N-palmitoylethanolamide derivatives: Synthesis and studies on anticonvulsant and antidepressant activities

Article abstract of DOI:10.1007/s00044-010-9357-7

A series novel of N-palmitoylethanolamide derivatives was synthesized and screened for their anticonvulsant and antidepressant activities. Anticonvulsant activities and neurotoxicities of compounds when injected intraperitoneally (i.p.) were determined by maximal electroshock seizure (MES) test and a rotarod test, respectively, in mice. Only four of the synthesized compounds (3a, 3b, 3c, and 3d) showed anticonvulsant activity at a dose of 100 mg/kg. Six compounds showed reduced immobility durations during the forced swimming test at a dose of 10 mg/kg, indicative of antidepressant activity. Among the compounds, N-(3-hydroxypropyl)cinnamamide (3a) was the most promising compound and significantly reduced the duration of immobility duration by 23.36% at a dose of 10 mg/kg compared with the control (P<0.01). Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9357-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:601–606
DOI 10.1007/s00044-010-9357-7
ORIGINAL RESEARCH
N-palmitoylethanolamide derivatives: synthesis
and studies on anticonvulsant and antidepressant
activities
•
Li-Ping Guan Xin Sui Xian-Qing Deng
•
•
•
Dong-Hai Zhao You-Le Qu Zhe-Shan Quan
•
Received: 20 November 2009 / Accepted: 3 May 2010 / Published online: 25 May 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series novel of N-palmitoylethanolamide
derivatives was synthesized and screened for their anti-
convulsant and antidepressant activities. Anticonvulsant
activities and neurotoxicities of compounds when injected
intraperitoneally (i.p.) were determined by maximal elec-
troshock seizure (MES) test and a rotarod test, respectively,
in mice. Only four of the synthesized compounds (3a, 3b,
3c, and 3d) showed anticonvulsant activity at a dose of
100 mg/kg. Six compounds showed reduced immobility
durations during the forced swimming test at a dose of
10 mg/kg, indicative of antidepressant activity. Among the
compounds, N-(3-hydroxypropyl)cinnamamide (3a) was
the most promising compound and significantly reduced
the duration of immobility duration by 23.36% at a dose of
10 mg/kg compared with the control (P \ 0.01).
Introduction
N-Palmitoylethanolamide (PEA) belongs to a family of
endogenous lipid amides, of which anandamide is a well-
known member (Bachur et al., 1965; Schmid et al., 1990).
Lambert et al. (2001) reported the effects of PEA on
electroshock-induced convulsion in mice and found dose-
dependent protection against maximal electroshock seizure
(MES) at nontoxic doses.
In our previous studies, we synthesized a series of N-(2-
hydroxyethyl) amide derivatives and tested them for their
anticonvulsant activities (Guan et al., 2009a, b). Among
this series, the compounds N-(2-hydroxyethyl) palmita-
mide (I), N-(2-hydroxyethyl) stearamdie (II), and N-(2-
hydroxyethyl)cinnamamide (III) (Fig. 1) were found to
show a better anticonvulsant activity and also had lower
toxicity. In the anti-MES potency test, these compounds
exhibited median effective doses (ED50) of 23.3, 20.5, and
17.7 mg/kg, respectively (Guan et al., 2009a, b).
Keywords N-palmitoylethanolamide derivatives ꢀ
Anticonvulsant activity ꢀ Antidepressant activity
As part of our continuous efforts in this area, a series of
new PEA derivatives have been synthesized according to
Scheme 1 and evaluated for their anticonvulsant activities
by using the MES test. Seizure assays and neurotoxicity
were evaluated by the rotarod toxicity test according to the
phase-I tests of Antiepileptic Drug Development (ADD)
program which were developed by the National Institute of
Neurological and Communicative Disorders and Stroke
L.-P. Guan (&) ꢀ Y.-L. Qu
Food and Pharmacy College, Zhejiang Ocean University,
Zhoushan 316004, Zhejiang, People’s Republic of China
e-mail: glp730@zjou.edu.cn; glp730@yahoo.com.cn
¨
(NINCDS) (Schafer 1985; Krall et al., 1978).
In addition, it is reported that the cinnamamide deriva-
tives exhibit a variety of biological activities, such as cen-
tral nervous depression, anticonvulsant, and antidepressant
activities (Moffet, 1964; Balsamo et al., 1975; Van Heyn-
ingen et al., 1966). Therefore, antidepressant activities of
the synthesized compounds were also determined using
Porsolt’s behavioral despair (forced swimming) test
L.-P. Guan ꢀ X. Sui ꢀ X.-Q. Deng ꢀ Z.-S. Quan (&)
College of Pharmacy, Yanbian University, Yanji 133000, Jilin,
People’s Republic of China
e-mail: zsquan@yub.edu.cn
D.-H. Zhao
Jilin Medical College, Jilin 132013, Jilin,
People’s Republic of China
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Med Chem Res (2011) 20:601–606
O
O
OH
OH
NH
NH
I
II
O
OH
N
H
III
Fig. 1 Structure of I, II, and III
O
Scheme 1 Synthesis of
compounds 1a–c, 2a–c,
and 3a–d
O
ClCOOCH
R
R
3
+
1
2
1
HN
R
N
R
OH
R
R2
1a-c, 2a-c
R
R1
H
R2
1a
C15H31
OH
OH
1b
C15H31
OH
1c
2a
C15H31
C17H35
H
OH
2b
2c
C17H35
CH3
OH
C17H35
O
C
O
C
R
1
ClCOOCH
R
OH
3
1
2
N
+
HN
R
R
2
3a-d
R1
H
R2
CH3
3a
OH
3b
3c
CH3
CH3
OH
3d
General procedure for the preparation
(Raiendra Prasad et al., 2005). The synthesized compounds
1
were characterized by IR, H-NMR, and MS.
of (1a–c, 2a–c, 3a–d)
In a three-necked round-bottomed flask containing substi-
tuted carboxylic acid (0.05 mol), 50 ml dichlorme-thane
and triethylamine (0.1 mol), methyl chloroformate
(0.1 mol) was added dropwise slowly under an ice bath with
stirring; the mixture was stirred for 2 h at room temperature.
Then, ethanolamine (0.1 mol) was added dropwise slowly
under an ice bath with stirring; the mixture was stirred
8–10 h at room temperature. The solvents were removed
under reduced pressure. The residue was poured into
100 ml ice water and stirred for 10 min. The precipitate
thus obtained after filtration was recrystallized in hot water
to afford a white color solid (Guan et al., 2009a, b).
Experimental
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on a
1
FT-IR1730 (Bruker, Switzerland), H-NMR spectra were
measured on an AV-300 (Bruker, Switzerland), and all the
chemical shifts were given in ppm relative to tetrame-
thysilane. Mass spectra were measured on an HP1100LC
(Agilent Technologies, USA). The major chemicals were
purchased from Aldrich Chemical Corporation. All other
chemicals were of analytical grade.
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Med Chem Res (2011) 20:601–606
603
N-(3-hydroxypropyl)palmitamide (1a)
N-(3-hydroxypropyl)cinnamamide (3a)
Yield = 82%, mp: 96–98°C. IR (KBr) cm-1: 1712 (C=O),
3090 (NH), 3320 (OH). H-NMR (CDCl3): 0.87 (t, 3H,
Yield = 57%, mp: 91–92°C. IR (KBr) cm-1: 1709 (C=O),
3127 (NH), 3315 (OH). H-NMR (CDCl3): 1.74 (m, 2H,
1
1
J = 6.9 Hz, CH3), 1.26–1.69 (m, 26H, (CH2)13), 1.85 (m,
2H, CH2), 2.19 (t, 2H, J = 7.5 Hz, CH2CO), 3.40 (m, 2H,
CH2), 3.48 (s, 1H, OH), 3.63 (m, 2H, CH2), 5.95 (s, 1H,
NH). C19H39NO2. MS: m/z 314 (M ? 1).
CH2), 3,49 (s, 1H, OH), 3.58 (t, 2H, –CH2NHCO), 3.68 (t,
2H, –CH2OH), 6.40 (d, 1H, J = 15.6 Hz, =CHCO), 7.65
(d, 1H, J = 15.6 Hz, CH=C), 7.36–7.51 (m, 5H, –C6H5).
C12H15NO2. MS: m/z 206 (M ? 1).
N,N-dimethylcinnamamide (3b)
N,N-bis(2-hydroxyethyl)palmitamide (1b)
Yield = 52%, mp: 101–103°C. IR (KBr) cm-1: 1705
(C=O), 1172 (C–N). 1H-NMR (CDCl3): 3.08 (s, 3H, CH3),
3.18 (s, 3H, CH3), 6.90 (d, 1H, J = 15.5 Hz, =CHCO),
7.68 (d, 1H, J = 15.5 Hz, CH=C), 7.36–7.55 (m, 5H,
–C6H5). C11H13NO. MS : m/z 176 (M ? 1).
Yield = 67%, mp: 89–91°C. IR (KBr) cm-1: 1705
(C = O), 1123 (C–N), 3317 (OH). 1H-NMR (CDCl3): 0.88
(t, 3H, J = 6.4 Hz, CH3), 1.25-1.63 (m, 26H, (CH2)13),
2.39 (t, 2H, J = 7.6 Hz, CH2CO), 3.50 (t, 2H, J = 6.0 Hz,
CH2), 3.56 (t, 2H, J = 6.0 Hz, CH2), 3.61 (s, H, OH), 3.65
(s, H, OH), 3.79 (t, 2H, J = 6.0 Hz, CH2), 3.85 (t, 2H,
J = 6.0 Hz, CH2). C20H41NO3. MS: m/z 344 (M ? 1).
N-(2-hydroxyethyl)-N-methylcinnamamide (3c)
Yield = 56%, mp: 96–97°C. IR (KBr) cm-1: 1698 (C=O),
1120 (C–N), 3309 (OH). H-NMR (CDCl3): 3.25 (s, 3H,
N,N-diethylpalmitamide (1c)
1
Yield = 75%, oil. 1H-NMR (CDCl3): 0.87 (t, 3H,
J = 6.5 Hz, CH3), 1.08–1.19 (m, 6H, (CH3)2), 1.25–1.65
(m, 26H, (CH2)14), 2.28 (t, 2H, J = 7.7 Hz, CH2CO),
3.26–3.40 (m, 4H, (CH2)2). C20H41NO. MS: m/z 312
(M ? 1).
CH3), 3.41 (s, 1H, OH), 3.68 (m, 2H, –CH2NCO), 3.85 (m,
2H, –CH2OH), 6.88 (d, 1H, J = 15.4 Hz, =CHCO), 7.71
(d, 1H, J = 15.4 Hz, CH=C), 7.38–7.52 (m, 5H, –C6H5).
C12H15NO2. MS: m/z 206 (M ? 1).
N,N-diethylcinnamamide (3d)
N-(3-hydroxypropyl)stearamide (2a)
Yield = 47%, mp: 86–87°C. IR (KBr) cm-1: 1706 (C=O),
1124 (C–N); 1H-NMR (CDCl3): 1.23 (m, 6H, (CH3)2), 3.49
(m, 4H, (CH2)2), 6.82 (d, 1H, J = 15.4 Hz, =CHCO), 7.72
(d, 1H, J = 15.4 Hz, CH=C), 7.36–7.54 (m, 5H, –C6H5).
C13H17NO. MS: m/z 204 (M ? 1).
Yield = 79%, mp: 90–92°C. IR (KBr) cm-1: 1709 (C=O),
3209 (NH), 3324 (OH). H-NMR (CDCl3): 0.87 (t, 3H,
1
J = 6.9 Hz, CH3), 1.64 (m, 2H, CH2), 1.24–1.68 (m, 30H,
(CH2)15), 2.18 (t, 2H, J = 7.5 Hz, CH2CO), 3.37 (m, 2H,
CH2), 3.41 (s, 1H, OH), 3.63 (m, 2H, CH2), 5.99 (s, 1H,
NH). C21H43NO2. MS: m/z 342 (M ? 1).
Anticonvulsant activity
The MES test and the rotarod test were carried out
according to the standard protocols described in the ADD
Program of the National Institute of Neurological and
N-(2-hydroxyethyl)-N-methylstearamide (2b)
Yield = 63%, mp: 96–97°C. IR (KBr) cm-1: 1684 (C=O),
1176 (C–N), 3326 (OH). H-NMR (CDCl3): 0.87 (t, 3H,
¨
Communicative Disorders and Stroke (NINCDS) (Schafer,
1
1985; Krall et al., 1978). All the compounds were tested for
anticonvulsant activities with Kunming mice in the 18–
25 g weight range purchased from the Laboratory of Ani-
mal Research, College of Pharmacy, Yanbian University.
Mice were housed collectively in groups of 10 in poly-
carbonate cages. They were maintained on a 12-h light/
dark cycle in a temperature-controlled (23 2°C) labora-
tory. Food and water were available ad libitum. The tested
compounds were prepared as a suspension in a 0.5%
aqueous solution of methylcellulose and injected i.p. in a
standard volume of 0.05 ml/20 g body weight.
J = 6.3 Hz, CH3), 1.25–1.63 (m, 30H, (CH2)15), 2.33 (t,
2H, J = 7.6 Hz, CH2CO), 3.06 (s, 1H, OH), 3.46 (m, 3H,
CH3), 3.55 (m, 2H, CH2), 3.77 (m, 2H, CH2). C21H43NO2.
MS: m/z 342 (M ? 1).
N,N-diethylstearamide (2c)
Yield = 71%, oil. 1H-NMR (CDCl3): 0.86 (t, 3H,
J = 6.7 Hz,CH3), 1.06–1.18 (m, 6H, (CH3)2), 1.24–1.64
(m, 30H, (CH2)15), 2.27 (t, 2H, J = 7.3 Hz, CH2CO),
3.25–3.39 (m, 4H, (CH2)2). C22H45NO. MS : m/z 340
(M ? 1).
In Phase-I screening (Table 1), each compound was
administered at the dose levels of 30, 100, and 300 mg/kg
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Med Chem Res (2011) 20:601–606
Table 1 Phase-I evaluation of anticonvulsant activity in mice (i.p.)
Compounds
MESa
1/2 h
mg kg-1
30
Toxicityb
1/2 h
4 h
4 h
mg kg-1
30
mg kg-1
30
mg kg-1
100
300
100
300
100
300
30
100
300
I
2/3
3/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
3/3
3/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
1/3
2/3
3/3
3/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
3/3
3/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
0/3
1/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
1/3
1/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
3/3
3/3
3/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
II
III
1a
1b
1c
2a
2b
2c
3a
3b
3c
3d
a
Maximal electroshock test (number of animals protected/number of animals tested)
b
Rotarod toxicity test (number of animals exhibiting toxicity/number of animals tested)
for evaluating the anticonvulsant activity, and its neuro-
aqueous solution of methylcellulose injected i.p. in a
standard volume of 0.05 ml/20 g body weight, 30 min
prior to the test. Control animal received 0.5% aqueous
solution of methylcellulose. Then, the mice were dropped
individually into the pelxiglass cylinder and left in the
water for 6 min. After the first 2 min of the initial vigorous
struggling, the animals were immobile. A mouse was
judged immobile if it floated in the water in an upright
position and made only slight movements to prevent
sinking. The duration of immobility was recorded during
the last 4 min of the 6 min test.
toxicity was measured at 30-min and 4-h intervals after
administration. Anticonvulsant efficacy was measured in
the MES test. In the MES test, seizures were elicited with a
60-Hz alternating current of 50 mA intensity in mice. The
current was applied via corneal electrodes for 0.2 s. The
protection against the spread of MES-induced seizures was
defined as the abolition of the hind leg and tonic maximal
extension component of the seizure. Anticonvulsant drug-
induced neurologic deficit was detected in mice by using the
rotorod ataxia test on a 1-inch diameter knurled wooden rod,
rotating at 6 rpm.
Statistical analysis
Antidepressant activity
Results are expressed as mean S.E.M.; n represents the
number of animals. Data obtained from pharmacological
experiments were analyzed with one-way analysis of var-
iance (ANOVA) followed by Dunnet’s post hoc test, using
Pharmacologic Calculation System Version 4.1. (Micro-
computer Specialists). A P-value of less than 0.05 was
considered statistically significant.
The synthesized compounds were screened for their anti-
depressant activities using Porsolt’s behavioral despair
(forced swimming) test (Raiendra Prasad et al., 2005)
Local breed, male Kunming mice (20–24 g) were used in
the forced swimming test under standard conditions with
free access to food and water. They were housed in groups
of six. On the test day, mice were dropped one at a time
into a plexiglass cylinder (height 25 cm, diameter 10 cm)
containing 10 cm of water at 23–25°C (Porsolt et al.,
1977). On this day, mice were assigned into different
groups (n = 8–10 for each group). The synthesized com-
pounds (10 mg/kg) and fluoxetine as a reference antide-
pressant drug (10 mg/kg) were suspended in a 0.5%
Results and discussion
Target compounds were prepared according to Scheme 1.
Compounds 1a–c, 2a–c, and 3a–d were obtained in good
yield through a one-step reaction using substituted
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Med Chem Res (2011) 20:601–606
605
carboxylic acid, methyl chloroformate, triethyl amine, and
ethanolamine as the starting material. Reaction mixture
was maintained at room temperature for 8–10 h. All the
compounds were identified by the spectral data (Guan
et al., 2009a, b). In general, IR spectra showed the C=O
peak at 1684–1712 cm-1, the NH stretching vibrations at
3090–3209 cm-1, the C–N stretching vibrations at 1098–
1176 cm-1, and the OH stretching vibrations at 3309–
3326 cm-1. In the nuclear magnetic resonance spectra
(1H-NMR), the signals of the respective protons of the
synthesized compounds were verified on the basis of their
chemical shifts, mutiplicities, and coupling constants. The
spectra showed the amide (NH) proton as a singlet at 5.30–
5.99 ppm, and the hydroxyl proton (OH) at 3.06–3.65 ppm.
Pharmacological tests of the PEA derivatives 1a–c, 2a-
c, and 3a–d were conducted at the Epilepsy Branch of the
National institute of Neurological Disorders and Stroke
(NINDS) following the protocol adopted by the ADD
compounds’ neurotoxicity was not observed at a dose of
300 mg/kg (Table 1).
Analyzing the anticonvulsant activities of the synthe-
sized compounds 1a–c, 2a–c, and 3a–d, the following SAR
was gained (Table 1). Compounds I (N-(2-hydroxyethyl)
palmitamide) and II (N-(2-hydroxyethyl) stearamdie)
showed activity against MES-induced seizures at 30 mg/kg
dose level, however, compounds 1a–c and 2a–c had not
shown anticonvulsant active at a dose of 300 mg/kg. These
results indicated that the N atom of compounds I and II
with
a
substituted N-(3-hydroxypropyl)-, N,N-bis(2-
hydroxyethyl)-, N,N-diethyl-, and N-(2-hydroxyethyl)-N-
methyl- had not shown anticonvulsant activity. However,
compounds 3a–d showed significant anticonvulsant activ-
ity, in which the N atom of compound III was substituted
with a N-(3-hydroxypropyl)-, N,N-dimethyl-, N,N-diethyl-,
and N-(2-hydroxyet-hyl)-N-methyl-.
The forced swimming test is a behavioral test used to
predict the efficacy of antidepressant treatments. It is used
effectively in predicting the activity of a wide variety of
antidepressants such as MAO inhibitors and atypical anti-
depressants (Porsolt, 1981). It has good predictive value for
antidepressant potency in humans (Willner, 1991). The
obtained data on the antidepressant activity of the com-
pounds (1a–c, 2a–c, and 3a–d) and reference drug (Flu-
oxetine) are given in Table 2. The results showed that
N-(2-hydroxyethyl)cinnamamide (III), N,N-bis(2-hydroxy-
ethyl)palmitamide (1b), N-(2-hydroxyethyl)-N-methyl-
stearamide (2b), N,N-dimethylcinnamamide (3b), and
¨
program (Schafer, 1985; Krall et al., 1978).
The anticonvulsant activities of the synthesized com-
pounds were investigated by MES, and results from these
experiments are shown in Table 1. According to the results
of the experiments, it is clear that anticonvulsant activities
of all compounds were weak. Only N,N-dimethylcinn-
amamide (3b), N-(2-hydroxyethyl)-N-methylcinnamamide
(3c), and N,N-diethylcinnamamide (3d) exhibited activity
against MES-induced seizures at 100 mg/kg dose level.
Only compounds 3b, 3c, and 3d showed neurotoxicity at a
dose of 300 mg/kg, while with the remaining synthesized
Table 2 Antidepressant activities of the compounds
Compounds
Dose (mg/kg)
Antidepressant activities
Duration of immobility(s)
(mean S.E.M.)
Change from control (%)
I
10
10
10
10
10
10
10
10
10
10
10
10
10
10
–
126.0 9.0
-6.25
-5.65
II
126.8 5.3
III
99.6 14.7*
104.6 19.9
99.0 18.5*
111.1 17.7
115.5 18.5
104.8 13.7*
109.6 18.5
103.0 11.8**
107.8 15.1*
123.1 15.7
109.9 9.7*
81.5 12.8***
134.4 24.4
-25.89
-22.17
-26.34
-17.34
-14.06
-22.02
-18.45
-23.36
-19.97
-8.41
1a
1b
1c
2a
2b
2c
3a
3b
3c
3d
-18.23
-39.36
–
Fluoxetine
Control
Values represent the mean S.E.M. (n = 8)
Significantly compared to control (Dunnet’s test: * P \ 0.05, ** P \ 0.01, *** P B 0.001)
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the most promising compound and significantly reduced
the duration of immobility by 23.36% at a dose of
10 mg/kg compared with the control (P \ 0.01); it is
similar to reference drug fluoxetine.
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Conclusion
In conclusion, the results of this study demonstrated that
four of the synthesized compounds (3a–d) have anticon-
vulsant activities. However, the synthesized compounds
have also possessed remarkable antidepressant activities.
Therefore, they may be really promising compounds for
the treatment of depression. In fact, N-(3-hydroxypro-
pyl)cinnamamide (3a) was the most promising compound
and significantly reduced the duration of immobility by
23.36% at a dose of 10 mg/kg compared with the control
(P \ 0.01); it is similarly to reference drug fluoxetine.
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Kumar P (2005) Synthesis and antidepressant activity of some 1, 3,
5-triphenyl-2-pyrazolines and 3-(200-hydroxy naphthalen-100-yl)-1,
5-diphenyl-2-pyrazolines. Bioorg Med Chem Lett 15:5030–5034
¨
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Acknowledgment This study was supported by the National Nat-
ural Science Foundation of China (No. 30960458).
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