Synthesis and antinociception properties of phencyclidine derivatives with modified aromatic or cycloalkyl rings and amino group

Article abstract of DOI:10.1007/s00706-015-1472-1

Phencyclidine is an arylcyclohexylamine compound which has received a lot of investigative attention due to the complex spectrum of behaviours and its complicated interactions with the central nervous system. Phencyclidine administration may act as stimulant, depressant, hallucinogen, and analgesic depending on dose and tested species. In this study, new phenyl and thienyl analogues with specific affinity for the phencyclidine sites in NMDA receptors, dopamine uptake blocking, or both of them were synthesized. The acute and chronic pain properties of these compounds were studied using the tail immersion and formalin tests on mice and the results were compared with control and phencyclidine groups at a dose of 10 mg/kg. The outcomes indicated that all synthesized compounds showed better activities to decrease acute thermal and chemical, but not chronic pains. Also, these effects were more significant for phenyl (group 1) compared to thiophene (group 2) analogues, which is probably due to the higher affinity of group 1 for inhibition of dopamine reuptake compared to binding to the phencyclidine sites in NMDA receptors in this family.

Full text of DOI:10.1007/s00706-015-1472-1

Monatsh Chem
DOI 10.1007/s00706-015-1472-1
ORIGINAL PAPER
Synthesis and antinociception properties of phencyclidine
derivatives with modified aromatic or cycloalkyl rings and amino
group
1
3
1
•
Abbas Ahmadi
Mohsen Pooladi
Babak Nahri-Niknafs
•
Mohsen Khalili
Fatemeh Bakhtiari
•
Mahnaz Barzin
1
2
1
•
•
•
Maede Barjeste
1
Received: 16 January 2015 / Accepted: 22 March 2015
Springer-Verlag Wien 2015
ꢀ
Abstract Phencyclidine is an arylcyclohexylamine com-
pound which has received a lot of investigative attention
due to the complex spectrum of behaviours and its com-
plicated interactions with the central nervous system.
Phencyclidine administration may act as stimulant, de-
pressant, hallucinogen, and analgesic depending on dose
and tested species. In this study, new phenyl and thienyl
analogues with specific affinity for the phencyclidine sites
in NMDA receptors, dopamine uptake blocking, or both of
them were synthesized. The acute and chronic pain prop-
erties of these compounds were studied using the tail
immersion and formalin tests on mice and the results were
compared with control and phencyclidine groups at a dose
of 10 mg/kg. The outcomes indicated that all synthesized
compounds showed better activities to decrease acute
thermal and chemical, but not chronic pains. Also, these
effects were more significant for phenyl (group 1) com-
pared to thiophene (group 2) analogues, which is probably
due to the higher affinity of group 1 for inhibition of
dopamine reuptake compared to binding to the phency-
clidine sites in NMDA receptors in this family.
Graphical abstract
Ar
Amine
R
Keywords Phencyclidine Á NMDA receptors Á
Dopamine reuptake blocking Á Tail immersion test Á
Formalin test
Introduction
Phencyclidine (1-(1-phenylcyclohexyl)piperidine, 9a) was
originally considered for humans as an anaesthetic, but was
soon striated due to its psychotomimetic properties, which
include prolonged thought, visual disturbances, and agita-
tion [1]. As a result, the scope of research on phencyclidine
has shifted from its use as an anaesthetic compound to
potential applications as a neuropharmaceutical [2]. It
correlates with some neurotransmitter systems in the cen-
tral nervous system. For instance, it is a noncompetitive
antagonist of the N-methyl-D-aspartate (NMDA) subtype of
the glutamate receptor, and it leads to the release and in-
hibits the reuptake of monoaminergic neurotransmitters, as
well as dopamine, serotonin, and norepinephrine [3].
In addition to binding to the NMDA receptors, it also
interferes with other brain functions. It blocks muscarinic
and nicotinic acetylcholine receptors [4] as well as
&
Abbas Ahmadi
ahmadikiau@yahoo.com
1
2
3
Department of Medicinal Chemistry, Pharmaceutical
Sciences Branch, Islamic Azad University, Tehran, Iran
Department of Chemistry, Faculty of Science, Karaj Branch,
Islamic Azad University, Karaj, Iran
Neurophysiology Research Center, Shahed University,
Tehran, Iran
123

A. Ahmadi et al.
preventing neuronal depolarization at the aspartate-sensi-
tive glutamate receptor [5]. It also binds to one of the
several types of opiate receptors (sigma) on nerve cell
membranes [6]. Up to now, many analogues of 9a have
been prepared and their pharmacological properties inves-
tigated [7–12].
Scheme 1
Furthermore, the unique pharmacology of 9a has already
resulted in several structure–activity studies which have
been researched in terms of its 3-cycle system; an aromatic
cycle producing an area of negative charge, a basic hete-
rocyclic nitrogen cycle bearing a localized positive charge,
and a lipophilic cycloalkyl cycle. Alternations on these
moieties could create many novel analogues with extensive
biological activities [13].
Compound
Ar
Amine
Piperidine
R
H
H
9a
9b
9c
9d
9e
Phenyl
Phenyl
Memantine
Phenyl
Memantine
CH
3
Therefore, as the first step a methyl group with high
electron donating and dipole moment characters [9, 11, 12]
were added on 4-position of the cyclohexyl ring to provide
Phenyl
Pseudoephedrine
Cyclohexylamine
N-Methylcyclohexylamine
Memantine
H
Phenyl
H
9c and 9h of specifically binding to phencyclidine sites in
the NMDA receptors [14].
9f
Phenyl
H
Second, because of many pharmacological effects of 3,5-
dimethyladamantan-1-amine (memantine), such as NMDA
9g
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
H
receptor antagonist [15], agonist of the dopamine D re-
2
9h
Memantine
CH3
H
ceptor [16], local analgesic against cutaneous nociceptive
stimuli [17], and treatment of moderate-to-severe Alzhei-
mer’s disease [18], it was used instead of the piperidine ring
of 9a to provide analogues 9b, 9c, 9g, and 9h. In addition,
this amine moiety was replaced by cyclohexylamines (cy-
clohexylamine and N-methylcyclohexylamine) and
pseudoephedrine with analgesic and many other pharmaco-
logical properties [19, 20] for synthesizing derivatives 9d,
9
i
j
Pseudoephedrine
Cyclohexylamine
N-Methylcyclohexylamine
9
H
9k
H
9
e, 9f, 9i, 9j, and 9k.
Third, due to the reports on specific high binding affinity
Grignard reagents 7, 8 and substituted a-aminonitriles 1–6
(Schemes 2, 3). This method is easy to use when the final
products are tertiary amines [22]. In the first step of this
reaction, a-aminocarbonitrile intermediates 1–6 were pre-
pared by the reaction of cyclohexanone or
4-methylcyclohexanone, amine (piperidine, memantine,
pseudoephedrine, cyclohexylamine, or N-methylcyclohexyl-
amine), KCN, and sodium bisulfite [23]. This compound
and selectivity for the phencyclidine sites in NMDA re-
ceptors, as well as neuroprotective potential properties of
thienylcyclidine (1-[1-(2-thienyl)cyclohexyl]piperidine) [7]
which was intended to replace the phenyl in 9a by a
bioisosteric 2-thienyl ring, this modification was also done
for investigation on analgesic effects for all newly synthe-
sized analogues with phenyl (group 1: compounds 9b–9f) or
thienyl (group 2: compounds 9g–9k) rings (Scheme 1).
Finally, antinociception activities of these compounds
were measured on mice using the tail immersion (acute
thermal pain model) and the formalin (acute chemical and
chronic pains model) tests and the outcomes are com-
pared with the control and phencyclidine groups.
(NaHSO ) coordinates with the cyclohexanone (or 4-
3
methylcyclohexanone), thus increasing its aqueous solubility
and furthermore promoting nucleophilic attack [24].
Then 9a–9k were obtained by the reaction of these
carbonitriles with Grignard reagents 7, 8. Nucleophilic at-
tack of the Grignard reagent upon carbonitriles does not
occur at the nitrile carbon, as in the classical sense [25] but
does occur at the electron-deficient carbon alpha to the
nitrile [26].
Results and discussion
Chemistry
For increasing the rate of reaction in the final step, the
molar ratio of Grignard reagents to carbonitriles were in-
creased. This higher ratio could also increase the yield of
reaction between these compounds to form the desired
1
13
Phencyclidine (9a) and its analogues 9b–9k were synthe-
sized via Bruylants method [21], by the reaction between
analogues 9a–9k. Spectroscopic (IR, H and C NMR,
mass) and elemental (CHN) data confirmed their structures.
1
23

Synthesis and antinociception properties of phencyclidine…
Scheme 2
O
H
N
NC
NC
N
NaHSO3
KCN
+
1
O
R
NH2
NH
NaHSO3
KCN
+
2
: R=H
R
3: R=CH3
Fig. 1 Analgesic effect of 9a–9k on pain threshold time produced by
tail immersion test. Bars show the mean ± SEM pain thresholds in
animal groups. Asterisk and dollar show p \ 0.05 in comparison to
the control and phencyclidine animal groups. n = 12
OH
O
NH
NC
N
NaHSO3
(except 9i). However, compounds 9b, 9c, 9g, and 9h could
exert prominent analgesic effects compared to the control
and PCP animal groups (p \ 0.05). Also, application of
compounds 9d and 9e, 9f, 9j, and 9k yielded a sensible
anti-nociceptive activity which was higher than for the
control mice (p \ 0.05).
+
KCN
OH
4
O
O
NH2
NC
NH
NaHSO3
KCN
+
Pain assessment by formalin test
5
6
The licking frequency and duration time of the animal due
to formalin injection are indicated in Figs. 2 and 3. As
shown in Fig. 2 the compounds 9b, 9d, 9i, and 9k could
significantly reduce the licking frequency at 10 min after
formalin injection. Nevertheless, compounds 9b, 9d, and 9i
could respectively diminish the acute formalin pain to 72.2,
HN
NC
N
NaHSO3
KCN
+
83.3, and 80 %, which was better than in the control group.
On the other hand, 9k has exerted a marked acute analgesic
effect compared to the control (94.4 %) and PCP (92.5 %)
animal groups (p \ 0.05).
Scheme 3
Licking duration time evaluation in concomitant to
licking frequency show that the compounds 9b, 9d, 9i, and
especially 9k could significantly reduce it. At 10 min after
formalin injection (acute pain phase) compounds 9b, 9d,
9i, and 9k, respectively, reduced the duration time to 93.1,
95.3, 95.7, and 95.9 % (p \ 0.05). However, the same
analgesic activity was found for compounds 9b, 9d, and 9i
at 5 min after formalin injection, 54.9, 72.1, and 68.2 %
(p \ 0.05). Also, there was obtained a long-lasting acute
analgesic effect for compound 9k at 15 min after formalin
The purity of each compound follows from the CHN
analysis, also was checked by TLC using ethyl acetate/n-
hexane as the eluent.
application (p \ 0.05).
Previous studies [14, 27] demonstrated that the two ac-
tivities of arylcyclohexylamines (inhibition of dopamine
reuptake and binding to PCP sites on NMDA receptors) are
clearlyseparated. Modificationofthearylgroupof9a changes
the selectivity of the compounds for the two sites: thus, BTCP
Anti-nociceptive activity of the compounds in tail
immersion test
(1-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine, the fa-
As indicated in Fig. 1 the pain threshold in the tail im-
mersion test was markedly elevated by all compounds
mous analogue of phencyclidine with a unique high affinity
for the dopamine transporter receptor with dopamine reuptake
123

A. Ahmadi et al.
Fig. 2 The licking frequency of 9a–9k in formalin test. Bars show mean ± SEM licking frequency. Asterisk and dollar show p \ 0.05 in
comparison to the control and phencyclidine animals. n = 12
Fig. 3 The licking duration time of 9a–9k in formalin test. Bars show mean ± SEM licking duration times. Asterisk and dollar show p \ 0.05
in comparison to the control and phencyclidine animals. n = 12
blockingeffects)isspecific forthe dopamineuptakeand N-[1-
moiety (an area with negative charge) with phenyl or thio-
phene rings could produce different affinity for inhibition of
dopamine reuptake (benzothiophene analogues), PCP sites
(thiophene analogues), or both of them (unmodified phenyl
analogues), two groups of compounds were synthesized;
group 1 contains compounds 9b–9f with a phenyl ring and
group 2 contains compounds 9g–9k with a thiophene ring.
The results indicated that compounds in group 1 showed
better activity to diminish acute thermal and chemical
(except to compounds 9c and 9h that are contrary, 10 min
after injection) but not chronic pains compared to group 2.
Secondly, because of addition of a methyl group with
high electron donating and dipole moment activities [9–12]
on the 4-position of the cyclohexyl ring of 9a could produce
(
2-thienyl)cyclohexyl]pideridine is unique for PCP sites.
Phencyclidine (9a) and its analogues with an unmodified
phenyl ring have close affinities for the two sites which are
not selective. Therefore, it is expected that 9a exerts its
pharmacological activity through an action on the dopa-
mine reuptake and on the PCP sites while the
pharmacological activity of N-[1-(2-thienyl)cyclo-
hexyl]pideridine is mediated mostly through correlation
with the PCP sites [14]. Also, in such inhibitory processes,
the role of cyclohexyl or piperidyl substitutions for
modulating the affinities to these sites is very effective.
Therefore, in this study, modification on the three ring
systems of 9a was done. Initially, exchanging the aromatic
1
23

Synthesis and antinociception properties of phencyclidine…
compounds with higher affinity for the PCP sites in NMDA
receptors, compounds 9c and 9h were synthesized with this
strategy. Comparison between substituted and unsubstituted
cyclohexyl with phenyl (9b and 9c) or thiophene (9g and
magnesium turnings, diethyl ether, and all other chemicals
were obtained from Merck Chemical Co. (Darmstadt,
Germany). Melting points were determined with an Elec-
trothermal digital apparatus (model 9100, Electrothermal
1
13
9
h) showed better analgesic effects for unsubstituted new
Engineering Ltd., Essex, UK). H and C NMR spectra
were obtained on a Bruker AMX 300 MHz spectrometer
(Karlsruhe, Germany) using TMS as internal reference. IR
spectra were recorded on a Thermo Nicolet FT-IR (model
Nexus-870, Nicolet Instrument Corp., Madison, Wisconsin,
U.S.A.) spectrometer. Mass spectra were recorded on an
Agilent Technology-5973 Mass Selective Detector (MSD)
spectrometer (Wilmington, USA). Column chromato-
graphic separations were performed over Acros silica gel
(No. 7631-86-9 particle size 35–70 lm, Geel, Belgium).
Elemental analysis was performed with a Perkin-Elmer
CHN elemental analyzer model 2400; their results agreed
favourably with the calculated values. Phencyclidine (PCP,
9a) and carbonitrile intermediates were synthesized ac-
cording to Refs. [22, 30].
analogues which may be due a higher affinity for both sites.
These results also confirmed that dopamine uptake has a
more effective role for antinociception in unsubstituted
compounds whereas substituted ones are specific for PCP
sites especially for compound 9h with a thiophene ring.
Third, the piperidine ring (basic ring bearing a localized
positive charge and with an affinity for both sites) of 9a
was changed pharmacologically potent amines (meman-
tine, pseudoephedrine, and cyclohexylamines).
Memantine is a NMDA receptorantagonist which reduces
certain types of brain activity by binding to the receptor on
brain cells and blocking the activity of the neurotransmitter
glutamate which plays a major role for treatment of Alz-
heimer’s disease [15]. It also acts as an agonist at the
dopamine D receptor [16] and produces local analgesia
2
against cutaneous nociceptive stimuli [17]. Also, cyclo-
hexylamines affect the central nervous system and produce
analgesic action as well as pseudoephedrine [19, 20].
Therefore, as shown in Figs. 1, 2 and 3, all of the ana-
logues 9b–9f with these pharmacological amines
Preparation of compounds 9a–9k
A solution of 0.0203 mol nitrile intermediates 1–6 in di-
ethyl ether and toluene (1:1) were added to phenyl or
2-thiophene magnesium bromide reagents (7 and 8, pre-
pared from refluxing of 0.0503 mol bromobenzene or
(
especially memantine) were more effective than 9a to
reduce pains. Also, according to the previous studies, N-[1-
2-thienyl)cyclohexyl]pideridine analogues have less affi-
3
2-bromothiophene and 0.505 g of Mg in 100 cm of dry
(
ether). These mixtures were refluxed for additional hours
(monitoring by TLC) and subsequently dipped into the
solution of ice-NH Cl and NH OH. The organic layers
nity for inhibition of dopamine reuptake compared to 9a
and BTCP but more specific for PCP sites [28].
4
4
However, unsubstituted N-[1-(2-thienyl)cyclohexyl]pi-
deridine has better analgesic effects than unsubstituted 9a
were decanted and washed. The bases were acidified with
10 % H SO , basified with 10 % NaOH, neutralized by
2
4
[
7, 29] analogues, but our results indicate less potent sub-
stituted N-[1-(2-thienyl)cyclohexyl]pideridine analogues
g–9k which proved that the affinity for dopamine uptake
washing with water, extracted with ether, dried, and con-
centrated. The products were obtained as solids or viscous
liquid compounds which for purification were passed
through a silica gel column using ethyl acetate/n-hexane
(95:5) as the eluent to yield 9a–9k.
9
is a more effective factor than for PCP sites with respect to
the analgesic activities in this family.
N-(1-Phenylcyclohexyl)-3,5-dimethyladamantan-1-amine
(
9b, C H N)
24 35
Conclusion
Yield 53 %; m.p.: 198 ꢁC; IR (KBr): mꢀ = 3411, 3230,
2
-
1
1
920, 1630, 1455, 1362, 698, 612 cm
;
H NMR
It can be concluded that unmodified phenyl analogues of
phencyclidine (9a) with close affinity for DA uptake and
PCP-binding sites on NMDA receptors are better candidates
for reduction of acute and chemical pains compared to thio-
phene substituted ones with specific affinity for PCP sites.
(
CDCl3): d = 0.73–2.49 (29H, m), 4.27 (1H, s),
.77–6.85 (5H, m) ppm; C NMR (CDCl ): d = 29.7,
2, 38.6, 38.9, 39.9, 40.0, 42.0, 42.8, 49.2, 50.0, 50.5,
26.3, 126.6, 128.8, 140.2 ppm; MS: m/z (%) = 337 (18),
86 (22), 259 (27), 229 (14), 202 (18), 179 (19), 163 (100),
22 (63), 107 (86), 93 (18), 71 (18).
1
3
6
3
1
2
1
3
Experimental
N-(4-Methyl-1-phenylcyclohexyl)-3,5-dimethyladamantan-
-amine (9c, C H N)
1
2
5 37
Cyclohexanone, 4-methylcyclohexanone, memantine,
pseudoephedrine, cyclohexylamine, N-methylcyclohexy-
lamine, piperidine, bromobenzene, 2-bromothiophene,
Yield 65 %; m.p.: 208 ꢁC; IR (KBr): mꢀ = 3404, 3031,
2906, 2842, 1593, 1482, 1454, 1356, 1250, 1071, 1008,
-
1
1
754, 738, 699 cm ; H NMR (CDCl ): d = 0.73–2.48
3
123

A. Ahmadi et al.
1
31H, m), 4.27 (1H, s), 7.04–7.44 (5H, m) ppm; C NMR
3
(
(CDCl ): d = 0.74–2.47 (31H, m), 4.26 (1H, s), 7.04–7.45
3
1
3
(
CDCl ): d = 25.9, 29.7, 29.9, 32.0, 38.6, 38.9, 39.2, 40.0,
(3H, m) ppm; C NMR (CDCl ): d = 25.9, 29.5, 30.0,
3
3
42.0, 42.8, 49.2, 50.0, 50.5, 126.3, 126.6, 128.8,
140.2 ppm; MS: m/z (%) = 352 (12), 306 (12), 232 (23),
163 (100), 107 (76), 77 (29).
31.8, 38.6, 39.7, 40.0, 41.4, 45.8, 49.3, 50.5, 52.2, 123.8,
125.1, 126.2, 136.5, 144.3 ppm; MS: m/z (%) = 358 (10),
315 (8), 287 (10), 220 (11), 179 (36), 122 (100), 107 (77),
80 (12).
2
-[N-Methyl-N-(1-phenylcyclohexyl)amino]-1-phenyl-
propan-1-ol (9d, C H NO)
2
2-[N-Methyl-N-[1-(2-thienyl)cyclohexyl]amino]-1-phenyl-
2 29
Yield 63 %; m.p.: 194 ꢁC; IR (KBr): mꢀ = 3368, 3030,
propan-1-ol (9i, C H NOS)
2
0 27
2
7
2
7
3
1
932, 2850, 1602, 1453, 1376, 1275, 1087, 1041,
-
Yellow viscous liquid; yield 57 %; IR (KBr): mꢀ = 3356,
3035, 2930, 2467, 1638, 1404, 1034, 761, 701 cm ; H
1
1
-1 1
57 cm ; H NMR (CDCl ): d = 0.93–1.65 (13H, m),
3
.13–2.54 (3H, m), 4.32–4.35 (1H, m), 4.57–4.59 (1H, m),
1
NMR (CDCl ): d = 0.82–1.57 (13H, m), 2.40–2.63 (3H,
3
3
.3–7.45 (10H, m) ppm; C NMR (CDCl ): d = 14.4,
m), 3.2–3.25 (1H, m), 4.13–4.53 (1H, m), 6.94–7.86 (8H,
1
3
3
8.6, 39.2, 39.7, 40.0, 59.5, 68.2, 84.3, 125.3, 126.7, 127.6,
m) ppm; C NMR (CDCl ): d = 12.2, 29.7, 38.6, 39.2,
3
28.8, 129.3, 140.2 ppm; MS: m/z (%) = 323 (14), 273
40.0, 59.2, 68.2, 86.7, 125.2, 126.6, 127.3, 128.2, 128.6,
(
20), 248 (14), 202 (17), 160 (100), 111 (46), 77 (20).
140.2, 141.5 ppm; MS: m/z (%) = 329 (14), 287 (10), 248
(
(
15), 195 (15), 179 (42), 166 (14), 149 (57), 127 (14), 111
50), 91 (35), 77 (95), 58 (100).
N-Cyclohexyl-1-phenylcyclohexanamine (9e, C H N)
1
8 27
Yield 64 %; m.p.: 136 ꢁC; IR (KBr): mꢀ = 3428, 2928,
-1 1
632, 1451, 1122, 1023, 875, 754, 699 cm ; H NMR
1
N-Cyclohexyl-1-(2-thienyl)cyclohexanamine
(
CDCl ): d = 1.07–2.9 (20H, m), 4.26–4.28 (1H, m),
(9j, C H NS)
16 25
3
1
3
7
2
1
.32–7.45 (5H, m) ppm; C NMR (CDCl ): d = 20.5,
Yield 68 %; m.p.: 160 ꢁC; IR (KBr): mꢀ = 3412, 2938,
2859,1638, 1456, 1281, 1125, 1022, 633 cm ; H NMR
3
-
1 1
4.2, 25.0, 30.6, 49.7, 67.4, 126.9, 127.8, 129.5,
40.8 ppm; MS: m/z (%) = 258 (15), 246 (18), 230
(CDCl ): d = 1.00–2.89 (20H, m), 4.26–4.28 (1H, m),
3
1
3
(
100), 215 (20), 198 (18), 183 (35), 170 (45), 152 (20),
41 (18), 127 (15), 115 (18), 100 (40), 85 (35), 71 (45), 56
78), 43 (80).
7.28–7.65 (3H, m) ppm; C NMR (CDCl ): d = 20.4,
24.1, 25.1, 28.7, 30.5, 49.7, 67.8, 125.8, 128.7, 132.0,
3
1
(
144.8 ppm; MS: m/z (%) = 263 (17), 170 (83), 149 (100),
1
13 (18), 98 (15), 84 (15), 71 (40), 56 (72), 43 (55).
N-Cyclohexyl-N-methyl-1-phenylcyclohexanamine
9f, C H N)
(
N-Cyclohexyl-N-methyl-1-(2-thienyl)cyclohexanamine
1
9 29
Yield 76 %; m.p.: 139 ꢁC; IR (KBr): mꢀ = 3425, 2939,
(9 k, C H NS)
7 27
1
-1 1
637, 1499, 1457, 1391, 1125, 1023, 663 cm ; H NMR
1
Yield 82 %; m.p.: 163 ꢁC; IR (KBr): mꢀ = 3420, 2939,
2860, 1637, 1499, 1457, 1391, 1125, 1023, 663 cm ; H
-1 1
(
(
CDCl ): d = 1.07–1.94 (20H, m), 2.50 (3H, s), 2.87–2.93
3
1
1H, m), 7.19–7.46 (5H, m) ppm; C NMR (CDCl3):
3
NMR (CDCl ): d = 1.06–1.92 (20H, m), 2.50 (3H, s),
3
1
2.87–2.92 (1H, m), 7.19–7.9 (3H, m) ppm; C NMR
3
d = 24.2, 25.0, 30.6, 49.7, 68.2, 80.02, 126.7, 127.9, 129.9,
1
2
1
40.6 ppm; MS: m/z (%) = 272 (12), 259 (14), 246 (21),
30 (32), 215 (33), 198 (30), 183 (59), 170 (47), 154 (67),
41 (18), 128 (14), 105 (35), 91 (18), 77 (35), 56 (100), 43
(CDCl ): d = 20.5, 24.2, 26.0, 28.7, 30.5, 49.7, 63.7,
3
125.5, 127.8, 128.8, 144.6 ppm; MS: m/z (%) = 278 (10),
264 (8), 236 (9), 202 (6), 171 (9), 149 (10), 138 (11), 125
(8), 111 (12), 99 (90), 82 (23), 70 (45), 56 (100), 43 (95).
(
59).
N-[1-(2-Thienyl)cyclohexyl]-3,5-dimethyladamantan-1-
Animals
amine (9 g, C H NS)
2 33
2
Yellowviscousliquid;yield50 %;IR (KBr): mꢀ = 3401, 2916,
Ninety-six laboratory male NMRI mice, weighing 25–31 g
at the starting of the test were randomly housed, four per
coop in a temperature-controlled colony room under 12 h
light/dark period. Animals free access to feed or water and
standard laboratory rat chow. All behavioural experiments
were performed between 9 am and 4 pm under the enough
room light and at 25 ꢁC. This study was done according to
the Guide for the Care and Use of Laboratory Animals and
those of the Research Council of Shahed University of
Medical Sciences (Tehran, Iran).
-1 1
1
693, 1513, 1455, 1417, 1235, 1206, 1048, 828, 693 cm ; H
NMR (CDCl ): d = 0.78–2.48 (29H, m), 4.24 (1H, s),
3
1
3
7
3
1
.04–7.44 (3H, m) ppm; C NMR (CDCl ):d = 29.5, 30,
3
1.8, 38.6, 39.9, 40.0, 41.4, 45.8, 49.4, 50.5, 52.2, 123.8,
25.1,126.2,136.5,144.3 ppm;MS:m/z(%) = 343(70), 279
(
18), 262 (10), 248 (90), 205 (18), 179 (54), 166 (68), 149 (41),
22 (100), 108 (90), 93 (14), 81 (10).
1
N-[4-Methyl-1-(2-thienyl)cyclohexyl]-3,5-dimethy-
ladamantan-1-amine (9 h, C H NS)
2
3 35
Yellow viscous liquid; yield 58 %; IR (KBr): mꢀ = 3401,
2
Mortality (number of death), morbidity (defined as any
abnormal condition or behaviour due to a disorder),
-1 1
919, 2609, 1451, 1412, 1045, 827, 696 cm ; H NMR
1
23

Synthesis and antinociception properties of phencyclidine…
irritability (a condition of aggressiveness or increased re-
sponse on handling), and other related abnormal states
were not observed in the experimental animals. In addition,
the motor coordination index (measured by Rota-rod ap-
paratus, Harvard, UK) did not indicate any significant
difference among the treated rats.
Experimental psychomotor coordination (PMC)
index
This test was done by means of Rota-rod Treadmill with
shock facility apparatus (Harvard model 865) after root or
new drugs administration. First, animals were trained by
their placing on the rolling bar where they had to walk on
it. Then, for 5 times, they were placed in the case with
these characteristics: initial speed = 4 rpm, final
speed = 30 rpm, initial to final speed time = 4 min, shock
intensity = 1.1 mA, shock duration = 0.2–0.8 s, ex-
perimental length time = 5 min, interval between
experiments = 2 min. The mean stay time on the rod per
trial was taken as a PMC index.
Formalin test
3
In this test, formaldehyde solution (20 mm , 3 %) was
subcutaneously injected into the plantar surface of control
mice hind paw [31]. Then, the animals were placed in a
3
Plexiglas chamber (30 9 30 9 30 cm ) with a mirror at
4
5ꢁ angle underneath for accurate observation. In the
treatment and control groups (n = 8 per group), the com-
pounds 9a–9k (10 mg/kg dosage) [32] and saline were
administered intraperitoneally 30 min before formaldehyde
injection. However, prior to the experiments, all animals
were habituated to the observation chamber for 30 min
prior to the experimental sessions 5 times at 5 min intervals
to adapt them with the environment. The behavioral pain
reactions i.e., the licking time and frequency were detected
and recorded in each 5 min intervals during 45 min period
after formalin injection. The first 10 min after formalin
injection is known as the acute neurogenic pain and the
period between 15 and 45 min is known as chronic in-
flammatory pain.
Acknowledgments This work was a research project at Islamic
Azad University and the authors would like to express their gratitude
to them. They thank Fariba Ansari for her assistance with the phar-
macological tests. They appreciate Mojtaba Chaichi, EFL educator at
Safir English Language Academy, for proofreading the initial draft of
this article.
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