylaminoethyl side chain like metoclopramide (fig. 1) and tiapride,
which belong to the benzamide derivatives and selectively block
dopamine D2 receptors. It was suggested that
these structures were involved in the induction of drug-induced
parkinsonism (Itou et al., 1996). It is likely that the
drug-induced parkinsonism is mainly due to the blocking of dopamine
receptors in the striatum by administrated drugs, although the
detailed mechanism of drug-induced parkinsonism is unclear (Gershanik,
1994).
In this study, we quantitatively estimated the occurrence of catalepsy
induced by amiodarone, aprindine and procaine as an index of the
behavioral pharmacological effect in mice (Sanberg et al.,
1988; Haraguchi et al., 1997, 1998). Moreover, it has been
reported that the drug-induced parkinsonism and catalepsy are related
to the specific binding to the dopamine D1 and
D2 receptors (Wanibuchi and Usuda, 1990) and mACh
receptor (Ushijima et al., 1997) in the brain. In this
study, the in vivo specific binding affinity and in
vitro occupancies to the dopamine D1, D2 and mACh receptors were estimated to predict
the intensity of catalepsy induced by drugs. Ogawa et al.
(1990) analyzed the tertiary structures of various drugs using computer
graphics and compared the structure of haloperidol and pimozide,
typical dopamine receptor blockers, and flunarizine. In this study, we
compared the tertiary structures of amiodarone, aprindine, procaine,
metoclopramide and tiapride with that of haloperidol according to the
method of Ogawa et al. and found a similar side chain in
these six drugs.
| |
Materials and Methods |
Animals.
Male ddY mice, 5 weeks old, weighing 25 to 30 g, were purchased from Seac Yoshitomi Co. (Fukuoka, Japan).
Drugs.
The following drugs were kindly gifted from the
respective companies: amiodarone hydrochloride (Taisho Pharmaceutical
Co., Tokyo, Japan); aprindine hydrochloride (Mitsui Pharmaceutical Company, Tokyo, Japan); haloperidol and biperiden hydrochloride (Dainippon Pharmaceutical Company, Osaka, Japan); tiapride
hydrochloride and metoclopramide (Fujisawa Pharmaceutical Co., Osaka,
Japan); nemonapride (Yamanouchi Pharmaceutical Co., Tokyo, Japan);
propantheline bromide (Monsanto, Co., Osaka, Japan). Procaine
hydrochloride and Clea-sol I as a scintillation cocktail were purchased
from Nakalai Tesque (Kyoto, Japan), atropine sulfate monohydrate from Wako Pure Chemical Industries (Osaka, Japan) and
(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine [(R)-(+)-SCH23390] hydrochloride from Funakoshi Co.
(Tokyo, Japan). [3H]SCH23390 (specific
activity, 70.3 Ci/mmol), [3H]raclopride
(specific activity, 79.3 Ci/mmol) and
[3H]L-quinuclizinyl benzilate
([3H]QNB, specific activity, 49.0 Ci/mmol) were
purchased from NEN Research Products (Boston, MA) and SOLVABLE from
Packard. All other chemicals used in the experiments were of analytical grade.
Preparation of drug solutions.
In the in vivo
study, amiodarone hydrochloride and biperiden were dissolved in
distilled water. Metoclopramide was dissolved in 1 N HCl and then
neutralized with 1 N NaOH and diluted with saline. Haloperidol was
dissolved in 0.3% tartaric acid and diluted with saline. Aprindine
hydrochloride, procaine hydrochloride, tiapride hydrochloride,
propantheline bromide and atropine sulfate were dissolved in saline.
The unlabeled drugs were injected into a volume of 2.5 ml/kg for
intravenous administration and a volume of 10 ml/kg for other
administration, and the solvent alone was used as a control.
In the in vitro study, aprindine hydrochloride, procaine
hydrochloride, tiapride hydrochloride and (R)-(+)-SCH23390
were dissolved in distilled water. Amiodarone hydrochloride was
dissolved in 10% ethanol. Haloperidol, metoclopramide and nemonapride
were dissolved in 0.3% tartaric acid.
Measurement of intensity of catalepsy.
Measurement of
catalepsy was performed according to the method of Fujiwara (1992) and
Haraguchi et al. (1997). Amiodarone hydrochloride (10-200
mg/kg), aprindine hydrochloride (5-30 mg/kg), procaine hydrochloride
(10-150 mg/kg), metoclopramide (1-25 mg/kg), tiapride hydrochloride
(10-50 mg/kg) or haloperidol (0.05-0.5 mg/kg) was intraperitoneally
injected. Control animals were administered with the respective solvent
alone under the same conditions. Catalepsy was assessed at 0.5, 1.5, 3 and 4.5 hr after administration of the drugs by the bar method; the
front paws were gently placed on a horizontal metal bar with 2 mm in
diameter suspended 4 cm above, and the length of time (in sec) the
mouse maintains this abnormal posture was measured. The measurement of
catalepsy was performed by an observer who did not prepare the drug
solutions according to the double-blind method.
Effects of central and peripheral anticholinergic drugs on
catalepsy.
Amiodarone hydrochloride (200 mg/kg), aprindine
hydrochloride (30 mg/kg), procaine hydrochloride (150 mg/kg),
metoclopramide (25 mg/kg), tiapride hydrochloride (50 mg/kg) or
haloperidol (0.5 mg/kg) was intraperitoneally injected. Catalepsy was
measured at 60 min after the injection of each drug under the same
conditions as in the section on "Measurement of intensity of
catalepsy" and then 10 mg/kg of biperiden, a central anticholinergic
drug, or 2.5 mg/kg of propantheline, a peripheral anticholinergic drug, were administered subcutaneously or intravenously, respectively. After
the injection of biperiden or propantheline, catalepsy was measured
every hour for 3 hr.
In vivo dopamine D1,
D2 and mACh receptor occupancy.
Measurement of in vivo receptor occupancy was performed
according to the method of Haraguchi et al. (1997). Each
drug or vehicle was administered to mice under the same conditions as
in the section on "Measurement of intensity of catalepsy." At 85 min after the administration of haloperidol and at 25 min after the
administration of the other drugs, D1-selective
antagonist [3H]SCH23390 (2 µCi/body),
D2-selective antagonist
[3H]raclopride (2 µCi/body) or mACh specific
antagonist [3H]QNB (2 µCi/body) was injected
intravenously. After 10 min, the mice were decapitated, and the
striatum and cerebellum were dissected on a glass plate. Each sample
was weighed in a vial, added to 1 ml of SOLVABLE and incubated at
50°C until it became a clear solution; 0.2 ml of 30%
H2O2 was then added, and
the vial was left at room temperature overnight. It was neutralized
with 70 µl of 6 N HCl and 10 ml of Clea-sol I was added. The
radioactivities were measured in a liquid scintillation counter
(LS6500, Beckman).
Dopamine and mACh receptor occupancies were calculated according to
equations 1 and 2, respectively:
|
(1)
|
where A and B are the ratio of radioactivities
(striatum/cerebellum) in the presence or absence of drugs,
respectively. The cerebellum was utilized as dopamine receptor-free
region to estimate the nonspecific binding of ligands.
|
(2)
|
where A' and B' are the radioactivities in the striatum in the
presence or absence of drugs, respectively. C is the nonspecific binding that was determined by subcutaneous administration of nonlabeled atropine (50 mg/kg) at 25 min before the administration of
[3H]QNB.
In vitro dopamine D1,
D2 and mACh receptor binding study.
Preparation of the membrane sample was performed according to the
method of Meltzer et al. (1989) and Haraguchi et
al. (1998). The mice were decapitated, and the striatum was
rapidly dissected. After weighing, homogenates of striatal tissue from
mice were prepared in 100 volumes (w/v) of ice-cold 50 mM Tris-HCl
buffer (pH 7.4) with a Teflon-on-glass tissue homogenizer. The
homogenates were centrifuged (20,000 × g for 10 min at 4°C)
twice with intermediate resuspension in ice-cold 50 mM Tris-HCl buffer
(pH 7.4). The final pellets were resuspended in 200 and 300 volumes
(w/v) of the buffer for dopamine and mACh receptor, respectively.
Aliquots of the membrane preparations were incubated with each drug and
0.3 nM [3H]SCH23390 (for
D1 receptor binding) or 1 nM
[3H]raclopride (for D2
receptor binding) for 15 min at 37°C in 50 mM Tris-HCl buffer (pH
7.4) containing (in millimolar): NaCl, 120; KCl, 5;
CaCl2, 2; and MgCl2, 1. For
mACh receptor binding, aliquots of the membrane preparations were
incubated with each drug and 0.2 nM [3H]QNB for
30 min at 37°C in 50 mM Tris-HCl buffer (pH 7.4). The final tissue
concentrations were 1 mg of the original wet weight tissue per 1 ml for
D1 and D2 receptor binding
and 2 mg/3 ml for mACh receptor binding. The amounts of protein in the
cells were measured by Lowry's methods (Lowry et al.,
1951).
The incubation was terminated by rapid pouring of the contents of the
tubes over Whatman GF/C glass fiber filters under vacuum. The filters
were rinsed twice with 5 ml of ice-cold 50 mM Tris-HCl buffer (pH 7.4)
and placed in glass scintillation vials; then 8 ml of Clea-sol I was added.
Nonspecific binding was determined in the presence of 100 nM SCH23390,
1 µM nemonapride and 1 µM atropine for D1,
D2 and mACh receptor binding, respectively.
Ki values were calculated according to the
following equation:
|
(3)
|
where R is the specific binding ratio (ratio of
[3H]count in the presence of drugs to that in
the absence of drugs), and D is the concentration of
[3H]ligand, I is the concentration of the drugs
as inhibitors and Kd is the
dissociation constant of the [3H]ligand
obtained from Scatchard analysis of saturation experiment data. Data
analysis and simulations used the nonlinear least-squares method MULTI
(Yamaoka et al., 1981).
The tertiary structures analysis of drugs using computer
graphics.
The tertiary structures of each drug were analyzed by a
Macintosh, using program CAChe by Sony Tectolonics (Tokyo, Japan). The
tertiary structures of each drug were superimposed on that of
haloperidol, and a highly similar side chain was found by eye-fit.
Statistical analysis.
Statistical analysis was performed by
Student's t-test. Statistical significance was considered
at a P value of <.05.
| |
Results |
In vivo induction of catalepsy.
Time courses of
the intensity of catalepsy induced by various doses of amiodarone
aprindine, procaine, matoclopramide, tiapride and haloperidol after
intraperitoneal injection are shown in figure 2, A-F. The intensities of drug-induced
catalepsy at 30 min after the administration were dose dependent (fig.
3). Drugs-induced catalepsy was observed
for several hours in all of the test drugs with a difference in dose
dependency among the drugs. The relative intensity was defined as the
ratio of the inverse of the dose at 20 sec as intensity of catalepsy in
various drugs to that of haloperidol (fig. 3). The relative intensity
of haloperidol, amiodarone, aprindine, procaine, metoclopramide and
tiapride was 1.0, 0.002, 0.01, 0.0005, 0.02 and 0.03, respectively
(table 1).
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Fig. 2.
Time courses of catalepsy induced by 6 drugs. The
intensity of catalepsy was assessed at 0.5, 1.5, 3 and 4.5 hr for (A)
amiodarone, (B) aprindine, (C) procaine, (D) metoclopramide, (E)
tiapride and (F) haloperidol after i.p. administration. The catalepsy
was measured as described in Materials and Methods. Data are mean ± S.E. (n = 6-10).
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Fig. 3.
Dose-dependent induction of catalepsy.  ,
amiodarone-induced,  , aprindine-induced,  , procaine-induced,  ,
metoclopramide-induced,  , tiapride-induced and  ,
haloperidol-induced catalepsy 30 min after i.p. administration. Data
are mean ± S.E. (n = 6-10).
|
|
Effect of central and peripheral anticholinergic drugs on
catalepsy.
Biperiden, a central anticholinergic drug, completely
reduced the catalepsy induced by any tested drugs to the base line
level (fig. 4, A-F). However, there was
no change in catalepsy in the presence of propantheline, a peripheral
anticholinergic drug (fig. 5, A-F).
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Fig. 4.
Effect of biperiden on drug-induced catalepsy.
Biperiden (10 mg/kg; ) or the solvent alone () was administrated
60 min after i.p. administration of (A) amiodarone (200 mg/kg), (B)
aprindine (30 mg/kg), (C) procaine (150 mg/kg), (D) metoclopramide (25 mg/kg), (E) tiapride (50 mg/kg) and (F) haloperidol (0.5 mg/kg). Data
are mean ± S.E. (n = 5-6). Significant
differences from the drug alone (*P < .05).
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Fig. 5.
Effect of propantheline on drug-induced catalepsy.
Propantheline (2.5 mg/kg; ) or the solvent alone () was
administrated 60 min after i.v. administration of (A) amiodarone (200 mg/kg), (B) aprindine (30 mg/kg), (C) procaine (150 mg/kg), (D)
metoclopramide (25 mg/kg), (E) tiapride (50 mg/kg) and (F) haloperidol
(0.5 mg/kg). Data are mean ± S.E. (n = 3). No
significant differences from the drug alone.
|
|
In vivo dopamine D1,
D2 and mACh receptor occupancy and
catalepsy.
The intensities of catalepsy measured at 30 min after
the administration of amiodarone (200 mg/kg), aprindine (30 mg/kg), procaine (150 mg/kg), metoclopramide (25 mg/kg) or tiapride (50 mg/kg)
and at 90 min after the administration of haloperidol (0.5 mg/kg) and
in vivo dopamine D1,
D2 and mACh receptor occupancies of the various
drugs are shown in table 1. The in
vivo occupancies to both D1 and
D2 receptors were 2% to 89% with any drug.
Moreover, the in vivo occupancies to the mACh receptor were
10% to 57%, except for aprindine, tiapride and haloperidol with low
occupancies (0-10%).
In vitro dopamine D1,
D2 and mACh receptor binding affinity to
striatum nervous membrane.
Figure 6
shows the inhibition curves for the in vitro binding of
dopamine D1, D2 or mACh
receptor-selective radioligands to the striatum membrane in the
presence of tested drugs. The Kd
values of [3H]SCH23390,
[3H]raclopride and
[3H]QNB obtained by the Scatchard analysis were
0.22, 1.0 and 0.075 nM, respectively. The calculated
Ki values are listed in table 2. The Ki
values of the tested drugs to dopamine D1,
D2 and mACh receptor were over a range of 60 nM
to 706 µM, 0.5 nM to 75 µM and 860 nM to 115 µM, respectively.
Aprindine showed strong binding affinity to the
D1 receptor next to haloperidol. Haloperidol, metoclopramide, tiapride and aprindine showed very strong binding affinity to the D2 receptor. For the mACh
receptor, metoclopramide, tiapride and haloperidol showed significantly
weak binding affinity as compared with that to the dopamine
D1 and D2 receptors,
although aprindine, amiodarone and procaine exhibited binding affinity to the mACh receptor comparable with that to the dopamine
D1 and D2 receptors.
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Fig. 6.
Inhibition curves for binding of (A)
[3H]SCH23390, (B) [3H]raclopride and (C)
[3H]QNB to mouse striatal membranes in the presence of
amiodarone (), aprindine (), procaine (), metoclopramide
(), tiapride () or haloperidol (). Data are mean ± S.E.
(n = 3).
|
|
Relationship between in vitro Ki
values for dopamine D1 or
D2 receptor and the relative intensity of
catalepsy.
As shown in figure 7, the
in vivo relative intensities of drug-induced catalepsies
(table 1) were significantly correlated with in vitro
Ki values for the dopamine
D1 or D2 receptor (r = .911 or r = .896, respectively, P < .05).
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Fig. 7.
Relationship between
Ki values for dopamine (A)
D1 or (B) D2 receptor and relative
intensity. Relative intensity is the ratio of the inverse of dose of
various drugs at 20 sec as catalepsy to that of haloperidol (relative
intensity; n = 6-10,
Ki values; n = 3).
|
|
The tertiary structures superimposed analysis of drugs by computer
graphics.
As shown in figure 8, the
tertiary structures of amiodarone, aprindine, procaine, metoclopramide
and tiapride were superimposed on that of haloperidol. Good fitting on
the closed part (diethylaminoethyl side chain) was obtained, indicating
that there was a high similarity among the drugs.
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Fig. 8.
Tertiary structures of amiodarone, aprindine,
procaine, metoclopramide, tiapride and haloperidol and their
superimposition among test drugs and haloperidol by computer graphics
as described in Materials and Methods.
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| |
Discussion |
It is well known that the antipsychotic drugs chlorpromazine and
haloperidol, and drugs used in the treatment of cerebral blood flow
disturbances such as flunarizine and cinnarizine, induce parkinsonian
side effects (Chouza et al., 1986; Kuzuhara et
al., 1989; Negrotti and Calzetti, 1997). Recently, it was reported that antiarrhythmic drugs amiodarone and aprindine and local anethetic drug procaine induced parkinsonism (Dotti and Federico, 1995; Itou
et al., 1996; Marti Masso et al., 1993; Gjerris
et al., 1971). We understood this investigation to predict
the intensity of parkinsonism induced by these drugs using catalepsy as
an index of behavioral pharmacology. In vivo and in
vitro specific binding to the dopamine D1,
D2 receptor and mACh receptor was also
investigated to predict the intensity of catalepsy induced by drugs.
Moreover, a comparison of the tertiary structures among the drugs was performed.
Antipsychotic drugs, including haloperidol, induced catalepsy in a
dose-dependent manner (Ossowska et al., 1990; Haraguchi et al., 1997). We found that catalepsy was also induced by
amiodarone, aprindine, procaine, metoclopramide and tiapride in a
dose-dependent manner (figs. 2 and 3).
To confirm whether the observed catalepsies were caused by enhanced
cholinergic central nervous system, the effects of a central anticholinergic agent biperiden (Yokogawa et al., 1986),
which was transported into the brain in vivo (Syvalahti
et al., 1987), on those drugs that induced catalepsies were
investigated after subcutaneous administration. The catalepsies induced
by the tested drugs were almost completely reduced in the presence of
biperiden (fig. 4, A-F). However, the peripheral anticholinergic drug
propantheline (Davis et al., 1983) did not reduce
catalepsies (fig. 5, A-F). These results suggested that the observed
catalepsy was due to the enhanced cholinergic central nervous system by
the blockade of the dopaminergic receptor.
The in vivo and in vitro binding assay of the six
drugs to the dopamine D1,
D2 and the mACh receptor was carried out (tables 1 and 2). The previously reported in vitro
Ki value of haloperidol in rats was 76 nM for
the D1 receptor (Andersen, 1988), and 2.6 nM
(Andersen, 1988) and 4.0 nM (Syvalahti, 1988) for the
D2 receptor. The Ki
of metoclopramide was 150 nM for the D2 receptor
(Syvalahti, 1988). Tiapride showed high binding affinity (114 nM) for
the D2 receptor (Woodward et al.,
1994), although it scarcely bound to the D1
receptor (Arima et al., 1986). The
Ki of amiodarone was 6.5 µM for the mACh
receptor in the rat brain (Cohen-Armon et al., 1984). The
Ki of procaine was 3.8 µM for the mACh
receptor in the rat hippocampus (Sharkey et al., 1988). Our
findings in this study in mice were almost in agreement with these
results. Each drug used in this study blocked both the
D1 and D2 receptor based on
in vivo and in vitro experiments, suggesting that
dopamine D1 and D2
receptors were related to this drug-induced catelepsy as drug-induced
parkinsonism. Because there was a possibility to reduce the catalepsy
by binding as an antagonist to the mACh receptor, we measured mACh
receptor binding. Procaine showed both in vivo and in
vitro binding to the mACh receptor (tables 1 and 2), suggesting
that procaine-induced catalepsy may be reduced by the mACh receptor blockade.
The in vivo relative intensity of drugs-induced catalepsy
significantly correlated with in vitro Ki
values for the dopamine D1 or
D2 receptor, suggesting that the
D1 and D2 receptors were intensely involved in the catalepsy in mice. These findings indicated that parkinsonism by amiodarone, aprindine and procaine in humans was
due to the dopaminergic neural system blockade.
The occurrence mechanism of aprindine-induced tremor was similar to
that of drugs used as local anesthetics such as lidocaine, and it was
considered that aprindine might suppress GABA release from the
inhibitory GABA neuron (Kamiya et al., 1985). Therefore, not
only the blockade of the dopaminergic neural system but also the
blockade of the GABAergic system might be involved in the tremor. It
was reported that the GABA receptor binding in the substantia nigra was
significantly decreased in the brains of subjects with Parkinson's
disease (Rinne et al., 1978; Lloyd et al., 1991).
The GABAergic neurons were involved in dopaminergic functional control
in the basal ganglia, which agrees with earlier reports (Gerlach
et al., 1996; Rosales et al., 1997), and
hypofunctions of the GABAergic system may play a role in the generation
of L-dopa-induced dyskinesia (Nishino et al., 1984). It was
also reported that stimulation of GABAA receptors
in the substantia nigra pars reticulata could block tacrine-induced
tremulous jaw movements (Finn et al., 1997); the
GABAA receptor was significantly up-regulated in
dyskinetic monkeys after chronic levodopa or D2
agonist administration (Calon et al., 1995). Therefore, a
loss of the GABAergic system was involved in human Parkinson's disease
(Kawabata and Tachibana, 1997). Moreover, serotonin
5-HT2 receptor antagonists have been reported to
reduce catalepsy (Balsara et al., 1979; Hicks, 1990;
Neal-Beliveau et al., 1993). Clozapine, an atypical
neuroleptic, scarcely induced extrapyramidal adverse effects, although
there was the specific binding to both D1 and
D2 receptors. This discrepancy was explained by
its relatively potent antagonistic activity in central serotonergic receptor functions (Meltzer et al., 1989; Okuyama et
al., 1997; Andree et al., 1997). Therefore, the
contribution of 5-HT2 receptor binding should be
taken into consideration for drugs that have a high affinity for the
5-HT2 receptor. The binding affinity of haloperidol to the 5-HT2 receptor measured using
[3H]spiperone is 46 nM (Okuyama et
al., 1997), 95 nM (Terai et al., 1989) in rats and 36 nM in humans (Wander et al., 1987), respectively.
It is known that drug-induced parkinsonism has a similar structure
(Ogawa et al., 1990). To function as dopamine
D2 receptor antagonist, the aminoethyl moiety at
the N-alkyl substituent of the amide side chain is contained and the
methoxy moiety at the 2-position of the benzoyl substituent is
necessary (Pannatiar et al., 1981). There were many reports
about the conformational analysis between the N-alkyl substituent of
the amide side chain and the methoxy moiety at the 2-position of the
benzoyl substituent (van de Waterbeemd and Testa, 1983), tertiary
structures of aminoethyl moiety (Pettersson and Liljefors, 1992) and
structure-activity relationship in various N-alkyl substituents of the
amide side chain to antidopaminergic activity (Usuda, 1987). However,
there were few reports about the diethylaminoethyl substituent for
metoclopramide or tiapride. Harrold et al. (1993) reported
that metoclopramide and sulpiride required a basic nitrogen atom in
their charged molecular form for binding the D2
receptor, and then differences in their biological profiles did not
appear to be due to any appreciable differences in the binding of the
basic nitrogen atom. The tertiary structure of amiodarone, aprindine
and procaine is similar to that of metoclopramide and tiapride in the
position of the diethylaminoethyl substituent (figs. 1 and 8). These
findings suggested that the diethylaminoethyl substituent might be
involved in the antidopaminergic activity. In the future, it would be
necessary to investigate the conformational analysis between the
dopamine D2 receptor and the interaction of each
drug as antagonists.
Drugs that possess the diethylaminoethyl group or a similar structure
to that may possibly to induce catalepsy and/or parkinsonism. For
example, a clinical case of parkinsonism by an anticancer drug
cyclophosphamide, possessing a similar structure has been recently
reported (Fleming and Mangino, 1997). The risk of induction of
parkinsonism may be increased when antipsychotics as dopamine antagonists are used concurrently. Thus, the occurrence of drug-induced parkinsonism may be partially predicted from the tertiary structures of drugs.
In conclusion, the occurrence of catalepsy by amiodarone, aprindine and
procaine was mainly caused by the blockade of the dopaminergic
D1 and D2 receptors and the
enhancement of the central cholinergic nervous system. The importance
of possessing a part of an analogous structure to haloperidol, the
diethylaminoethyl substituent was suggested. Moreover, a good
correlation between the in vivo relative intensity of
drugs-induced catalepsy and in vitro Ki
values for the dopamine D1 or
D2 receptor indicated that the in vivo
intensity of catalepsy could be predicted from in vitro
receptor binding affinity. Thus, the intensity of catalepsy and
parkinsonism may be predicted from both the biochemical and physicochemical information on drugs.
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Abstract
Introduction
-aminobutyric acid.
