НЕЙРОХИМИЯ, 2011, том 28, № 4, с. 323-327
ЭКСПЕРИМЕНТАЛЬНЫЕ РАБОТЫ
YM 577
PYRROLE ANALOGUES OF PHENCYCLIDINE DECREASE FOOD AND WATER CONSUMPTION IN MICE
© 2011 J. Solati"*, A. Ahmadi4, S. Pakzad4, A. A. Salaric
aDepartment of Biology, Islamic Azad University, Karaj Branch, Karaj, Iran bDepartment of Chemistry, Faculty of Science, Islamic Azad University, Karaj Branch, Karaj, Iran cIslamic Azad University, Tehran North Branch, Department of Biology, Tehran, Iran
Abstract — Various studies have shown that Phencyclidine (1-[1-phenylcyclohexyl] piperidine, PCP, I) and many of its analogues demonstrate pharmacological effects. In this paper effects of some new pyrrole derivatives of, (1-[1-phenylcyclohexyl] pyrrole I, II, and 1-[1-[4-methylphenyl][cyclohexyl]]-pyrrole III) on food and water intake in mice were investigated. Animals were deprived for 24 h before initial of each test for food and water intake evaluation. PCP and its derivatives were injected intraperitoneally (i.p.) and then in 1—12 h and 30—180 min post-injection, the treated groups were measured for food and water intake, respectfully. The results obtained from the present study show that the pyrrole derivatives of PCP (II and III), decrease food and water intake in the deprived mice dramatically in comparison with the vehicle treated control groups. Our results suggest that the pyrrole derivatives of phencyclidine (II and III) affect those parts of central nervous systems that are involved in feeding behavior.
Keywords:phencyclidine, pyrrole derivatives, food intake, water intake, mice.
INTRODUCTION
Phencyclidine (1 - [ 1 -phenylcyclohexyl] piperidine, I, PCP Scheme 1) was originally introduced as a general anesthetic agent, but it was subsequently withdrawn from using in humans because of severe psycho-mimetic side effects [1]. The focus of research on PCP has shifted from its use as an anesthetic towards potential applications as a neuropharmaceutical agent [2].
PCP primarily binds to the N-methyl-D-asparate (NMDA) receptor complex and blocks the conductance of NMDA-mediated gating of the calcium channel [3, 4]. However, various studies showed that different receptors in the central nervous system such as dopaminergic, seretonergic, and nicotinic cholin-ergic systems are involved in the modulation of behavioral effect of PCP and its analogues. All of the above mentioned neural systems are main parts of central systems that are involved in control of different behaviors including food and water intake [5—8].
Obesity is a health problem that is reaching epidemic proportions and is associated with a significant morbidity rate. Obesity and its associated pathologic features are major causes of illness and death worldwide. In the United States, obesity accounts for 280000 deaths annually, and at current rates of increase, it will supplant smoking as the primary cause of preventable death. Considering that relatively few
* Corresponding author: Department of Biology, Islamic Azad University, Karaj Branch, Karaj, Iran.
P.O.Box:31485-313,Karaj, Iran. Tel: 0261-4436978, Fax: 02614418156, e-mail: solati@kiau.ac.ir.
therapeutic approaches have been successful in inducing body weight loss in obese individuals, and also surgery has been shown to be of use only in some selected patients, it is clearly recognized that even moderate weight loss confers significant health benefits [9, 10].
Previous studies demonstrated that PCP and its analogues alter food and water intake in deprived and non-deprived animals [11, 12]. Because of some pharmacological properties of Pyrrole derivatives and effective physiologic activity of these analogues of PCP [13], in the present study, effects of the new pyrrole derivatives of PCP on food and water intakes were evaluated.
METHODS AND MATERIALS
Preparations of the Derivatives
1-[1-phenylcyclohexyl]piperidine (PCP) I. This compound was prepared in 58% yield from 1-piperid-inocyclohexanecarbonitrile (IV) and phenyl magnesium bromide according to a well-known procedure. The hydrochloride salt of I (m.p. 233—234°C) was prepared using 2-propanol and HCl, and then was re-crystallized from 2-propanol [14].
1-[1-phenylcyclohexyl]pyrrole (PCP-Pyrrole) II.
This compound was prepared from 1-pyrrolecyclo-hexanecarbonitrile (V) and phenyl magnesium bromide according to a known procedure. The hydrochloride salt of II was prepared using 2-propanol and HCl, and then was recrystallized from 2-pro-panol [13].
323
5*
1 - [ 1 - [4-methylphenylcyclohexyl] Pyrrole (Me-PCP-Pyrrole) III. Finally, this compound was prepared from 1-pyrrolecyclohexanecarbonitrile (V) and 4-methylphenyl magnesium bromide according to a known procedure. The hydrochloride salt of II was prepared using 2-propanol and HCl and was recrystal-lized from 2-propanol [13] Scheme 1.
IV
NC^
III
Scheme 1. Structure formulas of PCP (I), PCP-Pyrrole (II), Me- PCP-Pyrrole (III) and intermediates IV and V.
Animals
NMRI mice (Pasteur's Institute, Tehran), weighing 25—30 g were randomly housed at the beginning of the experiment; four per cage in a temperature-controlled colony room with a 12:12 h light/dark cycle (lights on 07:00—19:00 h) .Animals were given free access to water and standard laboratory rat chow (Pars Company, Tehran, Iran). All behavioral experiments were carried out between 11am and 4pm under normal room light and at 25°C. All animals were injected by one investigator and evaluated by another experimenter. This study was carried out in accordance with the guidelines set forth in the Guide for the Care and Use of Laboratory Animals (NIH) and those of the Research Council of Islamic Azad University.
The cumulative food and water intake were measured (1—12 h for food and 30—180 min for water) after administration of the drugs.
Food intake Evaluation
After a one-week period of habituation to new housing conditions, in order to evaluate the drug effects on the food intake, animals were deprived of food for 24 h (mice were fasted in separate cages with free access to water). Animals were divided into four equal groups and then were intraperitoneally (i.p) administered with the drugs (I—III) of different doses (1, 5, and 10 mg/kg, dissolved in 0.2ml DMSO) following the fasting period. Control group received equal volume of saline. Each mouse was immediately returned to its cage after injection and a weighed hopper of food was placed in the cage. The amount of consumed cumulative food (standard laboratory mice chow) was measured (1—12 h) after injection of the solutions [5, 15, 16].
Water Intake Evaluation
In order to evaluate the drug effects on food intake, mice were put in the separate metabolic cages at least 7 days before the initial of the experiments. The amount of water ingested in various experiments was measured with 0.1 ml graduated glass burettes adapted with a metal drinking spout. Thirst was induced by water deprivation during the 24 h preceding the experiment. All groups of animals received the i.p. administration of PCP and the derivatives of three doses (1, 5 and 10 mg/kg; 0.2 ml DMSO). Control group received equal volume of DMSO. Each mouse was returned to its cage immediately after the injection and the cumulative water intake was subsequently measured within 30—180 min after the solutions administrations [15, 17, 18].
Statistical Methods
Since data distributed normally and showed homogeneity of variance, one-way ANOVA and Tukey post hoc test (SPSS package) were used for comparing the effects of different doses of derivatives with control group. All graphs related to the results were drawn using the Microsoft excel software. The significance level of P < 0.05 was applied for all of the statistical tests.
I
Drug Injections
At the beginning of the experiment, the animals received the i.p. administration the experiment drugs (I—III) of different doses (1, 5, and 10 mg/kg dissolved in 0.2 ml DMSO) or an equivalent volume of DMSO (in control group). Number of mice (n) in each group was 10.
RESULTS
Results of the study demonstrated that the i.p. injection of pyrolle derivatives of phencyclidine (II, III) (1, 5 and 10 mg/kg) in the food deprived rats, drastically decrease food consumption in comparison with the control group (Figs. 2 and 3). However, food deprived animal showed no changes in food intake after PCP treatments (Fig. 1).
PYRROLE ANALOGUES OF PHENCYCLIDINE DECREASE FOOD
325
3.0 г 2.5
ад
о 2.0
м
ce
.S L5
13 § 1.0 F 0.5
0
control
5 10
PCP doses, mg/kg
3.0
2.5
g
e, 2.0 k
.S 1.5 d
g 1.0 F 0.5
control 1 5 10
PCP-Pyrrole doses, mg/kg
Fig. 1. Effects of i.p. injection of PCP (1, 5 and 10 mg/kg; 0.2 ml) or DMSO (0.2 ml) on cumulative food intake (12 h post-injection) in 24 h food deprived rats. Data expressed as the mean ± SEM (n = 6).
Fig. 2. Effects of i.p. injection of PCP-Pyrrole (1, 5 and 10 mg/kg; 0.2ml) or DMSO (0.2 ml) on cumulative food intake (12 h post-injection) in 24 h food deprived rats. Data expressed as the mean ± SEM (n = 6). **P < 0.01 and ***P < 0.001.
0
1
3.0 г 2.5 2.0 1.5 1.0 0.5 0
H T
1 1
control 1 5 10
Me-PCP-Pyrrole doses, mg/kg
Fig. 3. Effects of i.p. injection of Me-PCP-Pyrrole (1, 5 and 10 mg/kg; 0.2ml) or DMSO (0.2 ml) on cumulative food intake (12 h post-injection) in 24 h food deprived rats. Data expressed as the mean ± SEM (n = 7). ***P < 0.001.
3.5 3.0
S 2.5
e,
"ce 2.0
•S 1.5 r
e
at1.0 0
control
5 10
PCP doses, mg/kg
Fig. 4. Effects of i.p. injection of PCP (1, 5 and 10 mg/kg; 0.2 ml) on cumulative water intake (180 min post-injection), in 24 h water deprived rats. Data expressed as the mean ± SEM (n = 6).
1
When these derivatives were injected into the intra-peritonea of the 24-h water-deprived rats, a significant dose-dependent water intake decrease, compared with the control group was obtained (Figus. 5 and 6).
Water deprived rats showed no significant changes in water intake after administration of PCP (1, 5, and 10 mg/kg) (Fig. 4)
Для дальнейшего прочтения статьи необходимо приобрести полный текст. Статьи высылаются в формате PDF на указанную при оплате почту. Время доставки составляет менее 10 минут. Стоимость одной статьи — 150 рублей.